Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1.O>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1.1 g (2.06 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mMol) of potassium carbonate and 362 mg (2.2 mMol) of n-hexyl chloroformate were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). Yield: 78% of theory, C35H42N6O5 (626.8) Rf value: 0.49 (silica gel; dichloromethane/ethanol=19:1) ##EQU61##
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)COc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (4.3 g). M.p. 213°-215° C.
Reaction SMILES: [C:1]([O:5]CCCCCC(C)C)(=[O:4])[CH:2]=[CH2:3].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]>C(OCC)(=O)C.CCCCCCC.CO>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)OCCCCCC(C)C
Agent: C=CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCCC
Product: C=CC(=O)[O-]

Procedure:
Isooctyl acrylate/acrylic acid (191.6 g, in a weight ratio of 98/2) pressure sensitive adhesive, as a 27 weight percent solution in ethyl acetate/heptane (2/3 weight ratio), was mixed with a 1.0 weight percent TTC as a solution in methanol (5.1 ml, AMRESCO, Solon, Ohio). This adhesive solution was initially colorless.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](Cl)=[O:33].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([O:28][CH3:27])[CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cccc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3ccccc3)c2)cc1OC

Procedure:
Experimental condition analogous to Example 4, from 2-(S)-(biphenyl-3-ylaminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 1 g (2.84 mmol), 3,4-dimethoxy-benzoyl chloride 0.6 g (2.98 mmol), and triethylamine 0.43 g (4.26 mmol), and 25 mL of dichloromethane. After purification on silica using gradient of chloroform-ethylacetate (20-1 to 10-1) gave 1 g of white semi solid compound: LC-MSD, m/z for: C31H36N2O5 [M+H]: 517.6. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 7 minutes: 5.093
Reaction SMILES: C1C2C(=CC3C(C=2C[O:16][C:17]2[C:18]4[O:37][N:36]=[C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:19]=4[C:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:21][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=CC=CC=3)C=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:28]([C:20]1[C:19]2[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:36][O:37][C:18]=2[C:17]([OH:16])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.8 %

Procedure:
Ethyl 7-(anthracen-9-ylmethoxy)-4-benzyl-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (110 mg, 0.23 mmol) was dissolved in 2 mL of CH2Cl2 and cooled in an ice bath. Trifluoroacetic acid (0.18 mL, 2.30 mmol) was added and the mixture was stirred at 0° C. for 20 min. Solvent and excess TFA were evaporated off, and the residue was partitioned between 20 mL of EtOAc and 20 mL of saturated sodium bicarbonate solution. The pH of the mixture was adjusted to 3 by addition of 4M hydrochloric acid. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. Purification of the residue by flash chromatography (0-40% EtOAc/hexanes) gave 36 mg of the title compound. MS: (+) m/z 375.37 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6]Cl)=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([OH:36])[CH:33]([F:35])[F:34])=[CH:28][CH:27]=2)[CH:12]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:35][CH:33]([F:34])[C@@H:32]([C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:14]=[C:9]([N:8]3[CH2:6][CH2:5][O:4][C:2]3=[O:3])[CH:10]=2)=[CH:27][CH:28]=1)[OH:36]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1OCCN1c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloroethyl chloroformate (12.58 μL, 0.122 mmol) was slowly added to a stirred, cooled (0° C.) mixture of (1R)-1-(3′-amino-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)-2,2-difluoroethanol (40 mg, 0.097 mmol) and potassium carbonate (33.7 mg, 0.244 mmol) in acetonitrile (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then heated and stirred at 80° C. for 3 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate and concentrated in vacuo. Purification via silica gel column chromatography (20-80% ethyl acetate in hexanes) to give 3-(4′-[(1R)-2,2-difluoro-1-hydroxyethyl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-oxazolidin-2-one as a colorless solid. MS ESI calc'd. for C22H18F5N4O3 [M+H]+ 481, found 481. 1H NMR (500 MHz, DMSO-d6): δ 10.39 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.01 (s, 1H); 7.88 (s, 1H); 7.64 (d, J=7.8 Hz, 2H); 7.55 (t, J=8.9 Hz, 3H); 7.31 (d, J=4.8 Hz, 1H); 6.27 (d, J=4.8 Hz, 1H); 6.07 (td, J=55.5, 3.9 Hz, 1H); 4.83 (s, 1H); 4.48 (t, J=7.8 Hz, 2H); 4.13 (t, J=7.9 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:20][CH2:21][C@@H:22]([CH3:27])[CH2:23][CH2:24][CH2:25][OH:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl.C(OCC)C>[CH3:8][S:9]([O:26][CH2:25][CH2:24][CH2:23][C@H:22]([CH3:27])[CH2:21][O:20][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])(=[O:11])=[O:10]
Reactant: C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Triethyl amine (413 μl, 3.09 mmol, 1.53 equiv) and methanesulfonyl chloride (212 μl, 2.73 mmol, 1.35 equiv) is added to a solution of (S)-5-(tert-butyldimethylsilyloxy)-4-methyl-pentan-1-ol 6 (471 mg, 2.03 mmol) in 6.5 ml of dichloromethane. The mixture is stirred for 15 min at 0° C., diluted with diethyl ether (30 ml), washed with water (5 ml), 1.0 M hydrochloric acid (5 ml), saturated aqueous sodium bicarbonate solution (5 ml), and brine (5 ml). The organic phase is separated, dried over magnesium sulfate and concentrated in vacuo. (S)-1-methanesudonyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 7 (472 mg, 99%) is obtained as a colourless oil. 13C-NMR (100 MHz, CDCl3): δ=70.44; 67.98; 37.41; 35.31; 28.99; 26.80; 25.95; 18.34; 16.56; −5.37, −5.38 (—SiMe2tBu).
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:11]=[CH2:12])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: N#Cc1ncc(Cl)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cc(Cl)cnc1C#N
Temperature: 100 °C
Yield: 67.9 %

Procedure:
A microwave vial was charged with 3-bromo-5-chloropicolinonitrile (1.40 g, 6.44 mmol) and dichlorobis(triphenyl-phosphine)palladium (II) (0.54 g, 0.77 mmol). The vial was evacuated and backfilled with nitrogen and 1,4-dioxane (10 mL) was added, followed by tri-n-butyl(vinyl)tin (2.45 mL, 7.73 mmol). The reaction mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and EtOAc. The solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 50% EtOAc in hexane, to provide 5-chloro-3-vinylpicolinonitrile (0.72 g, 4.37 mmol, 67.9% yield) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:2].[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:23]=1[NH2:24])=[O:18].[Sn](Cl)(Cl)(CCCC)CCCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:23]=1[NH:24][CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[O:18]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-Cyclohexyl-3-oxo-propionic acid ethyl ester (1.0 g, 5.0 mmol, 1.0 equiv) in THF (5.0 mL) was added 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.17 g, 5.0 mmol, 1.0 equiv) and SnBu2Cl2 (0.15 g, 0.50 mmol, 0.1 equiv) at room temperature. After stirred at room temperature for 5 minutes, the solution was added PhSiH3. The resulting reaction mixture was stirred at 65° C. under N2 for 18 hours, after which the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography EtOAc/heptane, 10-60% to give product (0.7 g). MS: 416 [M+H+].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:12]#[N:13])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2ncccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a solution of 0.1810 g (0.870 mmol) 10 in 5 mL DMF was added 0.0630 g (0.54 mmol) zinc cyanide and 0.0640 g (0.055 mmol) tetrakis(triphenylphosphine)palladium(0). After 66 h under argon at 80° C., the reaction mixture was cooled to room temperature, diluted with 40 mL toluene and washed with 10 mL 2N NH4H. The aqueous layer was extracted with 10 mL toluene. The combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (25×130 mm silica gel, linear gradient 2-3% (10% NH4OH:MeOH):CH2Cl2) afforded 11. 1NMR (CDCl3, 400 MHz) 69.065 (dd, 1H, J=1.65, 4.21 Hz, ArH); 8.567 (d, 1H, J=8.50 Hz, ArH); 8.377 (d, 1H, J=8.50 Hz, ArH); 8.005 (dd, 1H, J=1.09, 7.22 Hz, ArH); 7.796 (dd, 1H, J=7.22, 8.59 Hz, ArH); 7.636 (dd, 1H, J=4.21, 8.51 Hz, ArH); MS (Electrospray): m/z 155.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Br:27])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Br:27])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 68 °C
Reaction time: 8 h

Procedure:
6.4 kg of methyl 2,4-bisbenzyloxy-5-bromobenzoate in 18 l of THF are added to a solution of 3 kg of sodium hydroxide in 30 l of water. After stirring overnight at 68° C., the mixture is cooled to 10° C., and 7.5 l of HCl (w: 37%) are added via a dropping funnel (pH 1). The mixture is stirred for a further 1 h and subsequently filtered. The residue is dried to constant weight in vacuo at 60° C.; 5.687 kg (91%) of 2,4-bisbenzyloxy-5-bromo-benzoic acid (m.p. 150-152° C.; MW 413.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH2:12])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H]1c1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@@H]1C[C@H]1c1ccc(F)cc1
Yield: 66 %

Procedure:
2-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dione (974 mg, 3.30 mmol) in ethanol (50 mL) was stirred with hydrazine monohydrate (825 mg, 16.5 mmol) at 100° C. for 30 minutes. The reaction mixture was concentrated to give the title compound as a colorless oil (360 mg, yield 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[C:11]=2[F:18])=[O:8])=[CH:5][CH:4]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:25]/[N+:22]([O-:24])=[O:23])[C:11]=2[F:18])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C=O)c2F)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)Nc2cccc(/C=C/[N+](=O)[O-])c2F)cc1
Yield: 31 %

Procedure:
A mixture of 4-(dimethylamino)-N-(2-fluoro-3-formylphenyl)benzamide (1.83 g, the crude product from previous step), nitromethane (0.859 mL, 15.98 mmol), and ammonium acetate (1.232 g, 15.98 mmol) in acetic acid (25 mL, 52.4 mmol) was heated at 100° C. for 2 hr. Acetic acid was removed under vacuum. To the residue was added CH2Cl2 (60 mL) and water (60 mL) and the mixture was basified with solid Na2CO3 to pH 9. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic phase was washed with saturated NaHCO3 solution (40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The desired product (0.786 g, 31% over 2 steps) was isolated by ISCO (120 g silica gel, 0-5% ethyl acetate/CH2Cl2) as a red solid.
Reaction SMILES: C(N1C2C=CC(OC)=C(COCOCCOC)C=2SC2C1=CC=C(OC)C=2)CCCCC.C([Li])CCC.C(N1CCCCC1)=O.[CH3:46][O:47][C:48]1[CH:49]=[CH:50][C:51]2[N:52]([CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:53]3[C:58]([S:59][C:60]=2[C:61]=1[CH:62]=[O:63])=[C:57]([CH2:64][O:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71])[C:56]([O:72][CH3:73])=[CH:55][CH:54]=3.[BH4-].[Li+]>C(OCC)C.O1CCCC1.O1CCCC1>[CH2:74]([N:52]1[C:51]2[CH:50]=[CH:49][C:48]([O:47][CH3:46])=[C:61]([CH2:62][OH:63])[C:60]=2[S:59][C:58]2[C:53]1=[CH:54][CH:55]=[C:56]([O:72][CH3:73])[C:57]=2[CH2:64][O:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71])[CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CCCCCCN1c2ccc(OC)c(C=O)c2Sc2c1ccc(OC)c2COCOCCOC
Agent: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2COCOCCOC
Agent: O=CN1CCCCC1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCN1c2ccc(OC)c(CO)c2Sc2c1ccc(OC)c2COCOCCOC
Yield: 51.7 %

Procedure:
A solution of 8.0 g (17.33 mmol) of 10-hexyl-3,7-dimethoxy-4-(2-methoxy-ethoxymethoxymethyl)-phenothiazine in 100 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 12.0 ml of n-butyllithium solution (1.6M in hexane) and 2.94 g (26.0 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The resulting 3,7-dimethoxy-10-hexyl-6-(2-methoxyethoxymethoxymethyl)phenothiazine-4-carbaldehyde was dissolved in 100 ml of tetrahydrofuran and reduced with 22 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The product was chromatographed on silica gel with ethyl acetate/hexane (1:1), whereupon, after drying in a high vacuum, 4.41 g (51.7%) of [10-hexyl-3,7-dimethoxy-6-(2-methoxyethoxymethoxymethyl)-phenothiazin-4-yl]-methanol were obtained as a light yellowish oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]1[CH2:21][C@@H:20]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])[C:25]=3[CH:24]=[CH:23]2)[C@H:19]([OH:43])[C@@H:18]1[OH:44].O=[C:46]1[CH2:49][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:30]1[C:25]2[CH:24]=[CH:23][N:22]([C@@H:20]3[CH2:21][C@H:17]([CH2:16][NH:15][CH:46]4[CH2:47][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49]4)[C@@H:18]([OH:44])[C@H:19]3[OH:43])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CCOC(=O)CCC1CC(=O)C1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@@H](O)[C@H]2O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@H](O)[C@@H]2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Sodium triacetoxyborohydride (2.43 g, 11.5 mmol) was added to a solution of (1S,2R,3R,5R)-3-(aminomethyl)-5-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2.6 g, 5.7 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.976 g, 5.73 mmol) and Acetic acid (0.326 ml, 5.73 mmol) in 1,2-Dichloroethane (20 ml) and reaction was stirred at RT overnight. NaHCO3 was added and the aqueous layer was extracted 3× with DCM. The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10) to give the desired compound (1.8 g) as a thick yellow resin.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:11]([OH:13])=O)[CH:3]=[CH:2]1.[Cl-].[NH4+:15].N>C(O)C>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:11]([NH2:15])=[O:13])[CH:3]=[CH:2]1
Reactant: [NH4+]
Reactant: O=C(O)Cc1ccnc2ccsc12
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: NC(=O)Cc1ccnc2ccsc12
Temperature: -78 °C
Yield: 55.6 %

Procedure:
In a high pressure flask, dissolve (thieno[3,2-b]pyridin-7-yl)acetic acid (3.02 g, 13.65 mmol) in absolute ethanol (100 mL). Add ammonium chloride (1.09 g, 20.38 mmol) to the solution. Cool the solution to −78° C. Condense ammonia gas into the solution by bubbling (15 minutes at 10 psi). Seal the flask and slowly bring to ambient temperature. Stir the reaction at room temperature for 4 days. Cool the reaction vessel to −78° C. Open the flask and allow it to slowly return to ambient pressure. Filter the contents and wash with water (10 mL) to obtain the title compound as a white solid (1.46 g). Concentrate the filtrate and triturate the residue with diethyl ether. Filter and wash with water (5 mL) to obtain additional pure product (0.46 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Br)c1

Procedure:
A mixture of 2.0 g (10.7 mmol) 2-chloro-5-nitroanisole, 1.65 g (11.2 mmol) 4-bromoimidazole and 5.21 g (16.0 mmol) cesium carbonate in 50 ml acetonitrile was refluxed overnight. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the residue purified on silica gel with ethyl acetate/heptane 3/7. After trituration with diethyl ether 707 mg (22%) of 4-bromo-1-(2-methoxy-4-nitro-phenyl)-1H-imidazole was isolated as a slightly brownish solid. MS ISP (m/e): 298.1/300.0 (100/87) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.96 (d, 2H), 7.77 (s, 1H), 7.44 (d, 1H), 7.26 (s, 1H), 4.02 (s, 3H).