Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:15]([O:17]CC)=[O:16])=[CH:7][N:8]([CH2:12][CH2:13][CH3:14])[C:9](=[O:11])[CH:10]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:15]([OH:17])=[O:16])=[CH:7][N:8]([CH2:12][CH2:13][CH3:14])[C:9](=[O:11])[CH:10]=1
Reactant: CCCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 100 %

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.13 (v br s, 1H), 9.70 (br s, 1H), 8.46 (s, 1H), 7.75 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.33 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.84 (t, J=7.2 Hz, 2H), 1.61 (sextet, J=7.4 Hz, 2H), 0.85 (t, J=7.4 Hz, 3H). HRMS (EI+) calcd C15H14FIN2O3 (M+) 416.0033, found 416.0036.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[CH:27]([S:29]([CH:32]=C)(=[O:31])=[O:30])=[CH2:28]>>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: C=CS(=O)(=O)C=C
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CCS(C)(=O)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 152, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with vinyl sulfone to give 157 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=0.64 Hz, 1H); 7.84 (d, J=2.19 Hz, 1H); 7.36 (dd, J=8.32, 2.21 Hz, 1H); 7.21 (d, J=8.30 Hz, 1H); 6.87 (s, 1H); 5.60-5.51 (m, 1H); 4.48 (t, J=6.03 Hz, 2H); 3.67 (s, 3H); 3.20-3.10 (m, 6H); 3.03 (s, 3H); 2.83 (t, J=6.83 Hz, 2H); 1.48 (d, J=6.58 Hz, 6H). LCMS: RT=5.99 min, M+H+=457
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:13]CC1C=CC=CN=1>>[C:3]([NH2:13])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCc1ccccn1
Reactant: O=C(c1ccccc1)C(Cl)(Cl)Cl
Product: NC(=O)c1ccccc1

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-α,α-dichloroacetophenone as an intermediate by chlorinating the α-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The (α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:30](=[O:31])[CH2:29][C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: O=C(O)Cc1ncccn1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)Cc4ncccn4)C3)c21

Procedure:
Prepared as in Example 2 from (S)-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (Example 2a) and 2-(pyrimidin-2-yl)acetic acid (Example 31a) (10% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.47 (m, 2H), 1.57-1.76 (m, 1H), 1.85 (m, 1H), 2.00 (d, 1H, J=7.9 Hz), 2.03-2.25 (m, 1H), 3.00 (m, 1H), 3.69-4.22 (m, 6H), 6.56 (m, 1H), 6.65 (m, 1H), 7.32 (t, 1H, J=4.9 Hz), 7.39 (t, 1H, J=4.9 Hz), 7.53-7.84 (m, 2H), 8.70 (d, 1H, J=4.9 Hz), 8.76 (d, 1H, J=4.9 Hz), 10.98 (br s, 1H). MS 431 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc2[nH]cc(C(C)=O)c(=O)c2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(=O)c(C(C)=O)cn2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a suspension of ethyl 3-acetyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (5.74 g, 22.14 mmol) in N,N-dimethylformamide (120 ml) was added potassium carbonate (9.18 g, 66.4 mmol) and methyl iodide (4.2 ml, 67.2 mmol). The mixture was stirred at 90° C. for 1 h. After cooling, the reaction was filtered, concentrated under high vacuum, diluted with dichloromethane/ethyl acetate, and filtered through a silica plug to afford ethyl 3-acetyl-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (3.64 g, 13.32 mmol, 60.2% yield. LCMS: (M+H)+: 274.0.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH2:11][CH2:12][OH:13])[O:7][C:6]1=[O:21])[CH3:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:13][CH2:12][CH2:11][C@@:8]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:7][C:6](=[O:21])[N:5]([C@H:3]([C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:4])[CH2:10][CH2:9]1)(=[O:34])=[O:33]
Reactant: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (220 mg, 0.68 mmol) and triethylamine (206 mg, 2.04 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (233 mg, 2.04 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude 2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (280 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [Na+].[CH:2]1([CH2:7][CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>CN(C)C=O>[CH:2]1([CH2:7][CH2:8][S:9]([Cl:15])(=[O:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCC1CCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCC1CCCC1
Temperature: 25 °C

Procedure:
Dimethylformamide (5 drops) was added over 1 minute to a stirred solution of 2-(cyclopentyl)ethylsulfonic acid sodium salt (1 5.5 g, 87.5 mmol) in thionyl chloride (60 ml) under a nitrogen atmosphere. The reaction mixture was stirred under reflux for 5 hours and was then cooled to room temperature and concentrated under vacuum. The residue was suspended in toluene (100 ml) and then concentrated under vacuum. The residue was dissolved in a mixture of ethyl acetate (150 ml) and water (150 ml) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic extracts were washed with brine (3×100 ml), dried (magnesium sulfate) and evaporated to give the title compound as a brown oil (14.1 g), Rf 0.5 (pentane/ethyl acetate 95:5).
Reaction SMILES: [CH3:1][C:2]1[C:23]2[CH2:22][C:21]3[C:8](=[CH:9][C:10]4[CH2:11][C:12]5[C:17]([C:18](=O)[C:19]=4[CH:20]=3)=[C:16]([CH3:25])[CH:15]=[CH:14][C:13]=5[CH3:26])[C:7](=O)[C:6]=2[C:5]([CH3:28])=[CH:4][CH:3]=1>COCCOCCOC>[CH3:28][C:5]1[C:6]2[C:23](=[CH:22][C:21]3[C:8]([CH:7]=2)=[CH:9][C:10]2[C:19](=[CH:18][C:17]4[C:12]([CH:11]=2)=[C:13]([CH3:26])[CH:14]=[CH:15][C:16]=4[CH3:25])[CH:20]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c2c1Cc1cc3c(cc1C2=O)Cc1c(C)ccc(C)c1C3=O
Solvent: COCCOCCOC
Product: Cc1ccc(C)c2cc3cc4cc5c(C)ccc(C)c5cc4cc3cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 grams of 7,14-dihydro-1,4,8,11-tetramethylpentacene-5,12-dione and 10 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 0.875 grams of sodium borohydride and stirring was continued at room temperature overnight. To the mixture was added 20 mL of 2-methoxyethyl ether and 0.75 grams of sodium borohydride and heating was continued overnight at 60° C. To the mixture was added 6.3 mL of methanol and 0.75 grams of sodium borohydride and stirring was continued for 6 hours at room temperature. To the mixture was added 15 mL of acetic acid and the mixture was stirred for one hour at room temperature. To the mixture was added 10 mL of concentrated hydrochloric acid and the mixture was heated to 60° C. for 1.5 hours. The solid was isolated by filtration and then washed with water and dried to give 1,4,8,11-tetramethylpentacene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:13]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A mixture of 4.0 parts of 2-chloro-4-hydroxybenzoic acid, 8.3 parts of 1-bromoheptane, 2.6 parts of potassium hydroxide, 10 parts of water and 90 parts by volume of ethanol was refluxed for 20 hours. A solution of 2.5 parts of potassium hydroxide in 50 parts of water was then added and refluxing continued for an additional 1.5 hours. The reaction mixture was diluted with 100 parts of water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were dried over sodium sulfate, the solvent evaporated and the resultant residue recrystallized from hexane. 4.5 Parts of 4-heptyloxy-2-chlorobenzoic acid (75% yield) was obtained having a melting point of 76°-78° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].C1N=C[N:27]([C:30](N2C=NC=C2)=[O:31])[CH:26]=1.CN>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:30]([NH:27][CH3:26])=[O:31])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Agent: CN
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)NC)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 100 mg (0.31 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) in 2 mL DMF, 87 μL (0.62 mmol) TEA and 52 mg (0.32 mmol) CDI are added at 0° C. and the mixture is stirred for 30 min at 0° C. Subsequently 48 mg (1.54 mmol) methylamine are added and stirring is continued for 1 h at 50° C. The mixture is filtered through basic aluminum oxide and concentrated in vacuo. The residue is purified using reversed phase column chromatography (water+0.15% NH4OH; acetone) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH:5]=[CH:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]#[CH:4].[H][H]>CO.[Pd].[Zn]>[CH3:1][C:2]([OH:11])([CH:5]=[CH:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH:3]=[CH2:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)C=CC(C)CC
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: C=CC(C)(O)C=CC(C)CC
Reaction time: 6 h
Yield: 94 %

Procedure:
154 g (1 mole) of 3,6-dimethyl-oct-1-yn-4-en-3-ol are dissolved in 100 ml of methanol, 1 g of an 0.1% strength palladium/calcium carbonate catalyst, which has been poisoned with zinc ions, is added, and hydrogen is passed in at 15°-20° C. under atmospheric pressure. After 6 hours, the mixture is worked up similarly to Example 2. 145 g of 3,6-dimethyl-octa-1,4-dien-3-ol, of boiling point 38°-39° C./0.01 mbar and nD25 =1.4502, are obtained. This corresponds to a yield of 93% of theory.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([NH2:29])=[O:28].C(N(CC)CC)C>COCCO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][NH:21][CH:22]([C:27]([NH2:29])=[O:28])[CH2:23]2)=[CH:8][CH:9]=1
Reactant: NC(=O)C1CNCCN1
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: NC(=O)C1CN(CCCCN(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 70 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 17.7 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 23.3 parts of 2-piperazinecarboxamide, 17.6 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 48 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water and a small amount of methanol. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume). The product was filtered off and dried, yielding 12.82 parts (55.0%) of 4-[4-[bis(4-fluorophenyl)amino]butyl]-2-piperazinecarboxamide; mp. 67.4° C. (int. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([OH:30])[CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:24]=2)[O:30][CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(O)c2)c2ccccc21
Reactant: COC(=O)C(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-fluoro-3-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (476 mg, 1.05 mmol) was dissolved in DMF at room temperature and Cs2CO3 (854 mg, 2.63 mmol) was added. Methyl 4-bromo-2,2-dimethylbutanoate (702 mg, 1.58 mmol) was added and the reaction was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford methyl 4-(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate (286 mg, 52%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]([NH2:53])=[O:52])=[O:48].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:51]([NH2:53])=[O:52])=[O:48])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
457 mg (0.81 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 384 mg (0.81 mmol) of the compound from example 21A, 141 μl (0.81 mmol) N,N-diisopropylethylamine and 307 mg (0.81 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 255 mg (0.22 mmol, 28% of theory) of the desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@H:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:28])([CH3:27])[CH3:26]>COCCO>[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@H:32]([NH:40][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C[C@@H](N)Cc1ccccc1
Solvent: COCCO
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 76.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg, 0.125 mmol) and (S)-3-amino-4-phenyl-butyric acid tert-butyl ester (88 mg, 0.375 mmol) (Acros Organics, Thermo Fisher Scientific, Morris Plains N.J.) in 2-methoxyethanol (10 mL) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, and the residue was purified by column chromatography (0-40% EtOAc/hexanes) to give 50 mg of the title compound. MS: (−) m/z 522.25 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][NH:16][C:35]([NH:34][C:32]([O:31][CH2:30][CH:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:29]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:33])=[S:36])([F:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester (1071 mg, 4.61 mmol) in tetrahydrofuran (10 ml), FmocNCS (9-fluorenylmethoxycarbonyl isothiocyanate) (1425 mg, 5.07 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=10/1-5/1) to obtain 4-[({[(fluoren-9-ylmethoxy)carbonylamino] thioxomethyl}amino)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS.
Reaction SMILES: S([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)(C)(=O)=O.[CH:18]([SH:21])([CH3:20])[CH3:19]>>[CH:18]([S:21][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Reactant: CC(C)S
Product: CC(C)Sc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and isopropyl mercaptan. ##STR10## NMR(CDCl3) δ: 1.30(s, 6H), 3.15-3.65(m, 1H), 6.85(d, 1H), 7.38(d, 1H), 7.62(s, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:14])[CH2:12][CH3:13]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[NH:9])[O:14][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=N)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
After 6-amino-3-cyanopyridine (1.0 g, 8.4 mmol) was dissolved in 1-propanol (50 ml) and hydrogen chloride gas was passed into the solution at a temperature of 0°-10° C. for 30 minutes, the reactor was tight sealed for stirring the mixture at 0° C. for 21 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the concentrated mixture to adjust the pH to alkaline. The mixture was extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 6-amino-3-pyridinecarboximidate (1.56 g).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:16][CH:15]=[CH2:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1ccc(C=O)cc1

Procedure:
3.8 g (12 mmol) of sodium hydride (80% in oil) and 100 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 15 g (10 mmol) of 4-formylbenzoic acid in 100 ml of DMF is added dropwise and the mixture is stirred until the evolution of gas has ceased. 10 ml (12 mmol) of allyl bromide are then added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 17.2 g (90%) of the expected allyl ester are collected in the form of a yellow oil.