Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[CH:40]1([C:27]2([CH2:26][NH:25][C:22](=[O:24])[C:3]3[C:2]([F:1])=[C:7]([S:8][C:9]4[S:13][C:12]([NH:14][C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[N:11][CH:10]=4)[CH:6]=[CH:5][N:4]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(C5CCCCC5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-cyclohexylpiperidine-1-carboxylate (amine intermediate “R”) were reacted to give the title compound. LC/MS (M+H)+: 641. Ret. time: 2.18 min. (Condition L); analytical HPLC Ret. time: 12.41 min (Condition O).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([CH:24]([N:27]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:25][CH3:26])=[N:11]2)=[O:6]>CO.C1COCC1>[CH2:17]([N:13]1[C:14](=[O:16])[C:15]2=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[CH:9][N:10]2[N:11]=[C:12]1[CH:24]([N:27]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C:28](=[O:36])[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(c1nn2ccc(C(=O)O)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
A mixture of lithium hydroxide (2 N, 0.122 mL, 0.24 mmol) and 3-benzyl-2-{1-[(3-tert-butoxycarbonylamino-propyl)-(4-methyl-benzoyl)-amino]-propyl}-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester, (Example 20 I, 0.003 g, 0.0049 mmol) in MeOH/THF (1:1, 0.20 mL) at 0° C. was stirred for 4 h. The reaction mixture was quenched with 1 N HCl (5 mL), extracted with EtOAc (3×10 ml), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a solid. This crude product (0.0029 g, 60%) was used without further purification: MS (ESI+) 602 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:39])([F:38])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([CH2:36]O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:36][C:29]3[C:30]([C:32]([F:34])([F:33])[F:35])=[N:31][C:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]([F:39])([F:17])[F:38])=[CH:25][CH:24]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3C(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide in tetrahydrofuran to yield the title compound as colorless crystals.
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.N1CCCC1>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)=[C:13]2[C:24]1[C:33]2[CH2:32][CH:31]=[C:30]([Cl:34])[CH2:29][C:28]=2[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(O)Cn1c(CN2CCCC2)c(-c2ccnc3c2CC=C(Cl)C3)c2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
1-Bromo-2,5-pyrrolidinedione (165 mg) was added to a solution of the product from Example 27 (0.3 g) in DMF (3 ml), and the solution stirred for 10 min. Pyrrolidine (0.5 ml) was then added and the mixture stirred for a further 30 min. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid which was filtered off and dried to yield the title compound as a white solid (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:11].[CH2:12](I)[CH:13]=[CH2:14]>CN(C=O)C>[CH2:14]([O:11][C:3]1[C:2]([Cl:1])=[CH:9][C:8]([Cl:10])=[CH:7][C:4]=1[CH:5]=[O:6])[CH:13]=[CH2:12]
Reactant: C=CCI
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CN(C)C=O
Product: C=CCOc1c(Cl)cc(Cl)cc1C=O
Temperature: 65 °C
Yield: 90.9 %

Procedure:
A solution of 5.0 g of 3,5-dichlorosalicylaldehyde in 50 ml of DMF was treated with 3.23 g of potassium-tert.-butylate and 6.6 g of allyl iodide and stirred under argon at 65° C. After 2 hours the reaction mixture was concentrated, treated with ice-water and extracted with ethyl acetate. The organic phases were dried over sodium sulphate and concentrated. The residue was chrromatographed over silica gel and gave 5.5 g of 2-allyloxy-3,5-dichloro-benzaldehyde; MS (EI) m/z 230/232 M+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: COc1ccc(-n2cc(C(=O)c3cc(Br)ccc3O)cn2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccc(OC)cc2)c1

Procedure:
Prepared from (5-bromo-2-hydroxyphenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ketone and ethyl bromoacetate according to GP2: LC/MS (an10p8): Rt 4.59 min, m/z 458.4/460.4 [M+H]+; 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 3.84 (s, 3H), 4.23 (q, J=7.1 Hz, 2H), 4.62 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.52 (dd, J=8.9, 2.6 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 8.13 (s, 1H), 8.46 (s, 1H); 13C NMR (CDCl3): δ14.3, 55.8, 61.9, 65.6, 114.1, 114.4, 114.8, 121.4, 125.0, 131.6, 132.4, 132.6, 133.2, 134.5, 142.5, 154.1, 159.2, 168.5, 186.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(F)cc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc(F)cc(C#N)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-fluorobenzonitrile (2.5 g, 12.5 mmol), (trimethylsilyl)acetylene (2.86 ml, 20 mmol), bis(acetate)bis(triphenylphoshpino) Palladium(II) (936 mg, 1.25 mmol) and triethylamine (35 ml) in toluene (35 ml) was 15 degassed by bubbling nitrogen through the solution and then stirred at 95° C. for 30 minutes. Filtration and concentration to yield a crude product. It was diluted with EtOAc (150 ml). The organic phase was washed with saturated NaHCO3 solution (50 ml), brine (50 ml) and the organic layer was dried over sodium sulfate. Filtration and concentration to yield a product A293.1 (2.4 g, 88%). HPLC: 95%, retention time: 4.05 minute (condition A). LC/MS (M+H)+=218.2.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=O)[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:22]([C:24]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:25])[NH2:23].CN(C)C=O>Cl.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=[N:23][NH:22][C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[S:25])[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 75.7 %

Procedure:
1-[5-(4-n-Pentylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2381 mmol, HPLC purity 86.3%, 79.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2381 mmol, 50.3 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (86.4 mg, yield 76%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O-:15])(=[S:14])[CH3:13].[K+]>C(O)C>[C:12]([S:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:15])[CH3:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-(bromomethyl)benzoic acid (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium thioacetate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].Cl>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([OH:10])=[O:9]
Reactant: O=C1OCCC1Br
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1NC1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 68.6 g of anthranilic acid, 132.2 g of sodium carbonate and 400 ml of water was stirred at room temperature for 1 hour and, under ice-cooling, 103.2 g of α-bromo-γ-butyrolactone was added dropwise. The mixture was stirred under ice-cooling for 5 hours and, then, at room temperature for 24 hours. The mixture was made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The ethyl acetate was distilled off and ethyl ether was added to the residue. The resulting crystals were recovered by filtration. By the above procedure was obtained α-[(2-carboxyphenyl)amino]-γ-butyrolactone, melting point: 197°-198° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (6.51 g, 32.3 mmol) and triethylamine (6.8 ml, 1.5 mol eq) in dichloromethane (70 ml) at 0° C. was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0° C. for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100%). NMR (CDCl3 7.27d) m 4.73(1H), m 3.63d(2H), m 3.44d(1H), m 3.32d (1H), s 3.05d(3H), m 1.95d(2H), m 1.83d(1 H), m 1.54d(1H), s 1.46d(9H)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[S:23][CH:22]=1>>[N:21]1[C:29]2[CH2:28][CH2:27][N:26]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:25][C:24]=2[S:23][CH:22]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1nc2c(s1)CNCC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncsc4C3)n2)c1

Procedure:
B45 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride. The title compound (B45) was purified by column chromatography (silica gel, DCM/MeOH gradient 100:0 to 85:15); yield: 28.9 mg (7%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.84-2.94 (m, 2H), 4.13 (t, J=5.8 Hz, 2H), 4.23 (s, 2H), 5.03 (s, 2H), 6.83 (s, 2H), 7.00 (d, J=7.1 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.42-7.63 (bm, 1H), 7.82-7.93 (bm, 1H), 8.28 (s, 1H), 8.96 (s, 1H), 9.77 (s, 1H). MS (ES) C16H17N7O2S2 requires: 403. found: 404 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH2:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:43])[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH:27][C:32]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)=[O:43])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CS
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 41.3 %

Procedure:
A solution of 650 mg of N-tert.butyl-1-[3(S)-[(L-cysteinyl)amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide and 242 mg of quinaldic acid was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered, and the filtrate was then evaporated. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic phase was washed with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution to give 350 mg of N-tert.butyl-1-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-cysteinyl]amino]butyl]-2(S)-piperidinecarboxamide as a white solid; MS: m/e 620 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][NH:28][CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCN(C)S(C)(=O)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Methanesulphonyl chloride (0.144 g) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(methylamino)ethoxy methyl]-1,4-dihydropyridine (0.50 g) and triethylamine (0.126 g) in dichloromethane (15 ml). The mixture was stirred at room temperature for 1 hour, poured into ice-water and the layers separated. The organic layer was washed with water, dried (Na2SO4) and evaporated. Scratching the residual oil afforded a solid which was recrystallised from methanol to give the title compound (0.33 g), m.p. 93°-95° C. Found: C, 53.32; H, 5.97; N, 5.64. C22H29ClN2O7S requires C, 53.32; H, 5.92; N, 5.71%.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[N:7][N:6]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5](=[O:19])[C:4]=1[CH:20]=O.[NH2:23]N.O>CCO>[CH3:18][C:11]1([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14][CH:9]([N:6]2[C:5](=[O:19])[C:4]3[CH:20]=[N:23][NH:2][C:3]=3[CH:8]=[N:7]2)[CH2:10]1
Reactant: NN
Reactant: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1C=O
Solvent: CCO
Solvent: O
Product: CC1(C)CC(n2ncc3[nH]ncc3c2=O)CC(C)(C)C1
Yield: 46.3 %

Procedure:
A solution of 5-dimethylamino-3-oxo-2-(3,3,5,5-tetramethyl-cyclohexyl)-2,3-dihydro-pyridazine-4-carbaldehyde (1.19 g, 3.903 mmol) in EtOH (30 mL) was treated with H2NNH2.H2O (1.2 mL, 39.03 mmol). After stirring at reflux for 20 h, the volatiles were removed in vacuo and the solid residue was extracted with EtOAc. The organics were then washed with brine, dried (Na2SO4). After evaporation of volatiles, the residue was purified by flash chromatography (50 g (solute SiO2 cartridge, continuous gradient 100% hexanes→hexanes/EtOAc, 1:1) to provide 5-(3,3,5,5-tetramethyl-cyclohexyl)-1,5-dihydro-pyrazolo[3,4-d]pyridazin-4-one (495.3 mg, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s), 8.31 (1H, s), 5.45 (1H, app heptet, J=4.6 Hz), 1.71-1.57 (4H, m), 1.40-1.22 (2H, m), 1.19 (6H, s), 1.00 (6H, s).
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@@H:23]([CH2:28][OH:29])[C@@H:24]([OH:27])[CH2:25][OH:26])=[CH:11]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:29][CH2:28][C@H:23]([NH:22][CH2:21][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)[C@@H:24]([OH:27])[CH2:25][OH:26]
Reactant: COc1ncnc2c(CN[C@@H](CO)[C@@H](O)CO)cn(COCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cnc2c(CN[C@@H](CO)[C@@H](O)CO)c[nH]c12
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a stirred solution of the product from Example 18.2 (0.056 g, 0.14 mmol) in DCM (7 ml) at −78° C. was added boron tribromide (1.39 ml, 1.39 mmol, 1.0M in DCM). After 15 mins the reaction mixture was warmed to ambient temperature and coevaporated with methanol (3×). The residue was stirred in methanol (7N ammonia solution) for 10 mins and evaporated on to silica gel. The material was chromatographed on silica gel (chloroform-methanol-conc. ammonia, 10:9:1) giving a white solid (17 mg, 46%). 1H NMR (D2O) δ 8.03 (s, 1H), 7.59 (s, 1H), 4.41 (ABq, 2H), 3.88 (dd, J=13.2, 4.2 Hz, 1H), 3.80 (m, 1H), 3.72 (dd, J=13.2, 5.3 Hz, 1H), 3.60 (dd, J=12.5, 3.4 Hz, 2H), 3.47 (dd, J=12.5, 4.5 Hz, 1H), 3.26 (m, 1H). +ESMS found 269.1262 (M+H)+ C11H17N4O4 requires 269.1250.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]1([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:30][CH2:29]1)(=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)c3ccccc3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with phenyl-piperazin-1-yl-methanone (CAS 13754-38-6) to give N-{4-[2-(4-benzoyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide, using general procedure C. White solid. MS 469.3 ([M+H]+)
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][OH:11].[ClH:12]>C1(C)C=CC=CC=1>[ClH:12].[C:2]1([CH2:1][C:8](=[NH:9])[O:11][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#CCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=N)Cc1ccccc1
Yield: 88.3 %

Procedure:
The same equipment as described in Example 3 was used. Benzyl cyanide (38.0 grams; 0.325 mole) was mixed with absolute methanol (10.3 grams; 0.322 mole) and toluene (195 ml). With cooling and agitation HCl gas (16 grams; 0.44 mole) was introduced from a weighed cylinder and the mixture was maintained under the same conditions overnight (26 hours). The resulting white slurry was filtered cold and the solid methyl phenylacetimidate hydrochloride (52.8 grams; 88.4% yield) was collected and a portion of it used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:19][C:18]=1[C:23]([F:25])([F:26])[F:24])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: O=C(O)c1cc(Br)ccc1O
Product: CCOC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1C(F)(F)F
Yield: 88.7 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.