Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].O>C1COCC1>[OH:5][CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of methyl magnesium bromide (1M in THF) (3.03 mL, 3.03 mmol) was added drop wise to a solution of methyl 6-formylpyridine-3-carboxylate (Intermediate 195, 0.50 g, 3.03 mmol) in THF (20 mL) at −78 C. The reaction mixture was stirred at −78 C for 1 h and water (20 mL) was added. The mixture was warmed to room temperature and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as an off-white solid (0.407 g, 74%). Method B HPLC-MS: MH+ requires m/z=182 Found: m/z=182, Rt=1.11 min (98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.[BH4-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([OH:10])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1
Reactant: CN1CCN(CC(=O)c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(CC(O)c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a stirred solution of 25 g (0.076 mol) of the 1-methyl-3-phenyl-4-(4-chlorophenacyl) piperazine in 450 ml of ethanol was added in portions 2.9 (0.076 mol) of sodium borohydride. The resulting mixture was stirred at ambient temperature for 2 hours, poured into 50% aqueous sodium chloride and extracted with ethyl acetate. The organic extracts were combined, washed with water and saturated sodium chloride and dried over sodium sulfate. The resulting crude product obtained from concentration of the filtrate was subjected to rapid liquid chromatography on a silica gel column to give 16 g (60% overall) of 1-methyl-3-phenyl-4-[2-hydroxy-2-(4-chlorophenyl)ethyl]piperazine as a white solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(OCC(=O)O)cc2)cc1)c1ccccc1
Yield: 13.72 %

Procedure:
Compound 117 was synthesized from Intermediate 13 (0.22 g, 1.020 mmol) and ethyl (4-hydroxyphenoxy)acetate (0.20 g, 1.020 mmol) by following the procedure described in scheme 41 (0.060 g, yield: 13.72%); Purity: 97.98%.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1.[OH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH:29]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.CO>[OH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][N:18]2[CH2:19][CH2:20][C:14]3([O:13][CH2:12][CH2:11][N:10]([C:8]([C:6]4[N:7]=[C:3]([CH3:2])[S:4][CH:5]=4)=[O:9])[CH2:15]3)[CH2:16][CH2:17]2)=[CH:25][CH:24]=1
Reactant: O=CCOc1ccc(CO)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CO)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.38 g) was added to a solution of 2-(4-(hydroxymethyl)phenoxy)acetaldehyde (example 1, step h) (0.17 g) in NMP (10 mL) and acetic acid (0.06 mL). The resulting mixture was stirred for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.32 g) was then added and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (250 mL) and eluted with 3M ammonia in methanol solution (150 mL). The eluent was evaporated in vacuo and the residue purified by column chromatography eluting with 95:5 ethyl acetate:triethylamine to give the subtitled compound as a gum. Yield 0.32 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=1.O>CS(C)=O.O1CCCC1>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCCCO)cc1
Reactant: O=Cc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CCCCOCc2cccc(C=O)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a suspension of 1.1 g of 60% sodium hydride in 30 ml of dimethyl sulfoxide under stirring at 70° C. for 30 minutes was added 4.1 g of 4-(4-methylphenyl)butanol at room temperature and stirred for 30 minutes. To a mixture was added 40 ml of tetrahydrofuran and was cooled at 0° C. To the resulting mixture was added dropwise a solution of 3.9 g of 6-chloromethyl-2-formylpyridine in 40 ml of tetrahydrofuran. After completion of the addition, the mixture was stirred at the same temperature for 30 minutes and further was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give a residue as an oily substance. The residue was purified by column chromatography on silica gel by passing chloroform and methanol(100:1 ) to give 1.3 g of 6-[4-(4-methylphenyl) butoxy]methyl-2-formylpyridine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH2:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:22])[CH2:20][Cl:21])=[O:10].[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>C(#N)C>[Cl:7][CH2:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:22])[CH2:20][Cl:21])=[O:10].[O:22]=[C:19]1[CH2:20][NH:30][CH:25]2[CH:24]([CH2:29][CH2:28][CH2:27][CH2:26]2)[NH:23][CH2:8][C:9](=[O:10])[NH:11][CH:12]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[NH:18]1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: O=C(CCl)N[C@@H]1CCCC[C@H]1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNC2CCCCC2NCC(=O)NC2CCCCC2N1
Temperature: 82 °C
Reaction time: 20 h

Procedure:
N,N'-bis(chloroacetyl)-trans-1,2-diaminocyclohexane was prepared according to the procedure outlined by Saburi, M. and Yoshikawa, S., "Stereochemical studies of N-methyl-(S)-alaninatocobalt(III) complexes with chiral tetraamines. II. Cobalt(III)-N-methyl(S)- and (R)-alaninate-N,N'-bis(β-aminoethyl)-1(R), 2(R)-diaminocyclohexane systems," Bull. Chem. Soc. Jpn., 1974, 47, 1184-1189. Anhydrous sodium carbonate (250 g., 2.36 mol.) was added to a solution of 33.4 g. (125 mmol.) of N,N'-bis(chloroacetyl)-trans-1,2-diaminocyclohexane and 15 ml. (125 mmol.) of trans-1,2diaminocyclohexane in 3750 ml. of acetonitrile. The temperature was raised to 82° C., and the reaction mixture was violently agitated for 20 hours. At the end of the reaction, sodium carbonate was eliminated by filtration and the solvent was evaporated under vacuum. The solid residue was recrystallized from ethanol. Up to five successive batches of the desired compound were obtained after the progressive concentration of the ethanolic solution under vacuum. The yield was 9.6 g. of compound (A) as a white powder.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Ca+2:18].[OH-]>O>[C:1]([O-:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].[Ca+2:18]
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCCCCC(=O)[O-]

Procedure:
The calcium dodecanedioate is prepared in situ in the carrier fluid by mixing together the necessary portions of Dodecanedioic acid and Calcium hydroxide in the carrier fluid. The mixture is stirred while heating. The heat is gradually increased to about 250 degrees F maximum until foaming ceases. The heating is then discontinued but the mixture is stirred until the temperature decreases to about 150 degrees F. This procedure reacts the calcium hydroxide and dodecanedioic acid to form calcium dodecanedioate and water, which is driven off during the heating cycle. The Dodecanedioic acid was obtained from the Petrochemicals Department Intermediates Division of E. I. DuPont de Nemours & Co. (Inc.). The Dodecanedioic acid has the following specifications:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[O:13]([CH2:20][CH2:21][CH2:22]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[O:13]([CH2:20][CH2:21][CH2:22][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCOc3ccccc3)cccc21
Temperature: 165 °C
Yield: 59.4 %

Procedure:
A mixture of 7.41 g (40.0 mmol) of potassium phthalimide and 6.30 mL (40.0 mmol) of 3-phenoxypropylbromide in 100 mL DMF was stirred at reflux (165° C.) under N2(g) for 90 min. Mixture was cooled and filtered, filtrate was condensed in vacuo. Residue was recrystallized from 95% ethanol to give 44 (6.68 g, 58%) as a white solid. UV λmax 222 (41700, 95% ETHANOL). 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.24 (t, J=10 Hz, 2H), 6.92 (t, J=7 Hz, 4H), 6.82 (d, J=4 Hz, 2H), 4.03 (t, J=6 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 2.20 (t, J=3 Hz, 2H); 13C NMR (CDCl3) δ 168.7, 134.7, 134.3, 132.6, 129.7, 124.0, 123.6, 121.1, 114.9, 65.9, 35.9, 28.7; IR (drift) 2474 (w), 2431 (w), 2417 (w), 2339 (w), 2305 (w), 1770, 1705 (s), 1600, 1397, 1388, 1249 (s), 1233, 756, 721 (s), 712, cm−1. HRMS (FAB) calcd for C17H15NO3+H1 282.1130, found 282.1129.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C(=O)(O)[O-].[Na+].[CH3:16][CH2:17][C@@H:18]([NH2:21])[CH2:19][OH:20]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:21][CH:18]([CH2:19][OH:20])[CH2:17][CH3:16])[C:5]#[N:6]
Reactant: CC[C@@H](N)CO
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CO)Nc1ccc(C#N)cc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A 100 mL round bottom flask was charged with 3,4-difluorobenzonitrile (2.013 g, 14.5 mmol), sodium bicarbonate (1.59 g, 18.9 mmol), and L-(−)-2-amino-1-butanol (1.33 mL, 14.5 mmol). The contents were then dissolved in 40 mL N,N-dimethylformamide (anhydrous). The flask was heated to 90° C. and stirred overnight under N2. The reaction mixture was cooled to room temperature, poured onto water, and extracted with EtOAc (2 times). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (gradient from 5% EtOAc/Hexanes to 10% EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 1.00 g (33% yield) of the title compound. 1H NMR (CDCl3, 500 MHz) δ: 7.28 (m, 1H), 7.21 (dd, J=11.3, 1.8 Hz, 1H), 6.72 (t, J=8.5 Hz, 1H), 4.49 (s, 1H), 3.77 (m, 1H), 3.68 (dt, J=10.0, 5.3 Hz, 1H), 3.48 (m, 1H), 1.87 (m, 1H), 1.72 (dqn, J=14.5, 7.5 Hz, 1H), 1.60 (dqn, J=14.5, 7.5 Hz, 1H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[ClH:15]>[Pd].CO>[ClH:15].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
Palladium on carbon (10 wt %, 1.67 g, 1.57 mmol) was added to a solution of 2-azido-1-[4-(methyloxy)phenyl]ethanone (3.0 g, 15.69 mmol) and hydrochloric acid (6.62 mL, 78 mmol) in CH3OH (90 mL) under nitrogen, and the reaction mixture was stirred under hydrogen overnight at 25° C. The mixture was filtered, washed by EtOAc (150 mL), and concentrated to afford an HCl salt of the title compound (3.0 g) as a yellow solid. LC-MS (ES) m/z=166 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:12][C:11](=[O:14])[C:10]3[C:16](=[CH:17][CH:18]=[C:19]([NH:15][C:4](=[O:3])[CH3:5])[CH:9]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCNC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2

Procedure:
A mixture of 24.8 g of 4-methoxyacetanilide, 37.3 mL of acetyl chloride and 250 mL of CH2Cl2 was refluxed until the insoluble solid was dissolved, and then cooled to 0° C. 70.0 g of AlCl3 was gradually added thereto, and then the mixture was heated under reflux for 5 hours. The reaction mixture was poured into 500 mL of water with ice, and stirred for 30 minutes. The resulting precipitate was collected through filtration, washed with water and dried under vacuum to obtain 23.5 g of 5-acetylamino-2-hydroxyacetophenone. 9.96 g of N-Boc-piperidin-4-one, 4.17 mL of pyrrolidine and 75 mL of MeOH were added to 9.66 g of the product, and heated under reflux for 13 hours. The reaction mixture was concentrated, cold MeOH was added to the residue, and the insoluble solid was taken out through filtration and dried under vacuum to obtain 16.3 g of N-{1′-[(tert-butoxy)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}acetamide. TFA (43 mL) cooled at 0° C. was gradually added to 16.1 g of the product, and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and TFA still remaining therein was removed through codistillation with toluene added thereto, and 50 mL of Et2O was added to the residue. The resulting insoluble solid was taken out through filtration, washed with Et2O/EtOAc (1/2), and dried under vacuum to obtain N-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}acetamide TFA salt.
Reaction SMILES: N#N.C([Li])CCC.C1(NC2CCCCC2)CCCCC1.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22].Cl[C:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29].C(O)(=O)C>O1CCCC1>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:22][C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCOC(C)=O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCC(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
A five liter round bottom flask was fitted with a mechanical stirrer, thermometer and a one liter additional funnel. The addition funnel was in turn fitted with a septum into which was introduced a N2 line, an equalizing line and a liquid reagent inlet line. The equalizing line was further connected with tubing to a straight vacuum adapter and this adapter was fitted between the addition funnel and the flask. The flask was charged with N2 and then with 976 ml. (2.05 moles=2.25 equiv.) n-butyllithium in 800 ml. of anhydrous tetrahydrofuran (THF), and the mixture cooled to -78° C. in a dry ice/acetone bath. To this was added 408 ml. (2.05 moles) of dicyclohexylamine in 375 ml. THF dropwise over 45 minutes (temperature kept below -67° C.). After equilibrating to -78° C., 201 ml. (2.05 moles) of ethyl acetate in 100 ml. THF was added dropwise over 45 minutes (temperture kept below -67° C.). The mixture was allowed to stir at -78° C. for 15 minutes and then 150 g. (0.91 mole) of methyl 4-(chloroformyl)butyrate in 200 ml. THF was added dropwise over 30 minutes (temperature kept below -70° C.). After stirring for 1 hour at -78° C., 231 ml. (2.05 moles) of glacial acetic acid was added dropwise over 25 minutes, after which the dry ice/acetone bath was removed, and the reaction allowed to warm to 0° C., diluted with one liter Et2O, and the white inorganics filtered. The solids were washed well with ether. The combined filtrate and washes were evaporated in vacuo and the residue was partitioned between one liter ether and one liter water. The ether was separated, washed in sequence 2x with 500 ml. 0.5N HCl, 1x with 500 ml. H2O, 1x with 500 ml. saturated NaHCO3, 1x with 500 ml. H2O and 1x with 500 ml. brine, dried over MgSO4, filtered and evaporated in vacuo to yield 108.5 g. (55.1%) of title product as a gold colored mobile liquid. Nmr (CDCl3): 4.1 (q, 2H), 3.6 (s, 3H), 3.4 (s, 2H), 1.7-2.7 (m, 6H), 1.25 (t, 3H). M/e: 216 (m+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].[CH3:11][N:12]([CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1(C)C=CC=CC=1>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([N:12]([CH3:20])[CH3:11])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CN(C)c1cccc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(Nc2cccc(N(C)C)c2)c1
Temperature: 90 °C
Yield: 75.5 %

Procedure:
Under dinitrogen atmosphere, 1 equivalent of 3-bromo-N,N-dimethylaniline (1 g), 1.5 equivalent of sodium tert-butylate (0.721 g), 0.1 equivalent of Pd(dba)2 (0.288 g), 0.12 equivalent of dppf (0.555 g) and 20 mL of toluene are introduced into a flask. The flask is fitted with a PTFE septum and 1.2 equivalent of N,N-dimethylbenzene-1,3-diamine (0,817 g) is added thereto using a syringe. The reaction medium is heated at 90° C. for 12 hours, thereafter is cooled to room temperature and concentrated under reduced pressure. The product is purified by flash chromatography using a gradient of 5% to 12% of ethyl acetate in hexane (Rf: 0.33) to give 0.963 g of the expected product with a yield of 75%.
Reaction SMILES: S(=O)(=O)(O)O.C(C1[O:11][C:12]2[C:18]([S:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)(=[O:21])=[O:20])=[C:17]([Cl:29])[CH:16]=[CH:15][C:13]=2[N:14]=1)(C)(C)C>O.O1CCOCC1>[NH2:14][C:13]1[C:12]([OH:11])=[C:18]([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[C:17]([Cl:29])=[CH:16][CH:15]=1
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Yield: 65.4 %

Procedure:
4.27 ml (0.08 mol; 1.20 V) of sulfuric acid diluted in 4.3 ml of water were added dropwise to 3.56 g of 2-tert-butyl-6-chloro-7-(4-methylpiperazine-1-sulfonyl)benzooxazole (0.01 mol; 1.0 eq) in solution in 15 ml of 1,4-dioxane. The reaction medium was refluxed for six and a half hours. The reaction medium was concentrated and 1 N sodium hydroxide was added (to pH 7). The solution was extracted with dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed on silica gel, eluent 95/5 ethyl acetate/dichloromethane. 2.0 g of 6-amino-3-chloro-2-(4-methylpiperazine- 1-sulfonyl)phenol were obtained in the form of a thick brown oil. Yield=68%.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2]>C(Cl)Cl.C(N(CC)CC)C.CCCCCCC>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]=[O:6])=[CH:13][CH:12]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CC(C)C(=C=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 41.6 %

Procedure:
To a solution of 2.31 g of isopropyl(4-chlorophenyl)acetyl chloride in 10 ml of methylene chloride was added in one portion 1.5 g of triethylamine. After 18 hours, 15 ml of heptane was added to the mixture and the triethylamine hydrochloride was removed by filtration. The filtrate was stripped and 10 ml of heptane was added and the resulting mixture was filtered and stripped to give a yellow residue, which was dissolved in 5 ml heptane for GLC analysis. The resulting solution was distilled through a Bantam-ware short-neck head from an oil bath at 125°-150° C. and head temperature of 110°-100° C. at 0.2-0.05 mm to give 0.95 g of distillate and 0.81 g of gum. The distillate was crystallized twice from 2 volumes of hexane at -80° C. The solid was melted and stripped to about 40° C. at 0.5 mm to give 0.42 g of the desired product as a yellow liquid.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccncc1C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of 3-(4-fluorobenzoyl)-4-carbomethoxypyridine (2.25 g, 8.68 mmol) in 10 mL of DMF is added dropwise to a solution of NaH (0.25 g, 10.21 mmol) and imidazole (0.59 g, 8.68 mmol) in 26 mL of DMF. The mixture, after heating at 120° C. for 1 day, is allowed to cool, quenched with ice water, and extracted with EtOAc (3×75 mL). The combined organic layers are dried (Na2SO4) and evaporated to produce crude product. Chromatographic purification on silica gel (using EtOAc-MeOH, 9:1 as the eluent) gives pure 3-[4-(1H-imidazol-1-yl)benzoyl]-4-carbomethoxypyridine as a light brown solid. M.P. 125°-128° C.
Reaction SMILES: [NH2:1][C:2]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH2:9]([OH:11])C>C(=O)(OCC)OCC>[OH:4][CH2:3][C:2]1([CH2:7][OH:8])[CH2:5][O:6][C:9](=[O:11])[NH:1]1
Reactant: CCO
Reactant: NC(CO)(CO)CO
Solvent: CCOC(=O)OCC
Product: O=C1NC(CO)(CO)CO1
Temperature: 25 °C

Procedure:
A suspension of 2-amino-2-(hydroxymethyl)propane-1,3-diol (51.37 g, 424.1 mmol) in diethyl carbonate (55 ml) was heated to 140° C. for 14 h, during which approximately 50 ml of ethanol was collected in a Dean-Stark trap. The reaction mixture was cooled to RT and the resulting thick, clear syrup was used without further purification. LRMS (ESI/APCI): 148 [M+H]+.