Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].[C:33](O)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:33](=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 15.2 %

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (20 mg) as a brown solid. M.P.: 186-190° C. MS (m/z): 424.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([N:12]=[CH:13][NH:14][NH:15][C:16](C2NC=CN=2)=[O:17])=[O:11])=[N:4][C:5]([F:9])=[C:6]([NH2:8])[N:7]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[C:3]([C:10]([N:12]=[CH:13][NH:14][NH:15][C:16]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:17])=[O:11])=[N:4][C:5]([F:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CC(C)N
Reactant: Nc1nc(N)c(C(=O)N=CNNC(=O)c2ncc[nH]2)nc1F
Product: CC(C)NC(=O)NNC=NC(=O)c1nc(F)c(N)nc1N

Procedure:
Following the procedure of Example 54, Step B but substituting 3,5-diamino-6-fluoro-N-{[(imidazolcarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide (1.3 g.) and isopropylamine (0.45 ml) in place of the corresponding reactants in Example 54, Step B there is obtained 3,5-diamino-6-fluoro-N-{[(isopropylaminocarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide. Yield: 600 Mg. M.P. 221° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[O:11][C:12]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][C:13]=3[CH:14]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1
Reactant: CCOC(=O)c1ccc2cc(CCCCN3C(=O)c4ccccc4C3=O)oc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc2cc(CCCCN)oc2c1

Procedure:
A solution of ethyl 2-(4-phthalimidobutyl)-benzofuran-6-carboxylate (3.9 g., 0.01 mole) and hydrazine hydrate (0.55 g., 0.011 mole) in ethanol (20 ml.) is heated at 60° C. for 8 hours. The solvent is evaporated at reduced pressure. The solid residue is treated with water and 5 N sodium hydroxide solution and then is extracted with chloroform. The evaporation of the solvent from the organic extract provides ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=2)O1>>[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:34]3[CH:35]=[N:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=3)=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cnc(C#N)nc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (87 mg, 0.24 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (83 mg, 0.36 mmol) to afford the desired product (24 mg, 23%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.62 (s, 2H), 9.23 (s, 1H), 8.68 (d, J=8.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 5.52-5.41 (m, 1H), 3.12 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.77 (s, 3H), 2.51-2.42 (m, 2H), 2.08-1.94 (m, 3H), 1.88-1.65 (m, 2H), 1.37-1.25 (m, 2H); ESI MS m/z 430 [M+H]+; HPLC>99% (AUC), tR=8.73 min.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:13][C:14]1[C:15]([C:20](OC)=[O:21])=[N:16][CH:17]=[CH:18][N:19]=1>CO>[CH3:9][O:8][C:6]([C:5]1[C:4](=[O:11])[NH:13][C:14]2=[N:19][CH:18]=[CH:17][N:16]=[C:15]2[C:20]=1[OH:21])=[O:7]
Reactant: COC(=O)c1nccnc1N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2nccnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (6.5 ml) (30% by weight in methanol) was dissolved in methanol (75 ml) at room temperature. Dimethyl malonate (3.7 ml) was added dropwise at ambient temperature over a period of 20 minutes and the reaction stirred at ambient temperature for 1 hour. Methyl 3-aminopyrazine-2-carboxylate (5.0 g) was added in portions at ambient temperature over a period of 40 minutes. The reaction mixture was heated to reflux for 3 days, and then allowed to cool. The solvent was concentrated. The residue was dissolved in water and acidified with concentrated hydrochloric acid (36% by weight in water). The precipitate was isolated, washed with water, methanol and ethyl acetate, and dried under high vacuum to give 8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as a beige solid (4.16 g). 1H-NMR (d6-DMSO): 3.80 (s, 3H), 8.59 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]2)=[CH:15][CH:14]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](Sc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of methyl cis-4-hydroxycyclohexanecarboxylate (500 mg, 3.16 mmol) in toluene (30 mL), 4-chlorobenzenethiol (457 mg, 3.16 mmol) and cyanomethylenetributylphosphorane (915 mg, 3.16 mmol) were added, and the resulting mixture was stirred at 100° C. for 2 hours. Then, the residue obtained by distilling off the solvent in the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 85:15 (v/v)), whereby the title compound was obtained as an oil (206 mg, yield: 26%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[N:7][N:6]2[C:15]=1[CH:16]([CH3:18])[CH3:17]>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH:16]([C:15]1[N:6]2[N:7]=[CH:8][C:9]3[C:14]([C:5]2=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]=1[CH:2]=[O:1])=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:18])[CH3:17]
Reactant: CC(C)c1c(CO)c(-c2ccccc2)c2c3ccccc3cnn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CC(C)c1c(C=O)c(-c2ccccc2)c2c3ccccc3cnn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 2-hydroxymethyl-3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine (1.22 g) and activated manganese dioxide (18 g) in diethyl ether (200 ml) was stirred at the ambient temperature under an atmosphere of argon for 24 hours. The suspension was then filtered and the solid was extracted with diethyl ether (3×50 ml). The extracts and filtrate were combined and evaporated, and the resulting residue was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (8 ml; 3:1 v/v), to give 3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine-2carboxaldehyde (0.88 g) in the form of a yellow solid, m.p. 163°-164° C. [Elemental analysis: C, 80.4; H, 5.78; N, 8.8%; calculated: C, 80.2; H, 5.77; N, 8.9%; NMR (in CDCl3): 1.52 (6H, d, J=7 Hz), 4.41 (1H, septet, J=7 Hz), 7.30-7.35 (3H, m), 7.42-7.50 (5H, m), 7.58-7.66 (1H, m), 8.34 (1H, s), 9.83 (1H, s); Mass spectrum (electron impact) m/z=314].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CCN
Product: CCNc1ccc([N+](=O)[O-])nc1
Yield: 97 %

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine was reacted with ethylamine to give 5-ethylamino-2-nitropyridine in 97% yield; 1H NMR: (DMSOd6) 1.96 (t, 3H), 3.21 (m, 2H), 7.05 (m, 1H), 7.4 (br s, 1H), 7.87 (m, 1H), 8.12 (m, 1H); Mass Spectrum: M+H+ 168; which in turn was converted into 5-(N-tert-butoxycarbonyl-N-ethylamino)-2-nitropyridine in 81% yield; 1H NMR: (CDCl3) 1.27 (t, 3H), 1.5 (s, 9H), 3.82 (m, 2H), 7.94 (m, 1H), 8.24 (m, 1H), 8.54 (m, 1H); Mass Spectrum: M+H+ 268; which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-ethylamino)pyridine in 59% yield; 1H NMR: (CDCl3) 1.12 (t, 3H), 1.4 (br s, 9H), 3.58 (q, 2H), 6.48 (d, 1H), 7.24 (m, 1H), 7.89 (m, 1H); Mass Spectrum: M+H+ 238; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-ethylamino)pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy) phenyl]acetamide; Mass Spectrum: M+H+ 560.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.COCCOC.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])(O)=O.[Na+]>O.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>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[C:3]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][C:5](=[O:14])[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[CH:31]=[N:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1cc(Oc2ccccc2)c(Br)nn1-c1ccccc1
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: O
Product: Cn1cc(-c2nn(-c3ccccc3)c(=O)cc2Oc2ccccc2)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
To a stirred mixture of 6-bromo-5-phenoxy-2-phenylpyridazin-3(2H)-one (see Example 2) (207 mg, 0.60 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and degassed DME (9 mL), 1-methylpyrazole-4-boronic acid pinacol ester (150 mg, 0.72 mmol), and subsequently, a solution of NaHCO3 (102 mg, 1.2 mmol) in H2O (2.1 mL) were added. The reaction mixture was heated with vigorous stirring under Ar atmosphere at 80° C. for 12 h. The mixture was then evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane:EtOAc=1:1) to yield the desired compound as a white crystalline solid (61 mg, 29%). Mp 195-197° C., 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H, CH3), 6.10 (s, 1H, H-4), 7.20 (d, 2H, J=7.6 Hz, C6H5), 7.33-7.55 (m, 6H, 2×C6H5), 7.64 (d, 2H, J=7.6 Hz, C6H5), 8.03 (s, 1H, NCH), 8.11 (s, 1H, NCH) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]2=[O:34])=[N:24][C:23]=1[CH3:35])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][O:33][C:30]1[CH:31]=[CH:32][N:27]([C:25]2[S:26][C:22]([C:20]([NH:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])=[C:23]([CH3:35])[N:24]=2)[C:28](=[O:34])[CH:29]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCc1nc2ccccc2s1
Product: Cc1nc(-n2ccc(OCc3nc4ccccc4s3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 14 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(bromomethyl)benzo[d]thiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.9 Hz, 1H), 8.66 (d, J=8.1 Hz, 1H), 8.13-8.11 (m, 1H), 8.03-8.00 (m, 1H), 7.55-7.42 (m, 2H), 7.34-7.18 (m, 5H), 6.48 (dd, J=8.1, 2.7 Hz, 1H), 6.34 (d, J=2.7 Hz, 1H), 5.68 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 489.1 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1)([O-:13])=[O:12]
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Temperature: 25 °C

Procedure:
4-(2-Nitro-phenyl)-thiazol-2-ylamine was prepared as follows: 2-Bromo-2′-nitroacetophenone (1.75 g, 7.2 mmol) was mixed with 50 mL of absolute EtOH along with thiourea (1.09 g, 14.4 mmol) and stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was basified with 20 mL of 1 N aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-(2-nitro-phenyl)-thiazol-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11]([NH2:13])=[O:12])=[N:8][C:4]=2[CH:3]=1>COC(OC)N(C)C>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:7]([C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](/[N:13]=[C:5](/[N:6]([CH3:18])[CH3:7])\[CH3:4])=[O:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2C(N)=O)nc2cc(Br)ccc21
Agent: COC(OC)N(C)C
Product: C/C(=N\C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C)N(C)C
Temperature: 110 °C
Reaction time: 5 h
Yield: 199.8 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzamide (400 mg, 1.075 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL). The reaction mixture is stirred at 110° C. for 5 hours. The reaction mixture is concentrated to remove all volatile material to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-eth-(E)-ylidene]-benzamide (474 mg, 100%) ready for next step. LCMS (ESMS): m/z 441.71, 443.71 (M++1)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][N:6]([CH2:8][CH2:9][CH2:10]N)[CH3:7]>>[CH3:7][N:6]([CH3:5])[CH2:8][CH2:9][CH2:10][N:1]([CH2:10][CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])[C:2]([NH2:4])=[S:3]
Reactant: CN(C)CCCN
Reactant: NC(N)=S
Product: CN(C)CCCN(CCCN(C)C)C(N)=S
Temperature: 145 °C

Procedure:
N,N-bis(3-(dimethylamino)propyl)thiourea was prepared as follows: To a reaction kettle was added 152.2 g (2 moles) thiourea and 449.6 g (4.4 moles) dimethylaminopropylamine and heated to about 145° C. for 10 hours. Thereafter, excess amine was stripped from the reaction mass, The resulting product was a clear amber liquid with a Brookfield viscosity of 2,500 cps at 25° C. using spindle #3 at 12 rpm.
Reaction SMILES: Cl[C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[O:21]2)[CH2:17][CH2:16]1.O>CN1C(=O)CCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22](=[O:29])[O:21]4)[CH2:17][CH2:16]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1OC2(CCN(c3nc4cc(C(F)(F)F)cnc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine (0.1 g, 0.45 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.2 g, 0.90 mmol) in dry NMP (5 mL) at 100° C. for 10 hours. Pour the cooled mixture into water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by preparative TLC (4% MeOH—CH2Cl2) to obtain 1′-(6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(-c2nc3cc(OC)cc(CO)c3o2)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 20, step e (Route b), from 5-methoxy-7-(hydroxymethyl)-2-(4-methoxyphenyl)-1,3-benzoxazole with prolonged stirring in the presence of boron tribromide, and was obtained as a light brown solid, m.p. 250–260° C. (dec); MS m/e 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1SC.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c1=O
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (30, 1.50 g, 5.0 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.500 g, 7.50 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 130° C. for 14 h. The mixture was separated by silica gel column, and eluted with 10-50% ethyl acetate in petroleum ether to give (R)-tert-butyl 1-(4-(2-chloro-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-ylpiperidin-3-ylcarbamate (31). MS: m/z, 396 (100%, M-56), 398 (35%), 452 (100%, M+1), 454 (35%), 474 (70%, M+23), 476 (25%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][C:10]3([CH2:14][NH:13][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:14][N:13]([CH:17]4[CH2:18][O:15][CH2:16]4)[CH2:12]3)[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1COC1
Reactant: Ic1ccc(N2CC3(CNC3)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Ic1ccc(N2CC3(C2)CN(C2COC2)C3)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(4-Iodophenyl)-2,6-diazaspiro[3.3]heptane (1.01 g, 3.4 mmol), and 3-oxetanone (0.29 g, 4.0 mmol) was dissolved in DCE (15 mL) and heated to 50° C. for 10 min. Acetic acid (5 drops) and NaBH(OAc)3 (1.07 g, 5.1 mmol) was added and the reaction was stirred for 16 h at 50° C. The mixture was concentrated under reduced pressure and suspended in NaHCO3 (50 mL) and extracted with EtOAc (2×40 mL) and washed with brine. The EtOAc layer was dried (MgSO4), and concentrated to dryness to give the title compound as a white solid (1.15 g, 96%). MS ESI 357.0 [M+H]+, calcd for [C14H17IN2O+H]+357.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C1NCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Yield: 79.1 %

Procedure:
5-Bromo-2,3-dihydro-isoindol-1-one (1.0 g, 4.72 mmol), 1-bromomethyl-4-methyl-benzene (1.14 g, 6.14 mmol) and cesium carbonate (3.08 g, 9.44 mmol) were suspended in anhydrous NMP (10 mL). The mixture was immersed in a 60° C. oil bath for 16.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Column chromatography (20% to 40% ethyl acetate/hexanes) provided the title compound as a yellow solid (1.18 g, 79%). 1H NMR CDCl3: 7.76 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 4.76 (s, 2H), 4.24 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[BH4-].[Na+].C(O)(=O)C.O>CO>[OH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[CH3:1]
Reactant: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1O
Reaction time: 0.5 h

Procedure:
To a suspension of 5-[4-(1-methyl-2-oxocyclohexylmethoxy)benzyl]thiazolidine-2,4-dione (5.2 g) in methanol (50 ml), sodium borohydride (0.757 g) was added under ice cooling. The mixture was stirred with ice cooling for 30 minutes, then acetic acid (2 ml) was added. The mixture was poured into water and extracted with benzene. The extract was washed with water and dried (MgSO4). The benzene was distilled off, and the oily residue was subjected to silica gel (100 g) column chromatography. From the benzene-acetone (10:1, v/v) eluate fractions, 5-[4-(2-hydroxy-1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione was obtained as a powder (4.2 g, 80.8%). m.p. 101°-103° C. The thus-obtained powder was a mixture of two isomers different in the configuration of the hydroxyl group on the cyclohexane ring.