Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>O1CCCC1>[NH:14]([C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)[NH2:15]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(NN)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 137.4 %

Procedure:
A To a stirred solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (10.00 g, 40.00 mmol) in tetrahydrofuran (125 mL), was added hydrazine monohydrate (6.01 g, 120.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo to dryness. The residue was purified by column chromatography to afford ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate as a white solid (11.06 g, 91%): 1H NMR (300 MHz, DMSO-d6) δ 5.02 (s, 2H), 4.13 (q, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J=6.0 Hz, 3H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Br)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
The product from Step 2 (7.55 g, 26.8 mmol) in THF (80 mL) and triethylamine (3.7 mL, 26.8 mmol) was treated with aniline (2.6 g, 27.9 mmol) and allowed to stir at rt until the reaction was judged complete by TLC. The solvent was removed in vacuo and the residue dissolved in ethyl acetate, washed (3×) with water and brinde, dried over Na2SO4 and concentrated in vacuo to afford the title compound (7.65 g, 97%). MS (ES+) m/e 294/296 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cnc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cnc(C)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylpyridine-3-carboxylate obtained in Example (171b) (113 mg, 0.4 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (64 mg, 0.37 mmol), WSC hydrochloride (211 mg, 1.1 mmol) and HOBt (49.7 mg, 0.37 mmol), to obtain 18.0 mg of the title compound as a pale yellow oily substance (11%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][N:21]=1>>[CH3:27][N:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:25]=1)[CH3:28]
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Reactant: CN(C)c1ccnc(Cl)n1
Product: CC(=O)NCc1ccc(CN2CCN(c3nccc(N(C)C)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide obtained in Example 78(2) instead of N-(4-chloromethylphenylmethyl)acetamide and 2-chloro-4-(N,N-dimethylamino)pyrimidine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=152-155° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A mixture of 4-fluoronitrobenzene (7.05 g), 4-pyridylpiperazine (8.15 g), anhydrous sodium bicarbonate (10.0 g) and dry N,N-dimethylformamide (100 ml) was heated under reflux with stirring for 3 hours and then cooled and poured into water. The solid was filtered off, washed with water and crystallised from ethanol to give 1-(4-nitrophenyl)-4-(4-pyridyl)piperazine (7.34 g), m.p. 213°-216° C. Further recrystallisation raised the m.p. to 219°-221° C. Found: C,63.76; H,5.85; N,19.96. C15H16N4O2 requires: C,63.36; H,5.67; N,19.71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:8]1=[O:28]
Reactant: COc1ccc(CC2(CCOS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(OC)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 18.5 using 1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.5 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.74 g, 1.5 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.17 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[N:16]([CH2:34][CH2:35][O:36]C2CCCCO2)[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2.Cl>CO.O1CCCC1>[CH:24]1([C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:20][CH:21]=3)[N:16]([CH2:34][CH2:35][OH:36])[C:15]=2[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[OH:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COCOc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2CCOC2CCCCO2)c(OCOC)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(O)cc3O)n(CCO)c2c1
Reaction time: 10 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate in methanol (525 ml) and tetrahydrofuran (30 ml) was added 6N hydrochloric acid (105 ml) and the mixture was stirred for 10 hr. The reaction mixture was concentrated and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give methyl 3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-indole-6-carboxylate (10.3 g, yield 68%).
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])OC)[S:3][CH3:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1.[Na]>C(Cl)Cl.CO>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([N:18]2[C:19](=[O:20])[NH:1][CH:2]([S:3][CH3:4])[NH:5][C:6]2=[O:9])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)N=C(N)SC
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CSC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
Methyl N-[1-(amino)-1-(methylthio)methylene]carbamate (14.8 g.) was dissolved in methylene chloride (150 ml.). 3-Trifluoromethylphenyl isocyanate (18.7 g.) was added to the solution during 5 minutes and the mixture was stirred at room temperature for 2.5 hours. A freshly prepared solution of sodium (2.3 g.) in methanol (20 ml.) was then added during 5 minutes and the subsequent mixture was stirred at room temperature for 16 hours. The mixture was then evaporated and the residue was dissolved in water (400 ml.). The aqueous solution obtained, was extracted with ethyl acetate (2×400 ml.) to remove neutral byproducts, and then acidified with concentrated hydrochloric acid to pH1. The solid which precipitated was separated by filtration, washed with water (3×500 ml.), and dried (over phosphorus pentoxide) to give 3-(3-trifluoromethylphenyl)-6-methylthio-tetrahydro-1,3,5-triazine-2,4-dione (25.9 g., 86%) as a white solid, m.p. 225°-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].I[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>O.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1

Procedure:
A solution of 6.0 g of 4-chlorothiophenol and 8.0 g of potassium hydroxide in 80 ml of water is heated to 50° C. and 0.8 g of copper powder and 10.4 g of 4-iodophenylacetic acid are added. The mixture is heated to reflux and maintained at reflux overnight. The mixture is then cooled and filtered. The filtrate is acidified with concentrated HCl to give a white solid which, on recrystallization from methanol, yields cream colored plates, mp 135°-140° C. A sample is recrystallized from chloroform-hexane to give white plates, mp 144.5°-148° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)=O.[OH-].[Na+]>CCCCCC.C1COCC1>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(CSC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
0.8 g (0.02 mol) of sodium hydride (60% dispersion in oil) was washed three times with hexane and suspended in 20 ml of THF. 2.24 ml (0.019 mol) of benzyl mercaptan in 12 ml of THF were added dropwise at 0°. The mixture was stirred at room temperature for 15 min. and subsequently 0.95 g (0.0037 mol) of 1-benzylpiperidin-4-yl methanesulfonate in 10 ml of THF was added dropwise. The reaction mixture was boiled at reflux for 22 hrs. and then poured into 200 ml of 2N aqueous NaOH. The inorganic phase was extracted with ether and the combined organic phases were washed with 2N aqueous NaOH and dried over magnesium sulfate. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:1) as the eluent. 0.444 g (40%) of 1-benzyl-4-benzylsulfanylpiperidine was obtained as a yellow oil. MS: me/e (% basic peak)=297 (C19H23 NS+, 1.4), 206 (62), 174 (23), 91 (199).
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[CH:14]3[CH2:15][C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]5[O:23][C@H:9]6[C:10]7[NH:31][C:30]8[C:25](=[C:26]([N:32]=[C:33]([NH2:35])[NH2:34])[CH:27]=[CH:28][CH:29]=8)[C:11]=7[CH2:12][C@:13]3([OH:24])[C@:8]6([C:17]=45)[CH2:7][CH2:6]2)[CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:2]1[CH:3]([CH2:4][N:5]2[CH:14]3[CH2:15][C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]5[O:23][C@H:9]6[C:10]7[NH:31][C:30]8[CH:25]=[C:26]([N:32]=[C:33]([NH2:35])[NH2:34])[CH:27]=[CH:28][C:29]=8[C:11]=7[CH2:12][C@:13]3([OH:24])[C@:8]6([C:17]=45)[CH2:7][CH2:6]2)[CH2:1]1
Reactant: NC(N)=Nc1cccc2[nH]c3c(c12)C[C@@]1(O)C2Cc4ccc(O)c5c4[C@@]1(CCN2CC1CC1)[C@H]3O5
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(N)=Nc1ccc2c3c([nH]c2c1)[C@@H]1Oc2c(O)ccc4c2[C@@]12CCN(CC1CC1)C(C4)[C@]2(O)C3
Temperature: 25 °C
Reaction time: 36 h
Yield: 74 %

Procedure:
Compound 6b (500 mg, 0.75 mmol) was dissolved in a mixture of TFA (3.0 mL) and dried CH2Cl2 (28 mL) and allowed to stir under N2 atmosphere at room temperature for 36 h. The reaction was worked up according to the procedure for compound 4a and purified by preparative TLC to give 4b (260 mg, 74%) as a free base; IR KBr disk υ (cm−1): 3450–3150 (br), 1683 (s), 1506, 1463, 1433, 1330, 1202, 1132; 1H NMR (DMSO-d6): δ 11.50 (s, 1H, NH), 9.96 (s, 11H, NH), 9.29 (s, 1H, NH), 8.95 (s, 1H, Ar—OH), 7.36–7.09 (m, 3H, ArH and NH2), 6.77 (d, 1H, J=8.10 Hz, ArH), 6.59–6.52 (m, 2H, ArH), 6.39 (s, 1H), 5.67 (s, 1H, 5-H), 4.05 (b, 1H, 14-OH), 3.43–3.23 (m, 3H), 3.18–3.06 (m, 2H), 2.96–2.91 (m, 2H), 2.68–2.57 (m, 2H), 2.50 (m, 1H), 1.78 (d, 1H, J=11.7 Hz), 1.05 (m, 1H), 0.68 (m, 1H), 0.58 (m, 1H), 0.40 (m, 2H). HRMS (FAB) m/z 472.2356 (M+H)+, C27H29N5O3 requires 471.2270.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1>>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]4)[C:3]([F:25])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:28]=[C:27]([I:26])[C:35]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Product: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 139 step 5, with racemic tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate from Example 139 Step 4 and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as starting materials. LCMS calculated for C23H28ClFIN6O3 (M+H)+: m/z=617.1; Found:617.1
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH:11]([N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I-].[Na+].Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C)C=O.C(O)(=O)C>[CH:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:12](=[O:20])[CH:11]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1Nc2ccccc2C(C2CCCCC2)=NC1N1C(=O)c2ccccc2C1=O
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(C2CCCCC2)c2ccccc2N1Cc1ccccn1
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (54 mg of a 64% dispersion of mineral oil) in N,N-dimethylformamide (3 ml) was added slowly (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1H-1,4-benzo-diazepin-2-one (0.50 g) at ambient temperature and the mixture was stirred for 2 hours under the same condition. To the mixture was added sodium iodide (0.213 g) and followed dropwise a solution of 2-chloromethylpyridine (0.213 g) at the same temperature. The mixture was stirred overnight at ambient temperature To the mixture was added acetic acid (0.4 ml) and stirred for 10 minutes. The resultant mixture was concentrated in vacuo and the residue was taken up with ethyl acetate and water. The aqueous layer was alkalined with sodium carbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude compound was purified by column chromatography on silica gel with a mixture of chloroform and methanol to give (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20]CC)=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[OH-].[K+]>C(O)C.O>[C:24]([NH:23][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:27])([CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:18]([OH:20])=[O:19])(=[O:26])[CH3:25]
Reactant: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)O
Yield: 90 %

Procedure:
Ex-8e) Following the procedure described in Tetrahedron Lett Vol.21, 4263, (1980) partial saponification of 10.2 g of ethyl-2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoate is carried out in ethanol with 1.5 equivalent of KOH in water at 20-25° C. for 3 h to give 2-Acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoic acid in 90% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:21])=[N:18][C:19]=1[CH3:20]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:21][C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[C:19]([CH3:20])[N:18]=2)[CH:7]=1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1nc(N)ccc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(Cl)c(C)n1
Temperature: 130 °C
Reaction time: 36 h
Yield: 20.4 %

Procedure:
A pressure tube was charged with methyl 4,6-dichloropyridazine-3-carboxylate (2 g, 9.66 mmol) and 5-chloro-6-methylpyridin-2-amine (2.76 g, 19.3 mmol). To the mixture was added acetonitrile (12 mL) and the reaction mixture heated with stirring at 130° C. for 1.5 days. After cooling to room temperature, the acetonitrile was removed in vacuo. The residue obtained was purified by chromatography (silica, 80 g, 50 μm from Analogix, 0% to 5% acetone in dichloromethane over 20 min., holding at 5% for 5 min, then increasing the gradient from 5% to 10% over the next 20 min) to give methyl 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (618 mg, 20%) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.70 (br. s., 1H), 9.18 (s, 1H), 7.63 (d, J=8.34 Hz, 1H), 6.78 (d, J=8.34 Hz, 1H), 4.12 (s, 3H), 2.66 (s, 3H), 1.58 (br. s., 1H); LC-MS 313 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[NH:3]1.[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[N:18]([C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[N:10]3)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc2[nH]c(=O)cnc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)cnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C[O:11][C:12](=[O:41])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3Br)[CH:23]=2)=[CH:17][C:16]=1[CH3:40]>>[CH3:40][C:16]1[CH:17]=[C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:30]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:23]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:12]([OH:41])=[O:11]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccnc1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 3-pyridyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 277 mg (88%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H22NO4F3 493, found 494 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(C)Cc1ccc(C(=O)Cc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A solution of the product from step (b) (11.1 g) in trifluoroacetic acid (16 ml) was stirred at room temperature and triethylsilane (12.5 ml) added. The mixture was stirred overnight at room temperature, followed by 3 hours at 50° C. during which further portions of triethylsilane (3 ml each) were added after 1.5 hours and 2.5 hours, then poured into water (250 ml). The latter was extracted with ether (×2) and the combined extracts washed with water (×2), dried over MgSO4, and evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (1:4v/v). The eluate was evaporated under reduced pressure to give 11.0 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Br:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2Br)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2Br)CC1)c1ccccc1
Yield: 70.8 %

Procedure:
0.108 g (0.0004 mol) of 1-(2-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.106 g (71%) of 1-(2-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:7](C(O)=O)=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2
Reactant: O=C(O)c1c[nH]c2cn[nH]c2c1=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2cn[nH]c12

Procedure:
4,7-Dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-6-carboxylic acid (7.0 g, 39 mmol) was suspended in Dowtherm A (250 ml) and the mixture was heated under reflux under nitrogen for 2.5 h. After cooling, the mixture was diluted with 60°-80° petrol and filtered. The precipitate was washed well with petrol and dried to give the crude product as an off-white solid (3.9 g, 74%). Recrystallisation from aqueous ethanol/ether gave the title compound as very fine needles, m.p. >320° C.