Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:23]=[C:24]([C:28]#[C:29]C(C)(O)C)[CH:25]=[CH:26][CH:27]=1.[OH-].[Na+].[ClH:36]>COCCO>[ClH:36].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: COCCOc1cc2ncnc(Nc3cccc(C#CC(C)(C)O)c3)c2cc1OCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 22.5 °C

Procedure:
4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, prepared above (5.0 g, 11 mmol), anhydrous solid sodium hydroxide (44 mg, 11 mmol) and 2-methoxyethanol (50 mL) were stirred together and heated at reflux for 47 hours. The reaction mixture was cooled to 20-25° C. and concentrated hydrochloric acid (1.1 mL) was added. The resultant mixture was granulated at 20-25° C. for 1 hour to establish crystallization. The title product crystals were isolated by filtration, washed with 2-methoxyethanol (10 mL) and dried under vacuum at 45-50° C. to remove 2-methoxyethanol. Yield (3.73 g, 78%).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(OC)(OC)(OC)C>[OH:10][C:9]1[N:11]=[C:12]([CH3:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: NC(=O)NNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Product: Cc1nc(O)nn1-c1ccccc1
Reaction time: 5 h

Procedure:
Twenty-five g of 1-phenylsemicarbazide and 150 ml of trimethyl orthoacetate were combined, and 100 mg of p-toluenesulfonic acid was added. The mixture was stirred on a steam bath for 5 hours, and was then cooled and evaporated under vacuum. The residue was recrystallized from ethanol to obtain 24.6 g of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.[CH2:25]([OH:28])[CH2:26][OH:27]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[CH:22]=[C:21]([O:27][CH2:26][CH2:25][OH:28])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: OCCO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(OCCO)ncn2)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To ethylene glycol (20 ml) is added sodium hydride (60% dispersion-type, 1.03 g), and thereto is added 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (1.66 g). The mixture is stirred at 60° C. for 20 hours. After cooling, the mixture is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from ethyl acetate to give 4-tertbutyl-N-{6-(2-hydroxyethoxy)pyrimidin-4-yl}benzenesulfonamide (1.58 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[C:4]([CH2:12][CH3:13])[N:3]=1.Cl[Sn]Cl.Cl.[OH-].[Na+]>>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[Cl:11]
Reactant: CCc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CCc1cc(Cl)c(N)c(Cl)n1

Procedure:
9 g (40.7 mmol) of 2,4-dichloro-6-ethyl-3-nitropyridine are introduced into a solution of 33 g (0.146 mol) of SnCl2. 2H2O in 100 ml of 36% strength HCl and the mixture is boiled under reflux for 30 minutes. It is then cooled and stirred into 400 ml of 12% strength NaOH with cooling. It is extracted three times using 150 ml of dichloromethane each time and the extract is dried using Na2SO4 and evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:34])(=[O:33])[NH2:35])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
A benzene (30 ml) solution containing 2.00 g (7.30 mmol) of 3-benzyloxy-4-nitrobenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 1.38 g (8.00 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 2.50 g (yield: 80.0%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:17]([F:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(F)c(-c3ccc(Cl)cc3Cl)c2O1
Yield: 85.6 %

Procedure:
Treatment of ((2R)-8-(2,4-dichlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (0.35 g, 0.73 mmol) with sodium azide (0.28 g, 4.38 mmol) in DMSO (10 mL) according to the procedure described for Example 69, Step 9 provided 0.22 g (86%) of (2R)-2-(azidomethyl)-8-(2,4-dichlorophenyl)-7-fluorochroman as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].C[O:28][C:29](=[O:39])[CH:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O>>[CH2:1]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1sc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: CCCCc1sc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-butyl-benzo[b]-thiophen-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp.159-161° C.; MS m/e 507 (M+H)+;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:21](=O)[CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1.ClCCl>[CH2:7]([N:14]1[CH2:15][CH:16]2[CH:20]([CH2:19][NH:18][CH2:17]2)[CH2:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CNCC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(CN2CC3CNCC3C2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of lithium aluminum hydride (15.0 mL, 1.0 M solution in ether) was added dropwise to a solution of compound 2 (1.15 g) in THF (50 mL) and dichloromethane (40 mL) at 0° C. The reaction mixture was stirred an additional 1.5 hour at 0° C. and water (0.5 mL) was added followed by the addition of aqueous NaOH solution (0.5 mL, 20%) and then water (1.5 mL). The resulting solids was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to provide the title compound 3 as a pale yellow oil (0.93 g, 92%). LCMS: Rf: 0.368 min, M+H+: 203.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([N:19]([CH3:35])[C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][N:19]([C:20]1[O:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:23][N:24]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH:9]([OH:8])[CH2:10][CH2:11]2
Reactant: CN(c1ncc(-c2ccc(C(F)(F)F)cc2)o1)c1cccc2c1CC(O[Si](C)(C)C(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(c1ncc(-c2ccc(C(F)(F)F)cc2)o1)c1cccc2c1CC(O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A solution of the product of Example 18E (56 mg, 0.112 mmol) in 6 mL of tetrahydrofuran was treated with a solution of tetrabutylammonium fluoride (1M-in-tetrahydrofuran, 1 mL, 1 mmol). The reaction mixture was stirred at rt for 4 h, then the solvent was evaporated, and the residue was chromatographed on silica gel, eluting with 70% ethyl acetate-hexane, to afford the title compound as a tan foam (27 mg, 62%). 1H NMR (DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.57 (s, 1H), 7.11-7.22 (m, 3H), 4.78 (d, J=3.7 Hz, 1H), 3.86 (m, 1H), 3.38 (s, 3H), 2.73-2.98 (m, 3H), 2.37 (m, 1H), 1.89 (m, 1H), 1.63 (m, 1H); MS (ESI+) m/z 389 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:36]([F:39])([F:38])[F:37])=[C:10]([C:12]([NH:14][CH2:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[O:18])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OC(C)C)=O.C([N:49](CC)CC)C.N>O1CCOCC1.O.C(OCC)(=O)C.CN(C=O)C.C(Cl)Cl>[C:33]([CH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([CH2:16][CH2:15][NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:36]([F:39])([F:38])[F:37])=[O:13])=[O:18])=[CH:25][CH:24]=2)[CH2:27][CH2:28]1)(=[O:35])[NH2:49]
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Reactant: CCN(CC)CC
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trans-[4-(4-{3-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid (41 mg, 0.07 mmol) was added to DCM (4 mL) and DMF (1 mL) solution. Isopropyl chloroformate (0.02 mL, 0.11 mmol) and triethyl amine (0.2 mL, 0.15 mmol) were added dropwise thereto at 0° C., a temperature of the product was raised to room temperature, and stirred for 2 hours. Then, 0.5 M ammonia dissolved in 1,4-dioxane was added and stirred for 2 hours. Ethyl acetate (20 mL) and water (40 mL) were added to the reaction mixture. Then, the organic layer was separated and the product was dried with anhydrous sodium sulfate to prepare a solid under reduced pressure. The product was purified by chromatography using methanol/DCM 2-10% to obtain the desired compound (38 mg, 93%) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:6][CH:7]=1.[ClH:13]>>[ClH:13].[Cl:13][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccsc2)nn1
Agent: Cl
Product: Clc1ccc(-c2ccsc2)nn1

Procedure:
A mixture of 3-bromo-6-thien-3-yl-pyridazine (1.39 g, 5.8 mmol) and conc. hydrochloric acid (25 ml) was stirred at reflux for 4.5 hours. The reaction mixture was evaporated and the product was isolated in quantitative yield (1.35 g, 5.8 mmol).
Reaction SMILES: Cl[C:2]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[O:33]1C2C=CC=C(C(NC3C(C(O)=O)=NNC=3)=O)C=2[O:36][CH2:35][CH2:34]1>>[N:22]1([CH2:21][C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:8]4[C:7]([NH:6][C:4]([C:3]5[C:28]6[O:36][CH2:35][CH2:34][O:33][C:29]=6[CH:30]=[CH:31][CH:2]=5)=[O:5])=[CH:11][NH:10][N:9]=4)=[N:13][C:14]=3[CH:20]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Reactant: O=C(Nc1c[nH]nc1C(=O)O)c1cccc2c1OCCO2
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1cccc2c1OCCO2

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid to give 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide (39 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+ 461.23).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:19]2[C:20]([Cl:24])=[N:21][CH:22]=[CH:23][C:18]=2[S:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:20]1[C:19]2[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16][S:17][C:18]=2[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Clc1nccc2scc(Br)c12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2csc3ccnc(Cl)c23)C1=O
Yield: 35.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 321.4 mg, 1.8142 mmol) was reacted with 3-bromo-4-chloro-thieno[3,2-c]pyridine (500 mg, 1.9956 mmol), 1,4-dioxane (50 mL), copper iodide (34.4 mg, 0.1845 mmol), trans-1,2-diamino cyclohexane (62.3 mg, 0.5434 mmol) and potassium phosphate (961.3 mg, 4.528 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 220 mg of 1-(4-Chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (35.2% yield).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:28][CH:27]=1)([CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH2:6][O:7][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:30][CH:31]=1)([CH2:15][OH:16])[CH2:6][OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(CO)(CO)CCc1ccc(C(=O)CCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-(1-oxo-5-phenylpentyl)phenyl)ethyl)propane (0.9 g) in tetrahydrofuran (10 ml) was added a solution of tetra-n-butylammonium fluoride (1.2 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give 2-acetamido-2-(2-(4-(1-oxo-5-phenylpentyl)phenyl)ethyl)propane-1,3-diol as a residue. The obtained residue was dissolved in water (5 ml)—methanol (5 ml)—tetrahydrofuran (3 ml), and lithium hydroxide monohydrate (0.3 g) was added thereto. The mixture was refluxed under heating for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a white solid. The obtained white solid was recrystallized from ethanol-ethyl acetate-hexane to give the title compound (220 mg) as white crystals, melting point 126-127° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]NC(=O)CCC(N)=O>CC#N>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])n1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: Nc1ccc(Br)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 153.3 %

Procedure:
To a stirred solution of 6-nitro-pyridin-2-ylamine (1.0 g, 7.18 mmol) in CH3CN (100 mL), protected from light and under nitrogen atmosphere, N-bromosuccinamide (636 mg, 3.59 mmol) was added at 0° C. After 1 hour, another portion of N-bromosuccinamide (636 mg, 3.59 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was then quenched by the addition of saturated aqueous Na2S2O3 and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4 (anhydrous) and concentrated in vacuo. The crude product was purified by Biotage using 10% ethyl acetate in hexane to afford 1.2 g of 5-bromo-6-nitro-pyridin-2-ylamine (10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:21][C:9]1([CH3:22])[O:8][CH:7]([OH:23])[C:6]([O:5][C:4]2[CH:24]=[CH:25][C:26]([F:27])=[C:2]([F:1])[CH:3]=2)=[C:10]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1(C)OC(O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a 0° C. solution of 3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one (500 mg, 1.27 mmol) in 10 mL of THF was added DIBAL (1.5M in toluene, 2.8 mL, 4.2 mmol). Warmed to r.t. and stirred 30 min. The reaction was quenched with acetone, followed by 0.5M sodium potassium tartrate and stirred overnight. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. Crystalization from CH2Cl2 /toluene provided 350 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].CC(C)=CCC/C(/C)=C/C=C/C(C)=O.CC(=CCCC(=CC=O)C)C.CC(C)=O>[Pd].C(O)C>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C=CC=C(C)CCC=C(C)C
Agent: [Pd]
Agent: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: CC(C)=CCCC(C)=CC=O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(=O)CCCC(C)CCCC(C)C
Yield: 86.7 %

Procedure:
A mixture of 17.82 g (92.8 mmoles) of 6,10-dimethyl-3,5,9-undecatrien-2-one ("pseudoionone", prepared from citral and acetone as described by A. Russell, et al., Organic Syntheses, Collective Volume 3, pages 747-750) and 1.0 g of 5% palladium on activated carbon in 50 mL of absolute ethyl alcohol was shaken vigorously under a hydrogen atmosphere (approximately 2-3 atm. pressure) for 30 minutes. After removal of the catalyst by filtration through a small pad of Hyflo Super-Cel® filtering aid, the filtrate was diluted with 150 mL of hexane. The organic layer was subsequently washed with water (2×400 mL), then dried over anhydrous magnesium sulfate, and re-filtered. Removal of the hexane by evaporation at reduced pressure, followed by distillation, afforded 15.95 g (87% yield) of 6,10-dimethyl-2-undecanone: boiling point 68°-72° C. at 0.15 mm. A previous synthesis of the latter ketone has been reported by F. G. Fischer, et al., Ann., 475, 183 (1929).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]([C:39]#[N:40])=[C:27]([CH3:41])[N:26]=1)[CH:22]([CH3:24])[CH3:23])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:50][C:51](OC(C)=O)=[O:52]>CC(O)=O.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]([CH2:39][NH:40][C:51](=[O:52])[CH3:50])=[C:27]([CH3:41])[N:26]=1)[CH:22]([CH3:23])[CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(NC(=O)OC(C)(C)C)N(C(=O)c1ccc(C)cc1)C(c1nc(C)c(C#N)c(=O)n1Cc1ccccc1)C(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)N(C(=O)c1ccc(C)cc1)C(c1nc(C)c(CNC(C)=O)c(=O)n1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a stirred solution of {1-[{1-[5-Cyano-3-benzyl-6-methyl-4-oxo-3,4-dihydro-pyrimidin-2-yl]-2-methyl-propyl}-(1-p-tolyl-methanoyl)-amino]-propyl}-carbamic acid tert-butyl ester (350 mg, 0.6 mMol) in HOAc (10 mL) was carefully added 10% Pd/C (150 mg). The reaction was hydrogenated under a balloon of H2 for 18 h at RT, filtered through a pad of Celite®, rinsed with HOAc and evaporated under vacuum. To the crude amine (˜34% pure by LCMS, MS (ES) m/e 576.4 (M+H)+) in CH2Cl2 (10 mL) was added with stirring Et3N (280 uL, 2 mMol) and Ac2O (114 uL, 1.2 mMol). After stirring at RT for 2 h the reaction was concentrated under vacuum, taken up in EtOAc, washed with 1 N Na2CO3, 1 N HCl, brine, dried (MgSO4), filtered and evaporated under vacuum. Purification by flash chromatography (80% EtOAc/hexane) gave the title compound (0.10 g, 27%) as an off-white solid: MS (ES) m/e 618.4 (M+H)+.
Reaction SMILES: [SH-:1].[Na+].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=1>CN(C)C=O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[S:1])=[C:15]([CH3:21])[CH:14]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: [SH-]
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(N)=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.1 %

Procedure:
To a slurry solution of sodium hydrosulphide (2.80 g, 50 mmol) and magnesium chloride hexahydrate (5.05 g, 25 mmol) in dimethylformamide (50 ml) is added 4-bromo-2-methyl benzonitrile (4.90 g, 50 mmol) in one portion and the resulting green slurry is stirred at room temp for 90 minutes. The reaction mixture is poured onto water (200 ml) and the resultant precipitate filtered and washed with water. This yellow solid is then suspended in 2N HCl (200 ml) and stirred for 1 hour, then filtered, washed with water and hexane and dried in vacuo to give 4-bromo-2-methyl-thiobenzamide (820 mg).