Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17](=[O:66])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]([CH2:37][C:38]4[C:47]5[C:42](=[CH:43][C:44]([Br:48])=[CH:45][CH:46]=5)[CH:41]=[CH:40][C:39]=4[O:49][CH3:50])[C:29](=[O:51])[C@@H:28]([NH:52][C:53](=[O:65])[C@@H:54]([N:56](C(OC(C)(C)C)=O)[CH3:57])[CH3:55])[CH2:27]3)=[O:25])=[CH:20][CH:19]=2)[CH2:13][N:12]1[C:67](=[O:89])[C@@H:68]([NH:75][C:76](=[O:88])[C@@H:77]([N:79](C)[C:80](=O)OC(C)(C)C)[CH3:78])[CH:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Cl:93])(=O)C>CO>[ClH:93].[ClH:93].[CH2:1]([NH:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17](=[O:66])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]([CH2:37][C:38]4[C:47]5[C:42](=[CH:43][C:44]([Br:48])=[CH:45][CH:46]=5)[CH:41]=[CH:40][C:39]=4[O:49][CH3:50])[C:29](=[O:51])[C@@H:28]([NH:52][C:53](=[O:65])[C@@H:54]([NH:56][CH3:57])[CH3:55])[CH2:27]3)=[O:25])=[CH:20][CH:19]=2)[CH2:13][N:12]1[C:67](=[O:89])[C@H:68]([CH:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74]1)[NH:75][C:76](=[O:88])[C@@H:77]([NH:79][CH3:80])[CH3:78])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N[C@H]3C[C@@H](C(=O)NCc4ccccc4)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C4CCCCC4)C3)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N[C@H]3C[C@@H](C(=O)NCc4ccccc4)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C4CCCCC4)C3)cc2)c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Product: Cl
Yield: 197.4 %

Procedure:
To tert-butyl N-[(1S)-2-[[(1S)-2-[(2S,4S)-2-(benzylcarbamoyl)-4-[[4-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]amino]pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (45 mg, 0.035 mmol) in methanol (2 mL) at room temperature was added acetyl chloride (25 μL, 0.035 mmol) dropwise. The mixture was allowed to stand at room temperature. After 16 h the mixture was concentrated and the residue was triturated with acetonitrile to give the title compound (40 mg, 98%) as a tan solid. MS: m/z 1085 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.[C:13]1([CH:20]=[CH:19][CH:18]=[C:16]([OH:17])[CH:15]=1)O.[OH-:21].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:13]=[CH:20][CH:19]=[CH:18][C:16]=1[O:17][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1cccc(O)c1
Reactant: [OH-]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Oc2ccccc2Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Reaction time: 50 h

Procedure:
In 100 ml of dimethyl sulfoxide, there were dissolved 129 g. (0.60 mole) of 3,4-dichlorobenzotrifluoride and 27.5 g. (0.25 mole) of resorcin. Then, a solution of 34 g. (0.60 mole) of potassium hydroxide dissolved in 15 ml of water was added to the resultant solution and the mixture was heated with stirring at 150° to 160° C. for 50 hours. After the reaction mixture was left to cool, water was added thereto and the oily product precipitated was subjected to extraction with benzene. The extract was washed with a dilute aqueous sodium hydroxide and with water to remove unaltered resorcin, followed by drying over sodium sulfate and evaporation of benzene under reduced pressure, to give crude bis(2-chloro-4-trifluoromethylphenoxy)benzene. Subsequently, said crude bis(2-chloro-4-trifluoromethylphenoxy)benzene was added dropwise into a mixed acid comprising 60 ml of conc. nitric acid (d=1.38) and 60 ml of conc. sulfuric acid under stirring at 10° to 15° C. After completion of the dropwise addition, the mixture was further stirred at 20° to 27° C. for additional one hour to complete the reaction. Then, ice-water was added to the reaction mixture and the resultant precipitate of an oily product was extracted with benzene. The extract was washed with a dilute aqueous sodium hydroxide, and then with water, followed by drying over sodium sulfate and evaporation of benzene. Recrystallization of the residue from isopropyl alcohol gave 2,4-bis(2-chloro-4-trifluoromethylphenoxy)nitrobenzene as pale yellow powders, melting at 111° to 113° C. (yield: 47%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[NH:11][CH:10]=1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23].N.[ClH:30]>CO.CCOCC.C(O)C>[ClH:30].[ClH:30].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[NH:23])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCC[C@H]1CCc1c[nH]c2ccc(N)cc12
Agent: Cl
Agent: I
Agent: N
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CN1CCC[C@H]1CCc1c[nH]c2ccc(NC(=N)c3cccs3)cc12

Procedure:
To an argon purged round bottom flask was charged 146 (40 mg, 0.164 mmol) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (94 mg, 0.329 mmol) followed by absolute ethanol (3 mL). The reaction was stirred using a magnetic stirbar for 60 hours at room temperature. TLC (10% 2 M ammonia in methanol/90% dichloromethane) revealed all starting amine had reacted. The reaction as treated with ether (50 mL). The resulting yellow precipitate was collected by vacuum filtration and washed with ether. The precipitate was washed from the filter using methanol. The residue was concentrated, and purified by silica gel column chromatography (5-10% 2M ammonia in methanol/95-90% dichloromethane) to afford a yellow oil. The purified product was dissolved in anhydrous methanol (3 mL) and treated with 1M hydrogen chloride in ether (5 mL). After stirring for 30 minutes the precipitate was collected by vacuum filtration. The precipitate was washed with ether, followed by washing from the filter with methanol. The filtrate was concentrated and dried under high vacuum. Yield: 21 mg of yellow solid, compound 147 (30%) Melting point 212° C. 1H NMR (MeOD-d3) δ 8.09 (br s, 2H), 7.76 (s, 1H), 7.59 (d, 1H, J=8.7 Hz), 7.41 (br s, 1H), 7.35 (s, 1H), 7.19 (d, 1H, J=8.7 Hz), 3.67 (br m, 1H), 3.19 (br m, 1H), 3.1-2.8 (br m, 2H), 2.91 (s, 3H), 2.46 (br m, 2H), 2.2-1.8 (br m, 5H). MS (TOF+): Exact calc. for C20H25N4S 353.1794 (MH+), found 353.1782.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(C)O)c2oc(-c3ccncc3)cc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(C)OS(C)(=O)=O)c2oc(-c3ccncc3)cc(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-(1-hydroxyethyl)-2-(4-pyridinyl)-6-methyl-4H-1-benzopyran-4-one (2.4 g) in dichloromethane (100 ml) in an ice bath, was treated with triethylamine (1.3 ml) followed by methanesulfonylchloride (0.67 ml) and the mixture stirred at 0° C. for 30 minutes. The solution was then washed with 0.1N HCl (aq) (2×30 ml), dried (Na2SO4) and the solvent removed to yield a oily brown solid, which was not further purified.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH2:16])[CH:15]=1.O.Cl>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:16][C:1](=[O:3])[CH3:2])[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C)c(N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Acetic anhydride (5.6 g, 54.66 mmol) was added to a solution of 5-methoxy-2-methyl-phenylamine (5.0 g, 36.44 mmol) in pyridine (30 mL) and the resulting mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 5 by addition of an aqueous solution of hydrochloric acid (3 M). The resulting mixture was extracted with dichloromethane; the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 5.93 g of N-(5-methoxy-2-methyl-phenyl)-acetamide as a white solid without further purifications.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]([CH3:16])=[O:15].C(OC(=O)C)C>C1COCC1.CCCCCC>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:14]([OH:15])([CH3:16])[CH3:13]
Reactant: Brc1cccnc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1ccncc1Br
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
n-Butyl Lithium (10.28 mL, 16.455 mmol) was added to a solution of DIPA (2.66 mL, 18.98 mmol) in THF (25 mL) at -78° C. The reaction mixture was stirred at -10° C. for 10 mins, followed by the addition of 3-bromo-pyridine (500 mg, 2.212 mmol) in THF (10 mL) at -100° C. The reaction mixture was stirred for a further 15 minutes at -90° C. and was followed by the addition of acetone (1.675 mL, 22.78 mmol) in THF (10 mL) at -78° C. with stirring over a period of 1 hr. The reaction was monitored by TLC (5% ethylacetate in hexane). The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (15% ethylacetate in hexane) afforded 200 mg of the product (11% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[S:30](Cl)(Cl)(=[O:32])=[O:31].[C:35](=O)(O)[O-]>C(Cl)Cl>[Cl:22][C:4]1[CH:3]=[C:2]([NH:1][S:30]([CH3:35])(=[O:32])=[O:31])[CH:20]=[C:19]([Cl:21])[C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C:8]1=[O:18]
Reactant: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Charge a flask with 3-(4-amino-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one (250 mg, 0.73 mmol) and dissolve in methylene chloride (3 mL). Add triethylamine (0.16 ml) followed by sulfonyl chloride (0.11 ml, 1.5 mmol) and stir at room temperature for 1 hour. Pour into saturated aqueous bicarbonate and extract with methylene chloride. Dry over soium sulfate, filter and concentrate in vacuo. Purify residue over silica gel (30% ethyl acetate in hexanes) to afford 184 mg (60%) of the title compound. Mass spectrum (apci) m/z=419.1 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[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.[CH3:53][N:54]([CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:63])[F:62]>CN(C=O)C.O>[CH3:53][N:54]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:62])[F:63])[CH:65]1[CH2:70][CH2:69][N:68]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:67][CH2:66]1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2ccc(Nc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.051 g, 0.00019 mol) in DMF (5 mL) was added DIPEA (0.061 g, 0.00048 mol), HOBt (0.025 g, 0.00019 mol) and EDCI.HCl (0.076 g, 0.00040 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.047 g, 0.00016 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [(column-Zorbax SB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/Acetonitrile (B), gradient: (Time): (% B)-0:30; 2:50; 8:80)]) to afford 0.031 (38%) of N-(2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-4-phenylamino-benzamide. LCMS: 511.22 (M+1)+, 99.08%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.7 (m, 3H), 7.4 (m, 3H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.4 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.1 (m, 3H), 2.6 (s, 4H), 1.8 (d, 2H), 1.4 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:19])[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([NH2:18])(=[O:17])=[O:16].[H][H].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>CN(C)C=O>[CH3:3][N:4]([CH3:19])[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([NH:18][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1)(=[O:17])=[O:16]
Reactant: [H][H]
Reactant: CN(C)c1cccc2c(S(N)(=O)=O)cccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc([N+](=O)[O-])cn3)cccc12
Temperature: 95 °C
Yield: 8.1 %

Procedure:
Sodium hydride (60% dispersion in oil; 160 mg) was added to a solution of 5-dimethylamino-1-naphthalenesulphonamide (500 mg) in N,N-dimethylformamide (30 ml). When evolution of hydrogen ceased, 2-chloro-5-nitropyridine (317 mg) was added and the solution was heated at 95° C. for 18 hours. Volatile material was removed by evaporation and water (50 ml) was added to the residue. The mixture was extracted with ethyl acetate (20 ml), and the aqueous layer was neutralised with 0.05M aqueous acetic acid (40 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with water (20 ml) and saturated sodium chloride solution (20 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column. The resulting foam was triturated with ether/hexane (1:1 v/v) to give 5(dimethylamino)-N-(5-nitro-2-Pyridyl)-1-naphthalenesulphonamide (60 mg), m.p. 196° C.; mass spectrum (+ve FAB, methanol/NBA): 373 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])#[N:24]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:23]#[N:24])[CH:26]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 61 mg of 3-cyanobenzoyl chloride (0.37 mmol, 1.20 eq), and 500 uL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3-cyano-N-(2-methoxy-ethyl)-benzamide. MS (ES) M+H expected=455.0, found=455.1.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17]#[N:18])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.ClCCl>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[C:7]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:6]=3[C:5]([C:17]#[N:18])=[CH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: N#Cc1cnc(Cl)c2nc(-c3ccccc3)sc12
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ncc(C#N)c3sc(-c4ccccc4)nc23)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 4-chloro-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile 47 (54.2 mg, 0.2 mmol) and potassium carbonate (66 mg, 0.48 mmol) in NMP (1 mL) was treated with 4-methoxybenzylamine (32.5 μL, 2.4 mmol) and the mixture stirred at 130° C. for 8 hours. Silica gel column chromatography (eluent: dichloromethane and ethyl acetate (10 to 1)) afforded 48 as a pale yellow solid (70 mg). 1H NMR (400 MHz, d6-DMSO) δ: 3.71 (s, 3H), 4.72 (d. J=5.9 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.60 (m, 3H), 8.15 (m, 2H), 8.47 (s, 1H), 8.84 (t, J=6.1 Hz, 1H). MS (EI) m/z (M+H+) 373.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]3[N:38]=[CH:39][C:40]([C:41]4[CH:42]=[N:43][C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[C:17]3[N:16]=2)[CH2:11][CH2:10]1>CC#N>[Br:8][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)=[N:16][C:17]2[N:18]([N:38]=[CH:39][C:40]=2[C:41]2[CH:42]=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]=1[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of NBS (20.6 mg, 0.116 mmoL) in CH3CN (1 mL) was added to a mixture of 5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70.0 mg, 0.116 mmoL) in CH3CN (6 mL). After stirring at room temperature for 10 min, the reaction mixture was concentrated and purified by column chromatography to afford 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine. LCMS tR=2.91 Min (5 min run, UV254nm). Mass calculated for, M+ 684.2, observed LC/MS m/z 685.2 (M+H).
Reaction SMILES: CC1O[N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)[N:3]=1.[C:15]([OH:18])(=[O:17])[CH3:16].O.[H][H]>[Ni].CO>[C:15]([O-:18])(=[O:17])[CH3:16].[OH:14][CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:4]([NH2:5])=[NH2+:3]
Reactant: [H][H]
Reactant: Cc1nc(-c2cccc(CO)c2)no1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(=O)[O-]
Product: NC(=[NH2+])c1cccc(CO)c1

Procedure:
40 g of Raney nickel (water-wet) are added to 124.84 g of [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methanol (569.39 mmol) in a mixture of 1300 ml of methanol, 100 ml of glacial acetic acid and 100 ml of water, and the mixture is hydrogenated at room temperature and atmospheric pressure until 14.7 l of hydrogen have been taken up (45 h). For work-up, the catalyst is filtered off, and the solution which remains is evaporated to dryness, and the residue is boiled up in methyl tert-butyl ether and filtered off. The crystals are dried overnight in vacuo.
Reaction SMILES: [C:1]1([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH2:21]([O:20][C:18]([C:17](=[C:31]1[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]1=[O:30])[C:15]1[N:16]=[C:12]([NH:11][C:10]([NH:9][C:1]2[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:8])=[O:24])[S:13][CH:14]=1)=[O:19])[CH3:22]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 1.74 g of ethyl 2-[3-(2,6-xylyl)ureido]thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, O.5 g of ammonium chloride. 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-e]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (150 mg, 0.33 mmol) and tetrahydropyran-4-ylcarboxylic acid (45 mg, 0.34 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (51 mg, 34%), MS (ISP) m/z=457.3 [(M+H)+].
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][C:10]#[N:11])=[O:8])[CH2:3][CH2:2]1.Br[CH2:13][CH3:14].[CH2:15]([Li])[CH2:16]CC.CCCCCC>C1COCC1>[CH2:15]([C:9]([C:7]([N:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)=[O:8])([CH2:13][CH3:14])[C:10]#[N:11])[CH3:16]
Reactant: CCBr
Reactant: [Li]CCCC
Reactant: N#CCC(=O)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(C#N)(CC)C(=O)N1CCCCC1

Procedure:
The compound was synthesized from 1-cyanoacetylpiperidine (1.52 g, 10 mmol), bromoethane (3.73 mL, 50 mmol) and 1.6M n-butyllithium in hexane (13.75 mL, 22 mmol) in 40 mL of THF according to the method described in Example 393A to give 0.92 g. MS (ESI(+)) m/e 209 (M+H)+; 226 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 3.44-3.67 (m, 4H), 2.00-2.10 (m, 2H), 1.79-1.86 (m, 2H), 1.43-1.70 (m, 6H), 1.03-1.07 (m, 6H).