Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[C:3]([C@@H:7]1[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]2[CH:32]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:19]2=[CH:33][C:15](=[CH:16][CH:17]=[CH:18]2)[CH2:14][O:13][C@H:12]2[CH2:34][N:9]([C@H:10]([C:35]([O:37]C)=[O:36])[CH2:11]2)[C:8]1=[O:39])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCO.O>[C:3]([C@@H:7]1[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]2[CH:32]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:19]2=[CH:33][C:15](=[CH:16][CH:17]=[CH:18]2)[CH2:14][O:13][C@H:12]2[CH2:34][N:9]([C@H:10]([C:35]([OH:37])=[O:36])[CH2:11]2)[C:8]1=[O:39])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCCCc1cccc(c1)-c1cccc(c1)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@@H]1NCCCCCCc2cccc(c2)-c2cccc(c2)CO[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
LiOH (3.0 eq.) was added to a 0.05 M solution of methyl (9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.1 9,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylate 104 in a mixture of THF:EtOH:H2O (2:1:1). The reaction mixture was stirred at 40° C. for 2 h then the solvent was evaporated under reduced pressure. Aqueous HCl (1N) was added to reach pH=6 and the mixture was evaporated to dryness to yield a dark solid which was used without further purification. MS (ES+) m/z 493 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCCC.CC(C)=O.Cl>[C:21]([C:17]1[C:16]([Cl:20])=[N:15][C:14]([Cl:13])=[CH:19][N:18]=1)([OH:23])=[O:22]
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)c1ncc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.78 g) in tetrahydrofuran (40 ml) is dropped a 1.6M solution of n-butyl lithium in hexane (4.82 ml) over a period of 3 minutes under cooling on dry ice in acetone bath. The mixture is stirred on the same bath for 30 minutes and thereto is added 2,6-dichloropyrazine 0.50 g in tetrahydrofuran 5 ml at the same temperature over a period of 15 minutes. After stirring for 1 hour, the mixture is poured into dry ice and stirred at room temperature for 1 hour. The mixture is diluted with 10% hydrochloric acid to be adjusted pH about 2 and extracted with ethyl acetate. The combined organic layer is extracted with an aqueous saturated sodium hydrogen carbonate solution. The water extract is washed with ethyl acetate and made acid with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is titrated with chloroform-hexane (1:1) to give 2-carboxy-3,5-dichloropyrazine 234 mg as a slightly brownish crystalline powder. mp 139-141° C., MS(m/z): 191 (M−H)−
Reaction SMILES: Br[C:2]1(Br)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>CC#N>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc2c(=O)c(N3CCC(O)(c4ccccc4)CC3)coc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3,3-Dibromo-7-(triisopropylsilyloxy)-4-chromanone (5.0 g, 10.5 mmol) was dissolved in CH3CN (150 ml) and 4-hydroxy-4-phenylpiperidine (2.2 g, 12.5 mmol) and triethylamine (2.9 ml, 20.8 mmol) were added. The mixture was stirred overnight at ambient temperature, then concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 ml) and brine, dried over CaSO4, concentrated, and the residue chromatographed on silica gel, using gradient elution with ethyl acetate/hexane to yield title product as a white solid (2.3 g, 54%). A portion was recrystallized from ethanol/ether; mp 163°-163.5° C.; IR (KBr) 3437, 2950, 2870, 1635, 1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690. Anal. Calcd. for C29H39NO4Si: C, 70.55; H, 7.96; N, 2.84. Found: C., 70.44; H, 7.76; N, 2.84.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH3:40][N:4]([C@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:1](=[O:3])[CH3:2]
Reactant: CI
Reactant: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](NC(C)=O)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](N(C)C(C)=O)[C@H]1OCc1ccccc1

Procedure:
Dissolve methyl 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-β-D-galactopyranoside (5.05 g.) in dry DMF (100 ml.). With stirring in an atomsphere of dry nitrogen add 0.25 g. of sodium hydride and allow the mixture to stir for 1 hour. Add methyl iodide (2.0 g.) and continue stirring at room temperature for 16 hours. Evaporate the mixture in vacuo to ca 10 ml. then dilute with chloroform. Cautiously add water and shake, separate the layers and re-extract the chloroform layer 3 times with water. Dry the chloroform solution and evaporate to 50 ml. Add hexane to precipitate the title product of this example. Yield ca 4.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:16])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]Cl)([O-:26])=[O:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][S:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])=[CH:11][C:10]=2[CH3:16])=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: Cc1cc(N)ccc1Oc1ncc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(NSc2ccccc2[N+](=O)[O-])ccc1Oc1ncc(Cl)cn1
Yield: 83.6 %

Procedure:
2.0 g of 4-(5 chloro-2-pyrimidinyloxy)-3methylaniline and 0.94 g of triethylamine were dissolved in 20 ml of toluene, and a solution of 1.61 g of 2-nitrobenzenesulfenyl chloride dissolved in 5 ml of toluene was dropwise added thereto at room temperature. The mixture was reacted at room temperature for 1 hour under stirring. After completion of the reaction, ethyl acetate was added to the reaction product, and the ethyl acetate layer was washed with water, dried over Glauber's salt and then purified by column chromatography to obtain 2.76 g of N-[4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl]-2-nitrobenzenesulfenamide (Intermediate Compound No. 37) (melting point: 74°-85° C.) in a yellow non-crystalline form.
Reaction SMILES: [Li+].[AlH4-].[O:3]1[CH2:38][C:4]1([CH3:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([N:21](C(OCC(C)C)=O)[C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC.C1COCC1>[OH:3][C:4]([CH3:39])([CH3:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2(C)CO2)cc1
Agent: [AlH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)(C)O)cc1
Yield: 7.9 %

Procedure:
Lithium tetrahydridoaluminate (20.5 ml of a 1M solution in ether) was added over 10 minutes to a solution of 2-[4-(2,3-epoxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.8 g) in anhydrous THF at 0° C. After 30 minutes the reaction mixture was poured into saturated aqueous ammonium chloride solution (50 ml) and was extracted with ethyl acetate (4×50 ml). The extracts were washed with brine and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-80% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(2-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.115 g) as a foam; 1H NMR (CDCl3+CD3COOD): 1.3 (s, 6H), 2.3 (s, 3H), 2.8 (s, 2H), 3.8 (s, 3H), 7.2-7.3 (m, 5H), 7.55 (dd, 1H), 8.7 (dd, 1H), 8.85 (dd, 1H); mass spectrum (+ve ESP): 429 (M+H)+.
Reaction SMILES: [P].II.CS(O)(=O)=[O:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)(=O)C.CO.CCOCC.O>[OH2:6].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)O
Agent: II
Agent: O=C(O)/C=C/C(=O)O
Agent: [P]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
A mixture of 30.6 g (0.99 mole) of phosphorous and 15.1 g (0.059 mole) of iodine in 90 ml of glacial acetic acid was stirred for 20 min at room temperature. A mixture of 6 ml of water, 70 ml of methanesulfonic acid, 56.19 g (0.197 mole) of 4-[bis(4-fluorophenyl)methylene]piperidine and 110 ml of glacial acetic acid was added, and the mixture was heated at reflux for 7 hr. The solvent was removed in vacuo, and the resulting viscous liquid was poured over ice. The icy mixture was made basic with 50% sodium hydroxide, and the basic suspension was extracted with methylene chloride. The methylene chloride solution was extracted with an aqueous solution of sodium thiosulfate and was dried over anhydrous sodium sulfate, and the solution was filtered through Celite®. The solvent was removed in vacuo to give a gum. The gum was dissolved in 400 ml of hot methanol, and 4.25 g of an unknown tan solid was collected from the warm solution. Fumaric acid (22 g, 0.19 mole) was added to the methanolic solution followed by the addition of ether. A white precipitate was collected to give 22.55 g (32%) of crystalline solid, mp 208°-209° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](I)[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[C:17]([N:25]2[CH2:36][CH2:35][N:34]3[C:27](=[CH:28][C:29]4[CH2:30][C:31]([CH3:38])([CH3:37])[CH2:32][C:33]=43)[C:26]2=[O:39])=[N:18][CH:19]=[CH:20][C:21]=1B(O)O)(=[O:13])[CH3:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:11]([O:14][CH2:15][C:16]1[C:17]([N:25]2[CH2:36][CH2:35][N:34]3[C:27](=[CH:28][C:29]4[CH2:30][C:31]([CH3:38])([CH3:37])[CH2:32][C:33]=43)[C:26]2=[O:39])=[N:18][CH:19]=[CH:20][C:21]=1[C:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: Cn1cc(I)cc(Br)c1=O
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3-bromo-5-iodo-1-methylpyridin-2(1H)-one 214b (1.57 g, 5.0 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.98 g, 5.0 mmol), PdCl2(dppf) (205 mg, 0.25 mmol), K3PO4 (2.12 g, 10.0 mmol), sodium acetate (820 mg, 10.0 mmol), acetonitrile (45 mL), and water (1 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 30° C. for 3 h. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 273a (580 mg, 22%) as a white solid. MS-ESI: [M+H]+ 539.2. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.09 (d, J=5.0 Hz, 1H), 6.79 (s, 1H), 5.15 (s, 2H), 4.55-4.51 (m, 1H), 4.27-4.25 (m, 1H), 4.15-4.13 (m, 1H), 4.06-4.04 (m, 1H), 3.68 (s, 3H), 2.58-2.56 (m, 2H), 2.51 (s, 2H), 1.86 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C.O.C(O)C>C(O)C>[F:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(c3cc(C(F)(F)F)ccn3)C[C@@H]21
Temperature: 82 °C

Procedure:
In a 4 mL vial were combined (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate from Example 617 Step 2 (80 mg, 0.234 mmol), 2-bromo-4-(trifluoromethyl)pyridine (74.1 mg, 0.328 mmol), and triethylamine (0.131 mL, 0.937 mmol) in ethanol (0.1 mL). The reaction was heated at 82° C. for 1 day. To the reaction mixture was added 90% water/ethanol (1 mL), and then the liquid layer was decanted. This crude material was purified using a 12 g silica gel cartridge eluted with a gradient of 0-60% acetone/hexane over 20 minutes to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-2-(4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.34 (d, J=5.2, 1H), 7.93 (bs, 1H), 6.73 (d, J=5.1, 1H), 6.60 (s, 1H), 5.33-5.10 (m, 1H), 4.62 (t, J=7.9, 1H), 4.34-4.22 (m, 1H), 3.96 (dd, J=21.9, 13.0, 1H), 3.66 (tdd, J=16.6, 12.2, 5.7, 3H), 3.57-3.50 (m, 1H), 3.30 (dd, J=10.9, 4.3, 1H), 2.76 (tdd, J=13.1, 8.5, 4.5, 2H), 2.54-2.35 (m, 2H), 2.16 (dd, J=12.5, 5.8, 1H), 2.04-1.91 (m, 1H), 1.72 (ddd, J=15.3, 12.9, 7.8, 1H), 1.51 (s, 9H), 1.44 (dd, J=9.2, 4.0, 1H); MS (ESI+) m/z 487 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.C(N(CC)CC)C.Cl.[NH2:24][OH:25].Cl>CN(C)C=O.O>[OH:25][NH:24][C:13](=[O:15])/[CH:12]=[CH:11]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(O)/C=C/c1ccc2ccccc2n1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc2ccccc2n1)NO
Reaction time: 2 h

Procedure:
To a solution of (E)-3-(2-quinolinyl)-2-propenoic acid (2) (0.4 g, 2.0 mmol) in dry dimethylformamide (3 ml), at ice bath temperature (˜0° C.), under an atmosphere of argon, N,N′-carbonyldiimidazole (0.65 g, 4.0 mmol) was added over 15 minutes and the reaction mixture was stirred at this temperature for 2 hours. Triethylamine (0.85 ml, 6.0 mmol), followed by hydroxylamine hydrochloride (0.42 g, 6.0 mmol), were added to the reaction, and the obtained mixture was stirred at ice bath temperature for 1 hour, and then at room temperature overnight. The reaction mixture was poured into water (30 ml), acidified with 1 N HCl to pH 5 and extracted with ethyl acetate (3×40 ml). The combined extracts were washed with water (50 ml), brine (20 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with acetonitrile-water (20:1) as eluent to give the title compound as white crystals. M.p. 159.5-160.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 7.12 (1H, d, J=16.0 Hz); 7.49-8.18 (6H, m); 8.44 (1H, d, J=8.0 Hz); 10.13 (2H, br s). HPLC analysis on Symmetry C8 column: impurities 2.0% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer, pH 2.5, 20:80; detector UV 254 nm; flow rate 1.2 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd for C12H10N2O2*H2O: C, 62.06; H, 5.21; N, 12.06. Found, %: C, 61.95; H, 4.91; N, 12.07.
Reaction SMILES: CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CN([CH:27]=[O:28])C>CCOCC>[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH:27]=[O:28]
Reactant: Brc1cccnc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCOCC
Product: O=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of TMEDA (1.91 mL, 12.7 mmol) and LDA (12.7 mmol) in ether (50 mL) at −78° C. was added 3-bromo-pyridine (1.22 mL, 12.7 mmol). After 60 minutes at −78° C., DMF (1.08 mL, 13.9 mmol) was added, and the mixture allowed to warm to room temperature. After 1 hour at room temperature the reaction was quenched with saturated aqueous NaHCO3 (100 mL), extracted with CH2Cl2 (4×15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes:EtOAc 4:1) afforded the title compound as a crystalline solid (1.2 g, 51%). 1H NMR (CDCl3) 7.70 (d, 1H, J=4.8 Hz), 8.71 (d, 1H, J=4.8 Hz), 8.91 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].CS(C)=O>O>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:17]([CH2:16][C:15]([F:19])([F:18])[F:14])[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)(F)F)C2
Temperature: 120 °C
Yield: 78.3 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c (632 mg, 2.0 mmol), 2,2,2-trifluoroethanamine (594 mg, 6.0 mmol), and DMSO (5 mL), and heated at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combiner organic layer was dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silical-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 134a (392 mg, 78%) as a yellow solid. MS-ESI: [M+H]+ 250.9
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27](I)=[C:26]([O:31][CH3:32])[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[N:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1COCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([NH:57][C:54]5[CH:55]=[CH:56][N:51]=[CH:52][CH:53]=5)=[C:26]([O:31][CH3:32])[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1Nc1ccncc1

Procedure:
A suspension of 6-fluoro-3-[4-(4-iodo-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.089 mmol), 18-CROWN-6 (28.3 mg, 0.107 mmol), pyridin-4-amine (9.24 mg, 0.098 mmol), BINAP (11.11 mg, 0.018 mmol), sodium tert-butoxide (17.15 mg, 0.178 mmol), and tris(dibenzylideneacetone)dipalladium (4.09 mg, 4.46 μmol) were combined in a microwave vial and dissolved in THF (892 μl). The reaction was irradiated in the microwave at 160° C. for 15 minutes. The reaction mixture was filtered, and the solvent was removed in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 6-fluoro-3-{-4-[3-methoxy-4-(pyridin-4-ylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:13][CH3:14])[C:10]([CH3:12])=[N:11][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].CC(OC)(C)C>C1COCC1>[CH2:13]([N:9]1[C:8]2[CH:15]=[CH:16][C:5]([CH2:3][OH:2])=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12])[CH3:14]
Reactant: CCn1c(C)nc2cc(C(=O)OC)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCn1c(C)nc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 450 mg (2.06 mmol) of the title D compound, 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 5 mL of THF is added dropwise 2.1 mL (2.1 mmol) of lithium aluminum hydride (LAH, 1.0M in THF). The mixture is stirred at RT for 90 min, then saturated aqueous sodium sulfate solution is carefully added dropwise until a thick precipitate formed. MTBE is added to the mixture and the insoluble aluminum salts are removed by filtration through Celite. The solvent is removed under reduced pressure to give (1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-methanol as an oil: 1H-NMR (CDCl3) δ 7.63 (s, 1H), 7.28 (m, 2H), 4.77 (s, 2H), 4.16 (q, 2H), 3.74 (t, broad, 1H), 2.60 (s, 3H), 1.40 (t, 3H); [M+1]+=191.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(O)[CH:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>S(Cl)(Cl)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C(c2ccc(C#N)cc2)n2ccnc2)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=C(c2ccc(C#N)cc2)n2ccnc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2,2-Bis-(4-methoxyphenyl)-2-hydroxy-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethane (10.2 g) is dissolved in thionyl chloride (25 mL) and the solution is stirred at room temperature for 36 hours. The solvent is evaporated and the residue is chromatographed on silica gel (250 g). Elution with ethyl acetate affords the crystalline 2,2-bis-(4-methoxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylene. The compound has m.p. 174°14 176° after recrystallization from isopropanol.