Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (86.2 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccn3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)pyridine hydrobromide and isolated as white gum (5.0 mg, 33%). MS (m/e): 374.4 (MH+).
Reaction SMILES: CO[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[S:11](=O)(=O)(O)O.N1CCOCC1.[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].[S]>C(O)C.O>[NH2:23][C:22]1[S:11][C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)=[CH:3][C:24]=1[C:25]([NH2:27])=[O:26]
Reactant: COC=Cc1ccccn1
Reactant: O=S(=O)(O)O
Reactant: N#CCC(N)=O
Agent: [S]
Solvent: O
Solvent: C1COCCN1
Solvent: CCO
Product: NC(=O)c1cc(-c2ccccn2)sc1N
Temperature: 80 °C
Yield: 17 %

Procedure:
2-(2-Methoxyvinyl)pyridine (1.28 g) was dissolved in ethanol (13 ml) and to the solution was added 6M sulphuric acid (3.6 ml). The solution was heated to 80° C. for 20 minutes then allowed to cool to 55° C. Morpholine (8 ml) was added followed by cyanoacetamide (0.796 g) and sulfur (0.334 g). The mixture was heated at 55° C. for 4 h. After cooling to room temperature the solution was poured into water (100 ml) and extracted with ethyl acetate. The extracts were dried (MgSO4), filtered and evaporated. The residue was adsorbed onto silica gel and eluted with 2-5% methanol in dichloromethane to give an orange solid (345 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH3:31]O>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:27]([CH3:31])(=[O:29])=[O:26])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[N:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C)cn2)cc1
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To solution of the methylthio compound from step 4 (3.95 g, 11.5 mmol) in 45 ml of methanol was added an aqueous solution of Oxone® (6.94 g dissolved in 28 ml of water). After stirring at 25° C. for 4-5 hours, the solvent was removed under reduced pressure, redissolved in 50 ml of methylene chloride and extracted with 50 ml of an aqueous solution of sodium bicarbonate. The organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; 50% ethyl acetate/toluene) to provide 1.6 g of the desired product: mp 196° C. Anal Calc'd. for C17H14N3SO2F3: C, 53.54; H, 3.70; N, 11.02; S, 8.41. Found: C, 53.09; H, 3.43; N, 10.75; S, 8.69.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[N:14][C:13](Cl)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:17]([O:21][CH3:22])(=[O:20])[NH:18][NH2:19].[CH2:23](O)CCC>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[N:14][C:13]([NH:19][NH:18][C:17]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[CH3:23])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)NN
Reactant: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCCCO
Product: COC(=O)NNc1cc(C)c(-c2cccc([N+](=O)[O-])c2)nn1

Procedure:
A mixture of 11.4 g. of 6-(m-nitrophenyl)-3-chloropyridazine, 8.25 g. of methyl carbazate and 150 ml. of n-butanol is refluxed for 3 hours. The solvent is removed and the oily redisue stirred with cold water. The solid is filtered to give 11.5 g. of crystals which are recrystallized from methanol-petroleum ether to give off-white crystals, m.p. 198°-199° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](Cl)=[O:27])=[CH:22][C:21]=1[CH3:31].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][C:20]([F:19])=[C:21]([CH3:31])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCC(=O)Cl)ccc1F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To the solution of (S)-4-Benzyl-2-oxazolidinone (857 mg, 4.8 mmol) in anhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.0 mL, 4.8 mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture was stirred for 30 min at −70° C. and to it was slowly added a solution of 2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF. The resulting mixture was stirred at −70° C. for 2 h and the temperature was slowly raised over a period of 1 h. The mixture was poured into 30 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 1.5 g of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH2:14](Cl)[CH3:15].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].Cl>CO.CCOCC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:21][CH2:22][N:17]2[CH2:15][CH2:14][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CCCl
Reactant: C1CCNCC1
Reactant: CC#CCOc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: CC#CCOc1ccc(OCCN2CCCCC2)cc1
Yield: 29.7 %

Procedure:
To a solution of the product from step 1 (200 mg, 1.23 mmol) in MeOH (10 mL) was added piperidine ethyl chloride hydrochloride (227 mg, 1.23 mmol), and K2CO3 (679 mg, 4.92 mmol), and the resulting mixture was refluxed for 10 h. Solvent was removed in vacuo and the crude product was dissolved in EtOAc and partitioned with water. Organic layer was separated and dried over anhydroua Na2SO4. Solvent was removed in vacuo to obtain a thick oil, which was added 2M HCl in ether. Solvent was decanted and the solid was triturated with ether to obtain the title product (100 mg, 30%); MS m/z 274.4 (M+H) 99%: 1H NMR (DMSO-d6, 400 MHz) δ 1.39 (1H, m), 1.67-1.82 (8H, m), 2.97 (2H, m), 3.41-3.50 (1H, m), 3.75 (1H, br m), 4.31 (2H, d, J=5.2 Hz), 4.67 (2H, s).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:22]([CH3:24])[CH3:23])[CH2:32][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CC(C)c1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3C(C)C)CC2)c(OC)nc1C
Yield: 65 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[N:17][N:16]([CH3:19])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:19][N:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([C:22]3[N:26]4[N:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]4=[N:24][CH:23]=3)[CH:13]=[CH:12][CH:11]=2)[CH:18]=[N:17]1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: Cn1ncc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
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
Product: Cn1ncc(-c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)n1
Yield: 33.7 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-2-methyl-2H-[1,2,3]triazole (190 mg, 0.7 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.156 g, 0.585 mmol), 2 M Na2CO3 (0.70 ml) and tetrakis(triphenylphosphine)palladium(0) (0.034 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 50% Et2O/toluene) and crystallized from toluene to yield the title compound (68 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 4.28 (3H, s), 7.63 (1H, t, J 7.8 Hz), 7.87 (1H, dt, J 7.8, 1.4 Hz), 7.91 (1H, s), 8.05-8.09 (1H, m), 8.52 (1H, t, J 1.4 Hz), 8.68 (1H, s), 8.85 (1H, s); MS (ES+) m/z 346 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:26](=[O:29])[CH2:27][CH3:28])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 5 °C

Procedure:
N4-(3-bromophenyl)quinazoline-4,6-diamine (100 mg, 0.32 mmol), pyridine (0.3 mL), and DMAP (20 mg) were dissolved in 10 mL of anhydrous THF. The solution was cooled to 5° C. Propionyl chloride (33 mg, 0.35 mmol) was added to the reaction flask dropwise. Ice bath removed was removed, and the reaction mixture was stirred at room temperature and filtered. The filtrate was dried in vacuo to give a yellow solid. The yellow solid was dissolved in ethyl acetate, washed once with saturated Na2CO3, then with 10% acetic acid, and then with brine. The organic phase was dried, filtered, and stripped of solvent in vacuo to give a crude product which was purified by TLC to give the title compound as a whitish product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (4.60 g, 15.8 mmol) and N,N-diisopropylethylamine (1.40 mL, 15.8 mmol) in 25 mL of dry methylene chloride was added propionyl chloride (1.40 mL, 15.8 mmol) dropwise at 0° C. After being stirred at room temperature overnight, the reaction mixture was quenched with 30 mL of H2O and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous HCl (5%, 20 mL), NaHCO3 (sat., 2×30 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 as a colorless oil (4.50 g, 82%). IR (film, cm−1) 2975, 2934, 2854, 1690, 1663, 1591, 1496, 1422, 1402, 1365, 1265, 1242, 1176, 1149, 1038, 962, 775, 702; 1H NMR (CDCl3, ppm) 7.44-7.22 (m, 5H), 4.09-3.22 (m, 4H), 2.80-2.09 (m, 2H), 2.06 (q, 2H, J=7.5 Hz), 1.75-1.19 (m, 5H), 1.48(s, overlap, 9H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](Cl)=[O:20].Cl>C(#N)C.O>[OH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:10][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CBr
Reactant: Cc1cc(O)cc(O)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(O)cc2c1NC(=O)CO2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.0 g (7.2 mmol) 4-amino-5-methylbenzene-1,3-diol and 2.2 g (15.8 mmol) potassium carbonate in 20.0 mL acetonitrile were cooled in the ice bath. 0.65 mL (7.9 mmol) bromoacetyl chloride were added dropwise and the reaction mixture was stirred for 30 min at RT and for 1 h at 70° C. The mixture was combined with water, acidified with aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.ClC1C=CC(C(O)=O)=NC=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C(O)c1ccc(Cl)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cn2)cc1

Procedure:
Following the procedure of Example 1, 5-chloro-2-pyridinemethanol, prepared from 5-chloropicolinic acid, is reacted with 1-fluoro-4-nitrobenzene to give 5-chloro-2-(4-nitrophenoxy)methylpyridine, which is converted to 5-chloro-2-(4-aminophenoxy)methylpyridine by reduction with iron and ammonium chloride. The 5-chloro-2-(4-aminophenoxy)methylpyridine and 3,4,5,6-tetrahydrophthalic anhydride are reacted to yield the final product N-4-[2-(5-chloropyridyl)methoxy]phenyl-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11](N(CC)CC)[CH3:12].ICC>>[CH2:11]([S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:12]
Reactant: CCN(CC)CC
Reactant: Sc1nc2ccccc2s1
Solvent: CCI
Product: CCSc1nc2ccccc2s1
Yield: 55.7 %

Procedure:
2-Mercaptobenzothiazole (16.72 g, 0.1 mol) in 52 ml 95% alcohol was reacted with 10.1 g (0.1 mol) triethylamine to give a brown solution. Iodoethane (15.6 g, 0.1 mol) was added and the mixture refluxed 45 minutes. The mixture was cooled and the solvent removed by rotary evaporation. Water (100 ml) was added to the residue and an oil separated. The aqueous phase was extracted 2×50 ml methylene chloride, the combined organic phases washed with 50 ml water, and then dried over Na2SO4. Filtration and rotary evaporation yielded a brown liquid which was distilled at 140°-141.5° C. (0.15 mm) to give 10.87 g (56%) pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: CC(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Nc1ccccc1
Product: CC(C)CN(CC(=O)Nc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-isobutylglycine and aniline: MS (APCI) m/z 376 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[ClH:1].[CH2:31]([CH:15]([CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([F:20])[CH2:13][CH2:12]1)[C:16]([O:18][CH3:19])=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCN1CCC(F)(c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccccc1)CN1CCC(F)(c2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of methyl 3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate (75 mg, 0.23 mmol) in toluene (5 mL) was placed under a dry nitrogen atmosphere and cooled in a dry ice acetone bath. A 1M solution of lithium hexamethyldisilazide (0.28 mL, 0.28 mmol) was then added drop-wise over 10 minutes. The resulting bright yellow solution was stirred for 1 hour then benzyl bromide (43 mg, 0.25 mmol) added in one portion. The reaction was then allowed to warm to room temperature with stirring over a 16 hour period then quenched by the addition of 25% aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts dried over magnesium sulfate, filtered and stripped to a viscous yellow oil. This oil was treated with 10% methanolic hydrogen chloride (5 mL) and the solution re-concentrated. The resulting oil was triturated with 1:1 ethyl acetate/heptanes (10 mL) to afford a light yellow solid which was collected by filtration. After drying under vacuum for 12 hours methyl 2-benzyl-3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate hydrochloride was obtained as a light yellow solid in 44% yield.
Reaction SMILES: N[C@@H]1CCCCN(C(NC2CCC2)=O)C1=O.CC(O[C:22](=[O:39])[NH:23][C@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([C:31]([NH:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)=[O:32])[C:25]1=[O:38])(C)C.C(O)(C(F)(F)F)=O.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(C(C)C)CC)(C)C.[Cl:69][C:70]1[CH:79]=[C:78]2[C:73]([C:74]([N:81]3[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]3)=[CH:75][C:76]([NH2:80])=[N:77]2)=[CH:72][CH:71]=1>>[NH2:80][C:76]1[CH:75]=[C:74]([N:81]2[CH2:82][CH2:83][N:84]([C:22]([NH:23][C@H:24]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][CH2:37]4)=[O:32])[C:25]3=[O:38])=[O:39])[CH2:85][CH2:86]2)[C:73]2[C:78](=[CH:79][C:70]([Cl:69])=[CH:71][CH:72]=2)[N:77]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(C(=O)NC2CCC2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: N[C@@H]1CCCCN(C(=O)NC2CCC2)C1=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NC4CCC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described example 78, (3R)-3-amino-N-cyclobutylhexahydro-2-oxo-1H-azepine-1-carboxamide by de-protection of [(3S)-1-[(cyclobutylamino)carbonyl]hexahydro-2-oxo-1H-azepin-3-yl] carbamic acid-1,1-dimethylethyl ester with TFA, p-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. 1HNMR (DMSO-d6): δ 1.24 (br. s, 1H), 1.5–1.9 (m, 7H), 2.2 (m, 2H), 2.99 (m, 4H), 3.6 (m, 4H), 4.17 (m, 1H), 4.52 (m, 1H), 4.66 (t, 1H), 6.14 (s, 1H, 6.42 (br. s, 1H), 6.8 (d, 1H), 7.1 (d, 1H), 7.39 (s, 1H), 7.76 (d, 1H), 9.3 (d, 1H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][F:42].C(OCC)(=O)C>CS(C)=O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[O:33][CH2:41][F:42])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FCBr
Reactant: CCOC(=O)/C(=N\O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
Ethyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-hydroxyiminoacetate (60.4 g) was dissolved in dimethylsulfoxide (210 ml), followed by an addition of potassium carbonate (96.48 g) under ice-cooling. The resulting mixture was stirred for 10 minutes. Bromofluoromethane (19 g) was thereafter added, followed by stirring at room temperature for 3 hours. Ethyl acetate (1 l) was added to the reaction mixture. The resulting mixture was washed with water and then with saturated saline, and was added with anhydrous magnesium sulfate to dry the mixture. The solvent was distilled out and ethanol (120 ml) was added to the residue. Crystals thus precipitated were collected by filtration and then washed to obtain 58.2 g of the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25]CO[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:35][OH:36]>>[N:20]1([C:17]2[CH:16]=[CH:15][C:14]([N:9]3[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]4[N:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:2]=[CH:3][CH:4]=4)=[N:8]3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][O:36][CH2:35][CH2:25]1
Reactant: CO
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 8 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (crude, 1100 mg, 3.11 mmol) in 20 mL of methanol was added phenylhydrazine (504 mg, 4.67 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-morpholin-4-ylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (95 mg, 8% for two steps) as a yellow solid.