Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>>[C:14]1([S:20]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=2)(=[O:11])=[O:12])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(NS(=O)(=O)c1ccc(CCBr)cc1)c1ccccc1

Procedure:
As an additional variation of the reaction sequence, the 4-(2-bromoethyl) benzenesulfonamide produced as in Example I was reacted with benzenesulfonyl chloride and sodium hydroxide and then acidified to produce N-benzenesulfonyl-4-(2-bromoethyl) benzenesulfonamide. Recrystallization of a small portion from toluene gave a white solid, having a melting point of 148°-150° C. and a neutralization equivalent of 405 (theory 404).
Reaction SMILES: C[CH2:2][O:3]C(C)=O.C1(C)C=CC=CC=1.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].[CH3:22][C:23]([C:25]([CH3:27])=[CH2:26])=[CH2:24]>CO>[CH3:24][C:23]1[CH2:22][CH:20]2[CH:21]([CH2:26][C:25]=1[CH3:27])[C:14](=[O:15])[C:16]([O:3][CH3:2])=[CH:17][C:18]2=[O:19]
Reactant: Oc1ccc(O)cc1
Reactant: C=C(C)C(=C)C
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC1=CC(=O)C2CC(C)=C(C)CC2C1=O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of NaIO4 (33.5 g, 157 mmol, Baker) in H2O (1500 mL), there was added solid 2-methoxyhydroquinone (11.00 g, 50.0 mmol) in portions. The reaction immediately became dark orange. The reaction was allowed to stir for 1 h at rt and was extracted with CH2Cl2 (3×150 mL). The extract was washed with half saturated brine (1×150 mL), filtered through cotton and the solvent removed in vacuo to yield 2-methoxybenzoquinone as an orange solid (10.5 g) which was of sufficient purity (TLC analysis, 10% EtOAc/90% CHCl3) for further reaction. The crude quinone was combined with toluene (150 mL) and hydroquinone (1.0 g, Mallinkrodt). Neat 2,3-dimethyl-1,3-butadiene (8.3 g, 101 mmol, Aldrich) was added. The reaction was allowed to stir overnight at 65° C. under N2. TLC (10% EtOAc/90% CHCl3) indicated total consumption of the dienophile. The solvent was removed in vacuo to yield a dark solid. This was triturated with MeOH (100 mL) at n to give a beige solid. Crystallization from MeOH (dissolved in 140 mL, allowed to cool to rt) yielded a fluffy colorless solid (10.2 g, 64%, >95% pure by 1H NMR analysis); mp 133°-134° C. (MeOH); 1H NMR (CDCl3) δ1.62 (s, 6H), 2.12 (m, 2H), 2.42 (m, 2H), 3.09 (m, 1H), 3.20 (m, 1H), 3.78 (s, 3H), 5.88 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:19]O.S(=O)(=O)(O)O>O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C

Procedure:
2.33 g (8.56 mmol) of 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoic acid were introduced into 30 ml of methanol and admixed with 2 ml of concentrated sulfuric acid. The mixture was subsequently heated at reflux until a check by HPLC indicated full conversion. The contents were freed from the solvent, and the residue was taken up in water. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium hydrogen-carbonate solution. The organic phase was dried and freed from the solvent. The residue obtained was 2.1 g of clean product.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:23])=[CH:15][CH:14]=1.[NH:24]([C:26]1[CH:31]=[C:30]([N:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35]([CH3:44])([CH3:43])[O:34][C:33]2=[O:45])[CH:29]=[CH:28][N:27]=1)[NH2:25]>C(Cl)Cl>[CH3:44][C:35]1([CH3:43])[O:34][C:33](=[O:45])[N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([NH:24][NH:25][C:2]([NH:23][C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][N:18]=4)[N:13]=[CH:14][CH:15]=3)=[O:4])[CH:31]=2)[C@H:36]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OC(=O)N(c2ccnc(NN)c2)[C@H]1c1ccccc1
Reactant: Nc1ccnc2cccnc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccnc(NNC(=O)Nc3ccnc4cccnc34)c2)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 10 mL round-bottomed flask was added triphosgene (109 mg, 0.369 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) in DCM (1.117 mL). The solution was cooled to 0° C., and 1,5-naphthyridin-4-amine (53.5 mg, 0.369 mmol) was added in one portion. Under argon, TEA (0.466 mL, 3.35 mmol) was then added dropwise. After stirring at room temperature for 15 minutes, (S)-3-(2-hydrazinylpyridin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (100 mg, 0.335 mmol) in 6 mL of DCM was added to the reaction mixture. After stirring at room temperature overnight, LC-MS indicated good conversion to the desired product. The reaction mixture was concentrated under reduced pressure to give the product as a black solid which was used directly in the next step without further purification. m/z (ESI) 470.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=O.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[C:3]2[C:2](=[N:1][C:17]3[C:18]4[CH:19]=[C:20]([CH3:22])[CH:21]=[C:12]([CH3:11])[C:13]=4[CH2:14][CH2:15][C:16]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1CO
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)-c1nc3cccc(Cl)c3cc1CC2
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(2-Amino-6-chlorophenyl)methanol (16 g, 101 mmol), 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 111 mmol), RuCl2(PPh3)3 (0.971 g, 1.01 mmol), and KOH (5.7 g, 101 mmol) were refluxed in 200 mL of toluene for 12 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with dichloromethane. The product was washed by methanol and recrystallized from hexane to obtain ˜20 gram of the desired product which was confirmed by GC-MS.
Reaction SMILES: [CH2:1]([CH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:29]=[CH:30][CH:31]=1>[OH-].[K+]>[CH2:1]([C:17]1([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33][CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=2)[C:18](=[O:23])[CH2:19][CH2:20][C:21]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Reactant: CCCCCCCCCCCCCCCCC1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O
Yield: 73.7 %

Procedure:
Reflux a mixture of 2-cetylcyclopentane-1,3-dione (10.1 g), 6-m-methoxyphenylhex-1-en-3-one (6.0 g) and 0.02% methanolic potassium hydroxide solution (120 cc) for 26 hours and then cool. Dissolve the residue obtained after removal of solvent under reduced pressure in a mixture of benzene (50 cc) and ether (50 cc), and wash the solution in turn with sodium carbonate solution, 10% aqueous sulfuric acid and water. Remove the solvent by evaporation under reduced pressure to obtain as residue crude 2-cetyl-2-(6-m-methoxyphenyl-3-oxohexyl)-1,3-cyclopentanedione (11.4 g).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[OH2:30].[CH3:31]O>>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[CH2:31][OH:30]
Reactant: CO
Reactant: Cc1ccc2cccc(F)c2n1
Reactant: O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(CO)c2cccc(F)c2n1
Yield: 32 %

Procedure:
Concentrated sulfuric acid (1.2 mL) was added to a solution of 2.70 g (16.8 mmol) of 8-fluoro-2-methylquinoline and 7.70 g (33.7 mmol) of ammonium peroxodisulfate in a mixture of methanol (35 mL)-water (25 mL) and heated under reflux for 15 hours. The reaction mixture was left to cool, followed by a removal of methanol under a reduced pressure. Sodium carbonate was added to the residue to adjust its pH to 10, and then the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was washed with ether to obtain 1.03 g (yield 32%) of (8-fluoro-2-methylquinolin-4-yl)methanol. Its physical properties are shown below.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[K+].[F:13][C:14]([F:18])=[C:15]([F:17])[Cl:16]>CN(C)C=O>[F:13][C:14]([F:18])([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH:15]([F:17])[Cl:16]
Reactant: FC(F)=C(F)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cccc(OC(F)(F)C(F)Cl)c1
Temperature: 60 °C

Procedure:
139 grams (1 mole) of 3-nitro-phenol and 28 grams (0.5 mole) of potassium hydroxide were dissolved in 400 milliliters of dimethyl formamide, and 140 grams (1.2 mole) of trifluoro-chloroethylene were introduced in a gas pipe at 40° C; the mixture was then maintained at 60° C for 2 hours. The main amount of dimethyl formamide was distilled off in vacuo. The residue was poured into ice water, separated, dried over Na2SO4 and distilled in vacuo.
Reaction SMILES: [Cl-].ClC[P+](C)(C)C.[CH2:8]([Li])CCC.CCCCCC.[C:19]([O:23][C:24]([NH:26][C:27]1([CH:30]=O)[CH2:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl-].[Na+]>O1CCCC1>[C:19]([O:23][C:24]([NH:26][C:27]1([C:30]#[C:8][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28][CH2:29]1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Reactant: [Li]CCCC
Reactant: CCOC(=O)Cl
Agent: C[P+](C)(C)CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC1(NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
Under a nitrogen atmosphere, chloromethyltrimethyl-phosphonium chloride (5.156 g, 14.85 mmol) was suspended in dry tetrahydrofuran (30 ml). After cooling the suspension to provide an internal temperature of -55° C., a 1.68 M solution of n-butyllithium in n-hexane (8.87 ml, 14.90 mmol) was added dropwise thereinto over a period of 5 minutes. Then, the reaction suspension was stirred under ice cooling for 30 minutes and then at room temperature for an additional 3 hours followed by cooling to provide an internal temperature of -55° C. Into this reaction suspension was added dropwise a solution of 1-tert-butoxycarbonylaminocyclopropane carbaldehyde (2.49 g, 13.50mmol) in dry tetrahydrofuran (10 ml) over a period of 10 minutes and the resultant mixture was stirred at -50° C. for 1 hour and then under ice cooling for additional 30 minutes. The reaction suspension was cooled to -78° C. and a 1.68 M solution of n-butyllithium in n-hexane (17.68 ml, 29.70 mmol) was added dropwise thereinto over a period of 10 minutes followed by stirring at -78° C. for 20 minutes. Next, ethyl chloroformate (1.61 ml, 16.88 mmol) was added dropwise into this reaction suspension followed by stirring at -78° C. for 1.5 hours and then under ice cooling for 1 hour. Under ice cooling, a saturated aqueous solution of sodium chloride (30 ml) was added to the reaction suspension and the organic layer was separated. The aqueous layer was extracted with diethyl ether (30 ml×2) and the combined organic layer was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1) to obtain 2.178 g (63.9%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:6]1C=CC=CC=1P(=CCl)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH:31]=O.[Cl:37]CCl>>[CH2:4]([O:3][C:1](=[O:2])[C:6]([Cl:37])=[CH:31][C:30]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=1)[CH3:5]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccccc1P(=CCl)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Product: CCOC(=O)C(Cl)=Cc1ccc(Cl)c(Cl)c1

Procedure:
Carboethoxychloromethylenetriphenylphosphorane (8.74 g) in dichloromethane (100 ml) under nitrogen at 25° was treated with 3,4-dichlorobenzaldehyde. After 18 hours at 25° removal of solvent in vacuo was followed by trituration from hexane and the hexane washings were concentrated in vacuo. Purification by chromatrography (silica; ether/hexane) gave ethyl-3-(3,4-dichlorophenyl)-2-chloroprop-2-enoate (6.3 g).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[N:15]=1)[C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:11])[C:8]([NH2:10])=[N:9][C:5]=2[CH:4]=1.[C:32]([N:39]1[CH:43]=[CH:42]N=C1)(N1C=CN=C1)=[O:33].N[C:45]1[CH:50]=CC=[CH:47][CH:46]=1>CN(C)C(=O)C>[CH3:11][N:7]1[C:6]2[CH:12]=[CH:13][C:3]([N:2]([CH3:1])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=4)[N:15]=3)=[CH:4][C:5]=2[N:9]=[C:8]1[NH:10][C:32]([NH:39][C:43]1[CH:42]=[CH:47][CH:46]=[CH:45][CH:50]=1)=[O:33]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(c1ccc2c(c1)nc(N)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Reactant: Nc1ccccc1
Solvent: CC(=O)N(C)C
Product: CN(c1ccc2c(c1)nc(NC(=O)Nc1ccccc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Reaction time: 24 h

Procedure:
To a solution of N5,1-dimethyl-N5-[2-({4-[(methylsulfonyl)methyl]phenyl}amino)pyrimidin-4-yl]-1H-benzimidazole-2,5-diamine (150 mg, 0.343 mmol) in N,N-dimethylacetamide (3 ml) was added 1,1′-carbonyldiimidazole (167 mg, 1.03 mmol). The mixture was stirred for 24 h and then aniline (192 mg, 2.06 mmol) was added. The mixture was stirred for 2 h. The reaction was quenched with saturated sodium bicarbonate solution (30 ml) and the product precipitated. The crude product was filtered, washed with water, diethyl ether and air dried to give the desired product without further purification. 1H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H), 9.26 (s, 1H), 9.12 (s, 1H), 7.86 (d, J=5.8 Hz, 1H), 7.76-7.68 (m, 4H), 7.42 (d, J=8.2 Hz, 1H), 7.30-7.20 (m, 5H), 7.12 (d, J=8.2 Hz, 1H), 6.89 (t, J=7.1 Hz, 1H), 5.75 (d, J=5.7 Hz, 1H), 4.34 (s, 2H), 3.57 (s, 3H), 3.44 (s, 3H), 2.84 (s, 3H). MS (ESI) m/z=557 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH:24][CH3:23])=[O:21])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCCc1cc(-c2ccc(Cl)cc2)no1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCCc1cc(-c2ccc(Cl)cc2)no1
Yield: 74.9 %

Procedure:
0.6 g (1.87 mmol) of 3-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}-1,3-oxazolidine-2,4-dione, prepared in stage 4.2., is dissolved in a mixture of 8 ml of tetrahydrofuran and of 15 ml of methanol. 2.8 ml of a 2M solution of methylamine (5.6 mmol) in tetrahydrofuran are added. Reaction is allowed to take place at ambient temperature overnight and then the mixture is evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 95/5 and 90/10 mixture of dichloromethane and of methanol. The product is recrystallized from a mixture of ethyl acetate and of methanol to produce 0.49 g (1.4 mmol) of white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH2:12])=[O:6].N#N.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH:12][CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])=[O:6]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in oil, 180 mg, 4,72 mmol) was added to an ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1000 mg, 4,29 mmol) in 25 ml of dimethylformamide in an atmosphere of N2. After 5 min, 2,4-dichloro-1-chloromethyl-benzene (755 mg, 3,86 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 30 min at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×20 mL) and the combined ether layer was dried (MgSO4) and concentrated. The residue obtained was then purified by precipitation. The crude product was taken in 25 ml of ethyl acetate, a yellow precipitate came out which was filtered to obtain 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester, 835 mg (55%). 1H-NMR (DMSO, 400 MHz): 7.67 ppm (m, 2H, Haro); 7.44-7.35 ppm (m, 6H, Haro); 7.26 ppm (s, 1H, Haro); 4.63 ppm (d, 2H, N—CH2); 3.75 ppm (s, 3H, O—CH3)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1.O>C(#N)C>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Temperature: 20 °C
Yield: 98 %

Procedure:
To a refluxing mixture of commercially available ethyl 5-nitro-1H-indole-2-carboxylate (420 g) and potassium carbonate (272.6 g) in acetonitrile (3360 mL) was added a solution of methyl p-toluenesulfonate (367.3 g) in acetonitrile (630 mL), and the resulting mixture refluxed for 18 hours. The mixture was then cooled to 20° C. over 3 hours and water (4200 mL) added over a 3 hour period. The product was granulated, filtered, washed with a 50/50 mixture of demineralized water and acetonitrile (630 mL), demineralized water (420 mL) and then with ethanol (420 mL), and dried, yielding the product ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (436.1 g, 96%).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:19](Cl)=[N:20][C:21]([NH2:25])=[N:22][C:23]=2[CH3:24])[CH:12]=1)[CH3:8]>CN1C(=O)CCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:23]([CH3:24])=[N:22][C:21]([NH2:25])=[N:20][C:19]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=1)[CH3:8]
Reactant: CCCCCN
Reactant: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(C(=O)OCC)c1
Temperature: 150 °C

Procedure:
Pentylamine (2.5 mL) was added to a stirred solution of the product from step (ii) (1.65 g) in NMP (3 mL). The mixture was heated at 150° C. for 15 h and allowed to cool. The solution was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) added. The aqueous phase was separated and the organic phase washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography eluting with 2% to 5% MeOH in DCM to give the subtitle compound as an orange solid. 0.7 g.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:63][CH2:62]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.134 g, 0.00053 mol) in DMF (2 mL) was added DIPEA (0.185 g, 0.00143 mol), HOBt (0.0646 g, 0.00048 mol) and EDCI.HCl (0.1098 g, 0.00057 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.118 g, 0.00048 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by preparative TLC using 30% ethyl acetate in hexane as eluent afforded 0.105 g (45%) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 448 (M+1)+, 97.78%, 1H NMR (CDCl3): δ 7.94 (d, 2H), 7.74-7.6 (m, 4H), 7.5-7.38 (m, 2H), 7.2-7.1 (m, 1H), 6.75-6.6 (m, 2H), 4.5 (m, 1H), 4.3 (d, 2H), 4.25 (d, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 3.3 (m, 2H), 3.1 (m, 1H), 2.2 (bt, 2H), 1.5 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([N:7]([CH2:20][C:21]2[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCNc1nc(-c2ccccc2)c(C)o1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)c(C)o1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a solution of 5-methyl-4-phenyl-N-propyl-1,3-oxazole-2-amine (407 mg, 1.88 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 82 mg, 2.04 mmol) at room temperature and the mixture was stirred for 30 min. Methyl 3-[4-[[4-(chloromethyl)benzyl]oxy]phenyl]propanoate (500 mg, 1.57 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (251 mg, yield 32%) as a pale-yellow oil.