Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15].C(O)(=O)C>C1(C)C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Methyl 3-amino-4-hydroxyphenylacetate (5.43 g, 0.03 mol) was suspended in toluene (60 ml) and 1,1′-thiocarbonyldiimidazole (5.34 g, 0.03 mol) was added. The resultant mixture was stirred for 30 minutes, then acetic acid (10 ml) was added and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate The organic extract was dried over magnesium sulfate, filtered and the filtrate was evaporated to give methyl (2,3-dihydro-2-thioxo-5-benzoxazolyl)acetate (6,2 g) as a light brown solid, m.p. 120-122° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([CH3:26])[C:5]([OH:27])=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([CH3:26])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:11]=1
Reactant: COc1cc(C(=O)Nc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: COc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
To a stirred solution of N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methoxy-benzamide (500 mg, 1.35 mmol, 1.0 eq) in anhydrous THF (10 mL) under N2 was added a solution of BH3 (1M in THF, 7 mL, 6.77 mmol, 5.0 eq) dropwise over 5 min. The reaction mixture was heated to 60° C. overnight. After cooling, the resulting mixture was quenched by addition of saturated aqueous NH4Cl. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 20:1) to give the title compound as a colorless oil (390 mg, 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1.O1CCCC1.C([Li])CCC.CCCCCC.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[C:8]=1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1
Reactant: COCc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(methoxymethyl)-1-methyl-1H-pyrazole (261.0 mg, 2.069 mmol) in tetrahydrofuran (5 mL, 60 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (3.88 mL, 6.21 mmol). The solution was stirred at room temperature for 1 h and cooled to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 mL, 2.3 mmol). The reaction was stirred at −78° C. for 0.5 h and then warmed up to 0° C. (taking 0.5 h). The reaction mixture was quenched with brine, adjusted to pH=6-7 with 1 N HCl aqueous solution, and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give brown oil, which was purified by combi-flash chromatography. LC/MS found: 253.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]([CH3:48])[C:18]([NH:20][CH:21]([CH2:38][C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:40]=1[F:47])[CH2:22][C:23](=[O:37])[N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=[C:26]2[CH2:25]1)=[O:19]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:16][CH:17]([C:18](=[O:19])[NH:20][CH:21]([CH2:38][C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:40]=1[F:47])[CH2:22][C:23](=[O:37])[N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:35])([F:34])[F:36])=[N:31][N:32]=[C:26]2[CH2:25]1)[CH3:48])[CH:13]([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)C(=O)NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Product: CC(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)C(=O)NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a stirred solution of 2-tert-Butoxycarbonylamino-3-methyl-butyric acid (0.390 gm, 0.00179 moles) in CH2Cl2 (40 ml) was added at 0° C. The reaction mixture was then stirred for 15 minutes. To this stirred solution was added 2-Amino-N-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide (0.860 gm, 0.00179 moles) at 0° C. The reaction mixture was then stirred for overnight. Dicyclohexyl urea was removed by filtration and filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography using CH2Cl2/MeOH (9.7/0.3) as an eluent to yield (2-Methyl-1-{1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-ethylcarbamoyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 7) (Yield=0.7 gm, 58%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.CCN(CC)CC.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:6]1[N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc[n+]([O-])c(NC(=O)C(C)(C)C)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)nc(NC(=O)C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To a solution of 4-methyl-2-pivalamidopyridine 1-oxide (3.0 g, 14 mmol) in POCl3 (30 mL) was added Et3N (6.0 mL, 43 mmol) drop-wise at 0° C. Then mixture was stirred at 100° C. for 3 days. The mixture was quenched with water, treated with aqueous NaOH to pH 8-9, and extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, evaporated under vacuum and purified by chromatography on silica gel (15% ethyl acetate in petroleum ether) to afford N-(6-chloro-4-methylpyridin-2-yl)pivalamide (520 mg, 16%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (s, 1H), 7.93 (br s, 1H), 6.87 (s, 1H), 2.33 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[NH:16]1[CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: C1CNC1
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)N2CCC2)ccc1Br

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.5 ml) and azetidine (1 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[C:16]([S:27][CH3:28])=[CH:15]2)=[N:12][CH:13]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(O)C>COCCOC.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>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=4)[C:16]([S:27][CH3:28])=[CH:15]3)=[N:12][CH:13]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cccc(OC)c4)cn3)c2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) and a 2M solution of sodium carbonate (8 mL) were added at room temperature and under an argon atmosphere to methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (3.0 g, 7.96 mmol) in DME (50 mL). The addition of 3-methoxy phenyl boronic acid (1.53 g, 9.94 mmol) and ethanol (50 mL) followed 10 min later, and the resulting mixture was heated at 90° C. for 5 h. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by flash column chromatography [silica; ethyl acetate/hexane=3:7]. Yellow solid. Yield: 2.6 g (80% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64]/[C:65](/[NH2:68])=[N:66]/O)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]>CN(C=O)C>[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64][C:65]4[N:66]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[O:9][N:68]=4)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]
Reactant: O=C(O)c1ccccn1
Reactant: CCc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccn4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of picolinic acid (10 mg, 0.09 mmol) in DMF (1 mL) were added DIPEA (16 μL, 0.09 mmol) and HATU (33 mg, 0.09 mmol). After stirring at rt for 15 min, 17a (30 mg, 0.09 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17a was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 7-ethyl-1-methyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A105). 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 9.09 (s, 1H), 8.81 (s, 1H), 8.18 (d. J=8 Hz, 1H), 8.10 (m, 2H), 7.75 (s, 1H), 7.71 (m, 1H), 7.47 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.01 (q, J=7.6 Hz, 2H), 2.10 (s, 3H), 1.36 (t, J=7.6 Hz, 3H). MS m/z 439.3 (M+1).
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([C:9]1[S:13][C:12]([S:14]([NH:17]C(C)(C)C)(=[O:16])=[O:15])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:24][CH:23]=2)[CH:10]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[CH2:5]([C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:24][CH:23]=2)[CH:10]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
BCl3 (1.0 mL, 1M, 1.0 mmol) was added to a solution of 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-1-ylmethylphenyl)thiophene-2-sulfonamide (177.0 mg, 0.408 mmol, see step (b) above) in CH2Cl2 (10 mL) under N2 (g), and the reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J7) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (326 mg, 82%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[CH:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35].C(=O)(O)[O-].[Na+]>C(O)C>[NH:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:34][NH2:35])=[O:2])=[CH:9][CH:8]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: NN
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 80 °C
Yield: 63.2 %

Procedure:
To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoic acid methyl ester (AMD9711) (140 mg, 0.33 mmol) in dry ethanol (3 mL) was added hydrazine monohydrate (0.5 mL, 10.3 mmol) and the resulting mixture was heated at 80° C. for 24 h. Saturated aqueous sodium bicarbonate (5 mL) was added, the phases separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 75:1:1 CH2Cl2—MeOH—NH4OH) afforded the title compound (89 mg, 61%) as a white solid. 1H NMR (CDCl3) δ 1.64–1.68 (m, 1H), 1.94–2.04 (m, 2H), 2.20–2.24 (m, 1H), 2.66–2.72 (m, 1H), 2.78–2.83 (m; 1H), 3.73 (s, 2H), 3.93 (d, 1H, J=16 Hz), 4.00–4.12 (m, 3H), 4.15 (d, 1H, J=16 Hz), 7.14–7.18 (m, 3H), 7.40 (d, 2H, J=8 Hz), 7.50 (br d, 1H, J=7 Hz), 7.58 (d, 2H, J=8 Hz), 7.62 (br d, 1H, J=7 Hz), 8.06 (s, 1H), 8.66 (dd, 1H, J=5, 1Hz); 13C NMR (CDCl3) δ 21.2, 23.6, 29.0, 48.7, 53.7, 60.4, 111.4, 118.4, 121.5, 122.3, 126.9, 128.6, 131.5, 134.7, 137.3, 143.5, 146.8, 155.8, 157.1, 168.4. ES-MS m/z 427 (M+H). Anal. Calcd. for C25H26N6O.0.5CH2Cl2: C, 65.31; H, 5.80; N, 17.92. Found: C, 65.22; H, 5.77; N, 17.97.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[C:14]([NH2:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH2:16]
Reactant: CN1CCN(c2ccccc2)CC1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCN(c2ccccc2)CC1CN

Procedure:
In a manner similar to preparation 2, react 1-methyl-4-phenyl-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[CH3:17])[CH:2]=[CH2:3].C1(C)C(C)=CC=CC=1.O.[CH3:27][CH2:28][CH:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>>[CH3:27][CH2:28][CH:29]([NH:33][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([CH3:17])[C:6]=1[N+:14]([O-:16])=[O:15])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(N)CC
Reactant: C=CCc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CCc1cc([N+](=O)[O-])c(NC(CC)CCC)c([N+](=O)[O-])c1C

Procedure:
One equivalent of 4-allyl-3-methyl-2,6-dinitrochlorobenzene is dissolved in three volumes of xylene containing two equivalents of 3-hexylamine. The mixture is refluxed for 5 hours and then poured into water. The organic phase is washed with 5% hydrochloric acid and then water, dried over calcium sulfate, and removed in vacuo to leave the above-named product.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:15]C(OC(C)(C)C)=O)[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([C:11]1([NH2:15])[CH2:12][CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(=O)OCc2ccccc2)CCC1
Reaction time: 4 h

Procedure:
To a solution of 2.2 g 1-tert-Butoxycarbonylamino-cyclobutanecarboxylic acid benzyl ester in 20 ml dichloromethane were added 8 ml TFA. After stirring for 4 h the mixture was concentrated and the residue codistilled with toluene. The free amine was obtained by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.7 g
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:7]1([NH:6][CH2:2][C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)CCl
Solvent: O
Product: O=C(O)CNc1ccccc1

Procedure:
475 g of chloracetic acid (5 moles) are heated with 930 g aniline (10 moles) in 2 l water for 1.5 h to 100° C. After cooling, the N-phenylglycine formed is suctioned off and washed with water. Yield is 468 g (=62% with respect to the chloracetic acid).
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[F:31][C:16]([F:15])([F:32])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9]#[N:10])[CH2:6][CH2:5]2)=[O:26])[N:18]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1cccnc1N1CCNCC1
Product: N#Cc1cccnc1N1CCN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CC1
Yield: 81 %

Procedure:
This compound was synthesized from 2-(piperazin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (135 mg, yield 81%). 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.43 (dd, J=4.8 Hz, 1.8 Hz, 1H), 8.18-8.15 (dd, J=7.3 Hz, 1.6 Hz, 1H), 8.13-8.10 (m, 2H), 7.78-7.71 (m, 2H), 6.99-6.96 (dd, J=7.5 Hz, 4.8 Hz, 1H), 3.81-3.75 (m, 4H), 3.63-3.54 (m, 4H). MS (ESI) m/z: Calculated for C20H15F3N6O2: 428.12. found: 429.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:26]1([NH:25][C:16](=[O:24])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)Nc3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), salicylanilide (213 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (86 mg, yield 86%).
Reaction SMILES: [OH-].[K+].I[CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([SH:22])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([S:22][CH3:4])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(Cn2c(S)nc3cncnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a stirred mixture of 4.6 parts of potassium hydroxide and 200 parts of water were added portionwise 1.7 parts of iodomethane, followed by the dropwise addition of 3.8 parts of 9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol. Upon complete addition, the whole was stirred for 2 hours at room temperature. The precipitated product was filtered off and dried, yielding 3.45 parts (73.9%) of 9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine; mp. 167.1° C. (interm. 25).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(NCC2CCCCN2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 50 °C

Procedure:
2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.102 mmol) in MeOH (10 mL) was treated with TFA (0.1 mL, 1.3 mmol). The resulting mixture was heated at 50° C. for 24 h. The reaction mixture was cooled to RT and neutralized to pH between 8–9. Solvent was removed. The residue was partitioned between H2O and CHCl3.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(O)C(Nc1ccc(Cl)cc1)c1ccccc1
Yield: 47 %

Procedure:
To a solution of α-bromophenylacetic acid (1.00 g, 4.65 mmol) in acetonitrile (20 mL), is added 4-chloro-phenylamine (1.18 g, 9.30 mmol) and the mixture reacted in a closed vessel under MW irradiation at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). Solvent is evaporated and residue is portioned between EtOAc and 1N HCl. The organic phase is dried over Na2SO4, filtered and evaporated to dryness to get intermediate I76 as a yellow solid (0.57 g; 47% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]COC)=O.[NH2:24][OH:25].CO>[Cl-].[NH4+]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:24][OH:25])=[O:20]
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Reactant: NO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1c(CCCCCCC(=O)NO)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (0.3 g) was added to 1M hydroxylamine/methanol (2.85 ml) and the mixture was stirred at room temperature for 1.5 hours. This reaction mixture was poured in saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness, and the residue was recrystallized from hexane-ether to provide the title compound (0.116 g).