Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]([C@@H:12]1[CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=2[CH2:14][CH2:13]1)[CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1.[N:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N+:24]=[N-:25].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][N:4]([C@@H:12]1[CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=2[CH2:14][CH2:13]1)[CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1.[N:23]([CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NCCC(=O)O
Agent: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCC(=O)[O-]
Reaction time: 8 h

Procedure:
In a 50 mL round bottom flask, rotigotine (500 mg, 1.56 mmol, 1 equiv.), 3-azidopropionic acid (447 mg, 3.73 mmol, 2.4 equiv.—in 5 mL DCM), and pyridine (302 μL, 3.73 mmol, 2.4 equiv.) were dissolved in 50 mL anhydrous DCM and allowed to stir under argon. The solution was cooled in an ice-water bath for 5 min, and the bath was removed. To the solution DCC was added (778 mg, 3.73 mmol, 2.4 equiv.). The solution was allowed to stir at room temperature under argon. Following overnight reaction, reverse phase HPLC analysis of the reaction mixture showed complete conversion of free rotigotine to the ester form. The reaction mixture was filtered and the filtrate was concentrated to dryness on a rotary-evaporator. The crude product was then purified by silica gel chromatography. The crude product was dissolved in a mixed solvent of hexane-ethyl acetate (6 mL, 4:1 v/v) and then loaded onto a 300 mL silica gel column (30 mm id). The column was eluted with hexane-ethyl acetate (4:1 v/v). The fractions (10 mL each) were analyzed by TLC and reversed phase HPLC. The product fractions were pooled, evaporated by rotary-evaporation, and then dried under vacuum overnight. Yield: 292 mg.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1C=C[CH:11]=[CH:10][C:9]=1O.C(OCC)C>N1C=CC=CC=1>[O:4]1[C:5]2[CH:6]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:2]1=[O:3]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=c1[nH]c2ccccc2o1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
38.4 cc (0.4 mol) of ethyl chloroformate are added, at a temperature between 0° and 10° C., to a solution of 38.4 g (0.35 mol) of o-aminophenol in 150 cc of pyridine. When the addition has ended, the reaction mixture is stirred for a further 2 hours and then poured into 1.5 liters of diethyl ether. The precipitate is filtered off. The ether in the filtrate is evaporated off on a rotary evaporator. The residue is heated to 180° C. in order to distill off the pyridine. After cooling, the residue is recrystallized from ethyl acetate. The melting point of the obtained compound is 136° C.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][C@H:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:23][C@H:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Yield: 89.8 %

Procedure:
The titled compound (83 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and the product from example 9, step (d) (72 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][C:28]1=[O:42]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:30]4[CH:31]=[CH:32][N:27]([CH3:26])[C:28](=[O:42])[CH:29]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccn(C)c(=O)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. LCMS (M+H)+: m/z=432.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12](I)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Li])CCC.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]([CH:28]([C:27]2[CH:26]=[C:25]([Cl:24])[CH:32]=[C:31]([Cl:33])[CH:30]=2)[OH:29])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1I
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1nc(COCc2ccccc2)n(C)c1C(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
In 30 ml of dry tetrahydrofuran was dissolved 3.31 g (8.94 mmol) of 2-benzyloxymethyl-5-iodo-4-isopropyl-1-methylimidazole (4c), followed by addition of 5.78 ml (9.83 mmol) of n-butyllithium (1.70 M hexane solution) at -70° C. over 30 minutes. Then, after 5 minutes, a solution of 1.56 g (8.91 g) of 3,5-dichlorobenzaldehyde dissoloved in 10 ml of dry tetrahydrofuran was added at -70° C. over 30 minutes. After 1 hour, the mixture was left to cool to room temperature, and an aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/methylene chloride 10:1) to give 1.25 g of [2-benzyloxymethyl-5-isopropyl-3-methyl-3H-imidazol-4-yl]-(3,5-dichlorophenyl)-methanol (56) (yield 33.3%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([CH:17]=[CH:18][N:19]=2)[CH:13]=[C:14]([CH3:16])[N:15]=1>C(Cl)Cl>[Br:1][C:17]1[N:12]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:10]([Cl:9])[C:11]2=[N:19][CH:18]=1
Reactant: Cc1cn2ccnc2c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cn2c(Br)cnc2c(Cl)n1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
N-bromosuccinimide (348 mg, 1.96 mmol) is added to a solution of 8-chloro-6-methyl-imidazo[1,2-a]pyrazine (337 mg, 2.02 mmol) in DCM (6.1 mL) and the reaction is stirred at 40° C. for 10 min and then at room temperature for 1 h 30 min. The reaction mixture is diluted with DCM and washed twice with 4 mL of Na2CO3 sat., dried with MgSO4 anh., filtered and concentrated in vacuo to give 3-bromo-8-chloro-6-methyl-imidazo[1,2-a]pyrazine as a yellow solid (470 mg, 95%).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](CC#N)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>O>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:23][C:22]([OH:25])=[O:24])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Temperature: 0 °C

Procedure:
A mixture of 8.6 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile, 18 parts of concentrated sulfuric acid, 10 parts of acetic acid and 10 parts of water is stirred and refluxed for one hour. The reaction mixture is cooled and poured onto 200 parts of ice-water. The product is extracted twice with 160 parts of ether. The combined extracts are washed with 100 parts of diluted sodium hydroxide solution and separated. The aqueous phase is acidified with concentrated hydrochloric acid solution, whereupon the product is separated as an oil. The latter is extracted with ether. The extract is dried and evaporated. The residue is triturated in petroleumether and the crude product is dissolved in chloroform. It is purified by column-chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is triturated in petroleumether and the solid product is crystallized from acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]acetic acid; mp. 126°-129° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:35]1([NH:41]N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:41][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and phenylhydrazine: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15]1([CH2:21]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH:15]1([CH2:21][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCC1CCCCC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1oc(=O)n(CC2CCCCC2)c2ccccc12
Temperature: 60 °C
Yield: 23.1 %

Procedure:
815 mg (5 mmol) of isatoic acid anhydride is dissolved in 15 ml of N,N-dimethylacetamide and mixed under cover gas and in a moisture-free environment with 220 mg (5.5 mmol) of sodium hydride (60% dispersion in mineral oil). It is heated for 1 hour to 60° C. After cooling, 885 mg (5 mmol) of cyclohexylmethyl bromide is added, and the batch is heated to 60° C. for 4 hours. It is then diluted with water to 60 ml and shaken out three times with ethyl acetate. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 300 mg of N-cyclohexylmethylisatoic acid anhydride is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH3:19].C(O)C>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([NH2:19])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: N
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)nc21

Procedure:
1 Gram of 1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-chloro-1,8-naphthyridine-3-carboxylic acid (for example, described in European Patent Application No. 0,027,752) is mixed with 25 ml of concentrated ammonia solution containing 20% of ethanol. The mixture is maintained in a sealed tube for 4 hours at 120°-125° C. The mixture is cooled, and acetic acid added until the pH is slightly acid, when the precipitate formed is filtered off and washed with water. The product is dried, 0.8 gram of 1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-amino-1,8-naphthyridine-3-carboxylic acid being obtained, of melting point 299°-303° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:51])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:47]2[CH:48]=[CH:49][C:44]([C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:51])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:45][CH:46]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (46 mg, 0.144 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (78 mg, 0.173 mmol), Pd(PPh3)4 (17 mg, 0.0144 mmol), CuI (5 mg, 0.0288 mmol) and triethylamine (0.200 mL, 1.44 mmol) were suspended in DMF (1.5 mL). The reaction mixture was stirred at 80° C. for 2 hours then 1 mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 24%). 1H NMR (MeOH-d4, 400 MHz) 7.65 (d, J=8.2 hz, 2H), 7.45 (d, J=8.2 hz, 2H), 7.38 (s, 1H), 7.22 (s, 1H), 6.98 (m, 1H), 5.17 (m, 1H), 5.11 (m, 1H), 4.25-4.20 (m, 2H), 4.01-3.79 (m, 4H), 3.66 (s, 6H), 2.37-2.00 (m, 10H), 0.99-0.89 (m, 12H); MS (ESI) m/z 687 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[N:7]=2)=[N:2]1.[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O.CCOC(C)=O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[N:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][N:2]=4)[O:10][N:9]=3)=[O:13])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1noc(-c2ccon2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1noc(-c2ccon2)n1
Yield: 0.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.933 mmol, 0.35 g) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (1.610 mmol, 0.449 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.0065 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 4.28 (dd, 1H), 4.46 (dd, 1H), 4.56-4.66 (m, 1H), 6.63 (d, 1H), 6.82 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.84-7.86 (m, 1H), 7.88 (d, 1H), 8.51 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.Cl.CN(C)CCCN=C=NCC.CC(N)CCC>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:29][CH:27]([CH3:28])[CH2:26][CH2:25][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: On1nnc2ccccc21
Agent: CCCC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCCC(C)NC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-methylbutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-N-(1-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[C@@H:3]([NH:12]C(=O)OCC1C=CC=CC=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C@H:3]([CH:2]([CH3:23])[CH3:1])[C:4]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:11]
Reactant: [H][H]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](N)C(=O)NCC(F)(F)F
Reaction time: 6 h
Yield: 65 %

Procedure:
A Parr shaker flask charged with (R)-benzyl (3-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)-butan-2-yl)carbamate (4.95 g, 14.9 mmol) in 100 mL of EtOAc and 25 mL of EtOH was treated with 175 mg of 10% Pd/C. The mixture was placed under 40 psi of hydrogen and shaken for 6 h. An additional 65 mg of 10% Pd/C was added to the reaction mixture which was then placed under 40 psi of hydrogen and shaken for 3.5 h. The reaction solution was then filtered through a pad of celite, concentrated in vacuo and purified by sublimation (75 to 85° C., 200-230 millibar) to afford the title compound as a white solid (1.92 g, 65%): mp 43-47° C.; 1H NMR (400 MHz, CDCl3) δ 8.04-7.74 (m, 1H), 3.92 (ddd, J=16.0, 9.3, 6.8 Hz, 1H), 3.84-3.60 (m, 1H), 3.23 (d, J=3.8 Hz, 1H), 2.23 (ddd, J=10.7, 7.0, 3.5 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:33]([NH2:34])=[CH:32][N:31]=[CH:30][N:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:35](=S)=[S:36].CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: Nc1cncnc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 11.3 parts of N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine, 3.75 parts of carbon disulfide and 117 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was 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 fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5 parts (40%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-9H-purine-8-thiol; mp. 163.7° C. (495).
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17](O)=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:27]=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.N>C(OCC)(=O)C.C(O)(=O)C>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17]([NH2:27])=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C(N)=O)c1ccc2c(c1)Sc1ncccc1CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
The mixture of 80 mg of 2-(5,6-dihydro benzo[b]pyrido-[3,2-f]thiepin-9-yl)-propionic acid, 120 mg of dicyclohexylcarbodiimide and 5 ml of chloroform was stirred at 0° C. for 20 minutes under a stream of nitrogen. To this was added dropwise 1 ml of chloroform containing excessive amount of ammonia and the resulting mixture was stirred for 2 hours at 0° C., then at room temperature for 1 hour. To this was added 50 g of ice-water and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water, 5% sodium hydrogencarbonate solution, then water, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was dissolved in ethyl acetate and filtered. The filtrate was freed of the solvent to obtain the residue, which was chromatographed over silica gel, eluted with chloroform/ethanol(100/1), and there was obtained 63 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-9 -yl)-propionamide as colorless glutinous substance.
Reaction SMILES: C(NC(OC1C=C(C(=O)C[Br:21])C=C(OC(=O)NCC)C=1)=O)C.[CH2:23]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[BrH:21].[CH2:23]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNC(=O)Oc1cc(OC(=O)NCC)cc(C(=O)CBr)c1
Agent: CC(C)(C)NCc1ccccc1
Solvent: CC(C)=O
Product: Br

Procedure:
To a solution of 8.0 g of 3',5'-bis-(N-ethylcarbamoyloxy)-2-bromo acetophenone in 100 ml of acetone was added 7.0 g of N-benzyl-t-butylamine. The mixture was refluxed for 18 hours. The 4.1 g of N-benzyl-t-butylamine hydrobromide formed and precipitated during the reaction was filtered off and the filtrate was acidified with conc. HCl. The filtrate was now evaporated to dryness and the title compound was isolated by column chromatography on Silica gel 60 using (1) CHCl3 /ethanol (2:1), (2) ethanol as eluants. The title compound was eluted in the ethanol fraction and recrystallized from ethanol/diethylether. The identity of the product was confirmed with NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].O.C(O)(=O)C>N1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: Cc1cc(O)ccc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(O)ccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 84.3 %

Procedure:
To a stirred mixture of 4-amino-3-methylphenol (24 g, 0.2 mole) in 600 ml of pyridine was added all at once p-nitrobenzenesulfonyl chloride (Eastman) (45 g, 0.2 mole) followed by heating on a steam bath for 2 hours. The dark oily solution was poured into 4 liters of water and then treated with glacial acetic acid until acid. The tar crystallized on standing to give after filtration 67 g (100%) of brown solid. The entire sample was recrystallized from CH3NO2 to give 52 g of pure intermediate.