Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1.O>O1CCCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:2][O:1][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1

Procedure:
1-Hydroxy-2-tetrahydropyranyloxy-2-(4-tert-butylphenyl)ethane (0.3 g, 1.07 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (30.96 mg, 1.29 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.175 g, 1.07 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:24][C:25]([O:27]C)=[O:26])[C:15]1[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=1.Cl>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:24][C:25]([OH:27])=[O:26])[C:15]1[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOc1ncccc1C1(CC(=O)OC)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 199.2 %

Procedure:
20 ml of water and 10 ml of 2N sodium hydroxide solution were added to a solution of 1.96 g (5.43 mmol) of methyl [5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate in 10 ml of ethanol. The reaction mixture was stirred at room temperature for 18 hours. The mixture was worked up by adjusting to pH 5 with 1N hydrochloric acid and then concentrating in a rotary evaporator. The residue was taken up in toluene and again evaporated to dryness, and the residue was dried in a vacuum drying oven. 3.75 g of crude product were obtained and were employed without further purification in the next stage.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:24]([O:23][P:22]([CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])([O:26][CH2:27][CH3:28])=[O:29])[CH3:25]
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of tert-butyl 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (2.91 g) and triethyl phosphite (3.20 g) was stirred at 160° C. for 15 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2-4:1, v/v) to give tert-butyl 4-{4-[(diethoxyphosphoryl)methyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate as a yellow oil (2.20 g, yield 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([OH:26])=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:25][C:24]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2)=[O:26]
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (170.00 mg, 0.465 mmol) was mixed with potassium carbonate (193.0 mg, 1.40 mmol) and methyl iodide (199.0 mg, 1.40 mmol) in DMF (2.0 mL) over a weekend. The reaction mixture was diluted with ethyl acetate, and washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:5]5[N:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1cc(C(=O)O)nn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1
Yield: 69.5 %

Procedure:
Using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (99 mg, 0.78 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 mL, 0.39 mmol), oxalyl chloride (135 μL, 1.55 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 119, the title compound (189 mg, 70%) was obtained as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[NH:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1.O>CN(C)C=O>[CH2:7]([N:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1)[CH3:8]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.9 %

Procedure:
3.7 g (26.8 mmoles) of anhydrous potassium carbonate and 4.2 g (26.6 mmoles) of ethyl iodide were added to a solution of 1.5 g (10.7 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 20hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.6 g (yield: 88.9%) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[C:5]#[N:6].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([CH3:20])[CH:13]=1.C([O:23][C:24](=O)[C:25](=[O:32])[CH2:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])C>C(O)(=O)C>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([N:1]2[C:24](=[O:23])[C:25]([OH:32])=[C:26]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:16]2[C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: N#Cc1cc(N)cc(Cl)c1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1cc(Cl)cc(C#N)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A mixture of 3-amino-5-chloro-benzonitrile (2.4 g, 15.7 mmol), 4-chloro-2-methyl-benzaldehyde (2.4 g, 15.7 mmol) and 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (2.9 g, 15.7 mmol) in acetic acid (15 mL) was stirred at 120° C. for 16 h. The reaction mixture was allowed to cool to rt, concentrated, diluted with acetonitrile (15 mL), and stirred for 4 h at rt. The resulting precipitate was collected by vacuum filtration and dried to afford 1.8 g of the title compound. tR: 6.50 min (HPLC 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.27 (hexane/EtOAc, 1:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.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>[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:20][C:15]=3[CH3:14])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: Cc1cc(OC(F)(F)F)ccc1B(O)O
Reactant: CC(C)c1nnc2ccc(Cl)nn12
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OC(F)(F)F)ccc1-c1ccc2nnc(C(C)C)n2n1

Procedure:
To a microwave reaction tube was added 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine prepared as described in Step 1 above (1.28 mmole), 2-methyl-4-(trifluoromethoxy)phenylboronic acid (1.40 mmole), tetrakis(triphenylphosphine)palladium (0.064 mmole), 2M Na2CO3 (1 mL), and DMF (3 mL). The resulting reaction mixture was heated in the microwave at 130 C for 10 min. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to afford 3-isopropyl-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23](Cl)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[O:33][C:34]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23]([C:38]2[CH:39]=[CH:40][C:34]4[O:33][C:32]([NH2:31])=[N:36][C:35]=4[CH:37]=2)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Yield: 37.2 %

Procedure:
Tert-butyl(1-(4-(6-chloro-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (20) (190 mg, 0.44 mmol, 1.0 eq) and (2-aminobenzo[d]oxazol-5-yl)boronic acid (94 mg, 0.53 mmol, 1.2 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). To this mixture, Pd(PPh3)4 (51 mg, 0.044 mmol, 0.1 eq) and sodium carbonate (140 mg, 1.32 mmol, 3.0 eq) were added sequentially. The resulting mixture was heated at reflux for 2 h with stirring under an argon atmosphere. The reaction was complete based on TLC analysis. The reaction mixture was concentrate in vacuo, and purified by silica gel column chromatography (1-5% MeOH—CH2Cl2) to afford the desired product, tert-butyl(1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-21) (87 mg, 37.2%) as a yellow solid. ESI-MS m/z: 532.22[M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[NH:18][C:17](=[S:19])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:15]1=[O:31].[C:39]([C:41]1[CH:50]=[CH:49][C:44]([C:45](=[O:48])[CH2:46]Br)=[CH:43][CH:42]=1)#[N:40]>C1COCC1>[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:15](=[O:31])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:17]([S:19][CH2:46][C:45]([C:44]2[CH:49]=[CH:50][C:41]([C:39]#[N:40])=[CH:42][CH:43]=2)=[O:48])=[N:18]1
Reactant: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)N=C2SCC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Potassium bis-(trimethylsilyl)amide (286 mg, 1.43 mMol) was dissolved in anhydrous THF (20 mL) under an atmosphere of dry N2. The mixture was cooled to -40° C. and then 5-(2-hydroxy-ethyl)-5-pyridin-4-ylmethyl-2-thioxo-3-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-4-one (548 mg, 1.37 mMol) was added. The mixture was warmed to ambient temperature and 4-cyanophenacyl bromide (350 mg, 1.43 mMol) was added. The reaction mixture was stirred for one hour after which time it was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give a red foam. The foam was chromatographed on flash silica gel eluting with EtOAc-hexanes (50:50) to give 700 mg of the titled compound as a yellow foam as a 1:1 mixture of diastereomers.
Reaction SMILES: [C@@H:1]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:21]=3[NH:32][C:33]([C:35]3[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=3)[C:38](O)=[O:39])=[O:34])[CH:15]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:44][NH:45][CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:44][N:45]([CH2:46][CH2:47][CH2:48][N:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([C:33]([NH:32][C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:25][C:20]=2[C:16]2[CH:15]=[C:14]([C:12](=[O:13])[NH:11][C@@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH:19]=[CH:18][N:17]=2)=[O:34])[CH:36]=1
Reactant: CNCCCN1CCOCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(CCCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+ (400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H).
Reaction SMILES: [CH3:1][I:2].[CH3:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1>C(#N)C>[I-:2].[OH:25][CH:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][S+:4]([CH3:1])[CH3:3])=[CH:13][CH:12]=1
Reactant: CSCCOc1ccc(OCC(O)COc2ccccc2)cc1
Reactant: CI
Solvent: CC#N
Product: C[S+](C)CCOc1ccc(OCC(O)COc2ccccc2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A 5 g quantity of methyl iodide was added to 3.34 g of 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyl methyl sulfide and 5 ml of acetonitrile. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was recrystallized from ethanol-ether, giving 4.45 g of 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyldimethylsulfonium iodide in 93.5% yield, M.P. 112° to 112.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][N:13](S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1.SCC(O)=O.O[Li].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][NH:13][CH2:12][CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(c3cc(F)ccc3F)=CC(c3ccccc3)C2)cc1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)CNC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,5-difluorophenyl)-1-[(4-nitrophenyl)sulfonyl]-3-phenyl-1,2,3,6-tetrahydropyridine (1-6, 140 mg, 0.31 mmol) was dissolved in DMF (2 mL) and treated sequentially with mercaptoacetic acid (113 mg, 1.2 mmol) and LiOH hydrate (140 mg, 2.4 mmol). The reaction stirred at 25° C. for 2 h until completion. The reaction was then diluted with EtOAc (20 mL), washed with H2O (3×100 mL) and NaCl (sat. aq.). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified using reverse-phase column chromatography (5-95% MeOH—H2O w/0.1% TFA) to provide 5-(2,5-difluorophenyl)-3-phenyl-1,2,3,6-tetrahydropyridine (1-7) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 5H), 7.00 (m, 2H), 6.95 (m, 1H), 6.17 (s, 1H), 4.03 (br s, 1H), 3.77 (in, 3H), 3.41 (dd, J=12.9, 5.6 Hz, 1H), 2.85 (dd, J=12.7, 7.5 Hz, 1H); MS 272.33 found 272.3 (M+H+) required.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]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.O[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:17][CH:16]([O:18][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:30])[CH2:15]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of N-benzhydrylazetidin-3-ol (1.0 g, 4.18 mmol) in anhydrous THF (66 mL) under nitrogen were added N-hydroxyphthalimide (750 mg, 4.60 mmol) and triphenylphosphine (2.19 g, 8.36 mmol). The reaction mixture was cooled to 0° C. and DEAD (1.52 mL, 8.36 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced. The residue was purified on column chromatography (eluent: pentane/EtOAc 7/3 to 4/6) to give the title compound (600 mg, 37%) as a wax.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25]>C(#N)C.CN(C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25])=[O:8])([O-:3])=[O:2]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
22.4 g of 3-nitro-4-fluorobenzoyl chloride (0.12 mols) were added dropwise at 0° C. to a suspension of 19.1 g of 5-amino-1-naphthol (0.12 mols) in 120 ml of acetonitrile and 14.2 g of N,N-dimethylaniline. The mixture was further stirred until it reached room temperature, and then heated for 30 minutes at 50° C. The yellow deposit was suction filtered and washed with acetonitrile. The deposit was dissolved in tetrahydrofurane and stirred with charcoal, filtered and the product was precipitated from the filtrate with petrol 50/75. Yield: 25.8 g=66% of the theoretical yield; mp. 235°-238° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(CC)CC.C(=O)([O-])[O-].C(O)C(N)(CO)CO>ClCCCl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:30]
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)NC(CCc1ccccc1)C(=O)N1CCC(C)CC1
Reaction time: 16 h

Procedure:
A mixture of 20 mg (0.077 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 0.11 mmol of 2-chloro-6-methylbenzene-sulfonyl chloride, and 0.2 mmol of Et3N in 1 mL of DCE is stirred for 16 h, and 240 mg of MP-carbonate and 170 mg of PS-trisamine are added. The mixture is shaken for 2 days, filtered, and concentrated to provide Example 54.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[N-:15]=[N+:16]=[N-:17].[Na+]>O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(-n2nnnc2S)cc1
Temperature: 80 °C
Yield: 55 %

Procedure:
20 g of 4-carboethoxyphenyl isothiocyanate and 6.5 g of sodium azide are added to water and heated at 80° C. After 2 hours of reaction, the reaction mixture is filtered, cooled and acidified with hydrochloric acid to give crystals of 1-(4-carboethoxyphenyl)-5-mercaptotetrazole. To the crystals are added 5 equivalents of sodium hydroxide (1N NaOH in water) and the mixture is heated at 80° C. for 5 hours. After cooling, the reaction mixture is acidified with hydrochloric acid to cause crude crystals of Compound III-4 to separate out. The crystals are recrystallized from methanol. Yield: 55%, m.p. about 195° C. (decomposed).