Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(=O)CC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C:16]([C:15]1[CH:20]=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:19]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COc1ccc(C(=O)COc2cccc(OC)c2)cc1
Temperature: 80 °C

Procedure:
In a one liter round-bottom flask, fitted with a condenser and nitrogen inlet, were added 3-methoxyphenol (12.4 g, 0.1 mole), 4-methoxyphenacyl bromide (22.9 g, 0.1 mole), potassium carbonate (17.3 g, 0.125 mole) in 100 ml of 2-butanone. This mixture was heated to 80° C. and was maintained at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography (silica gel, 9:1 toluene:ethyl acetate).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14][CH:13]=3)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[CH:23]1([C:29]([OH:38])([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[C:30]([OH:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([C@@:29]([OH:38])([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[C:30]([OH:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14][CH:13]=3)[N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(O)C(O)(c1cccs1)C1CCCCC1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(O)[C@](O)(c1cccs1)C1CCCCC1
Temperature: 65 °C

Procedure:
L-cinchonidine (30.2 g, 0.103 mol) is added to crude cyclohexyl-hydroxy-thiophen-2-yl-acetic acid (49.3 g, 103 mol assuming 50% purity of crude) followed by toluene (2.2 litres) and the mixture is heated to reflux for 70 minutes. The resulting solution is allowed to cool slowly and at 65° C., the solution is seeded. After further cooling to 40° C., the solution is placed in the fridge overnight. The resulting solid is filtered, washed with toluene and dried in vacuo. The recrystallisation process from toluene is repeated for a second time with seeding occurring at 85° C. to afford the titled compound as a salt of L-cinchonidine in 98% enantiomeric excess. The salt is added to a stirred mixture of 1M HCl (40 ml) and diethyl ether (500 ml) and stirring continues until a solution forms. The organic portion is separated, washed with brine (400 ml), dried over MgSO4 and concentrated in vacuo to give the titled compound in 98% enantiomeric excess.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH2:29][CH3:30]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:28][CH2:29][CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
tert-Butyl 4-((benzyloxycarbonylamino)methyl)piperidine-1-carboxylate (0.950 g, 2.726 mmol) was dissolved in dry DMF (25 mls). To this was added sodium hydride (0.164 g, 4.090 mmole, 60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 30 minutes. Propyl iodide (0.695 g, 4.090 mmole) was then added and the mixture stirred at room temperature for 16 hours, then diluted with brine (200 mls), extracted twice with EtOAc, extracts washed twice with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (100 g Biotage Snap cartridge, 30% EtOAc/Hexanes) to give 0.280 g (26%) of the title compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(O)(C)C.N.[Li]>C1COCC1>[CH2:1]([OH:9])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC#CCCO
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCC/C=C/CCO
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of oct-3-yn-1-ol (2.52 g, 20.0 mmol), t-BuOH (5 g), THF (10 mL) and liquid NH3 was cooled to −36° C. Pieces of Lithium (0.34 g, 50 mmol) were introduced with vigorous stirrng and maintaining the temperature. After 2 h, NH3 was allowed to evaporate overnight. Saturated NH4Cl solution was added and the reaction mixture was extracted with hexane. The combined organic layers were washed with 1 M HCl, aqueous NaHCO3 and brine successively and dried. Evaporation of the solvent gave trans-oct-3-en-1-ol (2.44 g, 95%) as a pale yellow oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 5.54 (1H, m), 5.36 (1H, m), 3.66 (2H, t, J=6.3 Hz), 2.25 (2H, m), 2.02 (2H, m), 1.74 (1H, br s), 1.31 (4H, m), 0.88 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 134.27, 125.78, 62.22, 36.22, 32.59, 31.86, 22.47, 14.20.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCO>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:8]=2)[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccc(-c2nc(Br)cs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Brc1csc(-c2ccnc(N3CCOCC3)n2)n1
Temperature: 90 °C
Yield: 30.6 %

Procedure:
To a solution of 4-(4-Bromo-thiazol-2-yl)-2-chloro-pyrimidine (25)(0.498 g, 1.8 mmol) in EtOH (8 ml) was added powdered potassium carbonate (0.274 g, 1.98 mmol) and morpholine (0.17 ml, 1.98 mmol). The mixture was heated under the influence of microwave radiation (10 minutes, 90° C., high absorption setting). The reaction mixture was then allowed to cool to room temperature and filtered through a thin pad of silica before being concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2) using Hexanes:EtOAc—(9:1) as eluent to give the title compound (0.18 g, 30.5%) in analytically pure form. m/z (LC-MS, ESP): 327 [M+H]+, R/T=3.92 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[N:9]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:13]([C:11]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:12][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]1)=[O:14]
Reactant: Fc1ccc(Cl)cn1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc(Cl)cn2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-chloro-2-fluoropyridine (0.5 g, 3.8 mmol, Eq: 1.00) and 1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate (818 mg, 3.8 mmol, Eq: 1.00) in toluene (5 ml) was added dropwise at 0° C. for 15 min a 0.5 M solution of KHMDS (7.6 ml, 3.8 mmol, Eq: 1.00) in toluene. The colorless solution turned into yellow-orange. After stirring at 0° C. for 45 min, the reaction mixture was allowed to warm to 20° C. and stirred for 2.5 h. A saturated aqueous NH4Cl solution (50 ml) was added and the aqueous phase was extracted with AcOEt (2×75 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 60% AcOEt in heptane) to yield a colorless gum (0.234 g; 19%). m/z=327.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39](Cl)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26]
Reactant: CCOC(=O)CCNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.594 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (370:30:4). The desired fraction was collected and recrystallized from ethyl ether to yield 0.347 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][CH2:8][C:9]([OH:11])=[O:10].NN.C([O-])([O-])=O.[K+].[K+].C(O)COCCO>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1cccs1
Temperature: 190 °C
Yield: 84.7 %

Procedure:
3.6 g (0.019 mol) of 4-(2-thienyl)-4-keto-butyric acid, 2.74 ml (0.07 mol) of hydrazine 98%, 3.69 g (0.066 mol) of potash and 42 ml of diethylene glycol are placed in a two-necked flask equipped with a magnetic stirrer. The medium is heated for 7 h at 190° C. The medium is a clear uniform yellow. When it has cooled to room temperature it is hydrolysed with 200 ml of water. The diethylene glycol is extracted with 5 times 100 ml of ether. The aqueous phase is then acidified to pH 1 and extracted. The acid is absorbed in a solution of soda 5% washed with ether then acidified and absorbed for the last time in ether which is dried over MgSO4 and concentrated. 2.74 g of a clear yellow oil is obtained. Yield=85%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][N:11]([C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCC(C)c3ccccc3N(Cc3ccccc3)C(=O)C2)c1

Procedure:
A solution of 1-benzyl-7-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (96 mg, 0.33 mmol) and 3-methylphenylisocyanate (47 μl, 0.36 mmol) was stirred in dioxan (2 ml) at room temperature for 2 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (1:2) as eluant gave the product. (102 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:17]([CH3:16])[NH2:18])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: CNN
Solvent: CCO
Product: Cc1nc(N(C)N)nnc1-c1ccccc1
Yield: 70.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (20 g) and methylhydrazine (15.3 g) in ethanol (30 ml) was heated under reflux for 66 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with water and brine successively, dried over sodium sulfate, and then evaporated. The residue was crystallized with diethyl ether, washed with diethyl ether, and dried to give 5-methyl-3-(1-methylhydrazino)-6-phenyl-1,2,4-triazine (13.91 g).
Reaction SMILES: [C:1]([CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19].C(=O)([O-])O.[Na+]>C(O)C>[CH3:16][C:15]1[NH:19][N:18]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of ethyl 2-isonicotinoyl-3-oxobutanoate (8.0 g) in ethanol (80 mL) was added hydrazine (1.7 g), and the mixture was stirred at room temperature for 1 hr, and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.4 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:35]>CO>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:35]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
3.65 g of Z-Ile-Phe-OBut are dissolved in 100 ml of methanol and subjected to catalytic hydrogenation at pH 4.5 after adding Pd-on-BaSO4 and 2 N methanolic hydrochloric acid. After the reaction is complete the catalyst is filtered off and the filtrate is concentrated. The residue crystallizes on being triturated with ether. Yield 2.57 g, melting point 107°-109°, [α]D24 =+15.9° (c=1, in methanol).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14](OC(C)(C)C)=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.7 %

Procedure:
LiAlH4 (378 mg, 10.0 mmol) was added at −15° C. to a solution of tert-butyl 2-(4-fluorophenoxy)acetate (2.03 g, 9.00 mmol) in tetrahydrofuran (10 ml) and stirred at room temperature for 20 minutes. Aqueous 15% NaOH solution (2 ml), Na2SO4 (2.84 g) and H2O (6 ml) were added to the reaction mixture and stirred for 1 hour. The resulting precipitation was filtered off and washed with tetrahydrofuran (30 ml×3). The filtrate was dried over Na2SO4, filtered and concentrated in vacuo to give 2-(4-fluorophenoxy)ethanol (1.12 g, 80%) as yellow oil: LC-MS: 157 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)nc1
Reaction time: 8 h

Procedure:
To a solution of the tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2 in DCM (3.0 mL) was added trifluoroacetic acid (1.0 mL) and the solution was stirred overnight. The reaction mixture was concentrated, redistributed between ethyl acetate and 5% Na2CO3 solution and the organic phase dried over Na2SO4. Concentration with rotavap gave crude N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-6-(piperazin-1-yl)nicotinamide 46-3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture containing 2,4-dinitrophenylacetic acid (100 g, 0.442 mol), concentrated sulfuric acid (1.5 mL) and ethanol (700 mL) is heated at reflux for 61/2 hours, cooled to room temperature and filtered. The filtrate is concentrated in vacuo to a volume of 200 mL then diluted with water. The pH of the aqueous mixture is adjusted to about a with solid sodium hydrogen carbonate and extracted with ether. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, decolorized with charcoal and concentrated in vacuo to obtain the title compound as a yellow oil (102.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:32][C:33](=[O:34])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
a mixture of 4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (100 mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) and α-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambient temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (30 mL), dried (MgSO4) and condensed to give the desired product (129 mg, 96%) as a yellow oil: NMR δH(400 MHz; d6-DMSO) 1.40 (9H, s), 3.30–3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s), 5.54 (2H, s), 6.86–6.91 (2H, m), 7.20–7.26 (2H, m), 7.54–7.60 (2H, m) and 7.66–7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56 min).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[SH:12].Br[C:14]1[N:15]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:16]2[C:21]([N:22]=1)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=2>CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[S:12][C:14]1[N:15]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:16]2[C:21]([N:22]=1)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=2
Reactant: COc1ccc(I)c(S)c1
Reactant: CC(C)=CCCn1c(Br)nc2c(N)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)c(Sc2nc3c(N)ncnc3n2CCC=C(C)C)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (96 mg, 4 mmol) in DMF (3 ml) was added 2-iodo-5-methoxy-benzenethiol (1.06 g, 4 mmol; J Org. Chem, 2001, 66(13), 4525-4542). After 30 min, a solution of 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine (296 mg, 1 mmol) in DMF (3 ml) was added, and the mixture was stirred for 12 h at 70° C. The reaction was quenched by addition of MeOH (2 ml), diluted with EtOAc (200 ml), washed with Na2CO3 (3×50 ml), brine (3×50 ml), dried (Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2: MeOH=100:5) to give 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine as a colorless powder (280 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([C:30](=[O:32])[CH3:31])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 122.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.5 mg, 0.101 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 1-acetylpiperazin (54 mg, 0.42 mmol), acetic acid (0.116 mL, 2.03 mmol) and sodium triacetoxyborohydride (51 mg, 0.25 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-acetylpiperazin-1-ylmethyl)indol-2-yl]isoindolinone (64.7 mg).
Reaction SMILES: C1(CN2CCN(C3SC(C(O)=O)=CN=3)C2=O)CC1.[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([OH:41])=O)=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1>>[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([NH:52][CH2:51][C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)=[O:41])=[C:33]([C:35]([F:37])([F:36])[F:38])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Agent: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Product: O=C(NCc1cccnc1)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 37 %

Procedure:
Following the procedure as described in Example 26, making variations as required to replace 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 37% yield: mp 161-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.31-7.22 (m, 3H), 7.05-7.00 (m, 2H), 6.55-6.47 (m, 1H), 4.61 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 4.09-4.03 (m, 2H), 3.48-3.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.2, 160.9, 159.5, 159.0, 155.2, 149.2, 135.6, 132.9, 131.0, 130.1, 127.2, 123.7, 122.2, 118.6, 116.0, 47.3, 41.9, 41.6, 30.9; MS (ES+) m/z 480.5 (M+1).