Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C:15]([CH3:25])([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1(C)Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1(C)Cc2ccccc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C@@H:5]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][C@H:6]1[OH:17].[H][H].[BrH:25]>C(O)C.[Pd]>[BrH:25].[CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C@@H:5]1[CH2:9][NH:8][CH2:7][C@H:6]1[OH:17]
Reactant: Cc1cccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: Cc1cccc(O[C@@H]2CNC[C@H]2O)c1C
Yield: 55 %

Procedure:
A solution of 9.1 g. (0.031 mole) of trans-4-(2,3-dimethylphenoxy)-1-phenylmethyl-3-pyrrolidinol in 100 liters of ethanol was hydrogenated over 10% palladium-on-charcoal at 50 psi and 60° C. until hydrogen uptake ceased. The mixture was filtered through Celite and the filtrate was concentrated to give an oil as residue which solidified upon standing. The solid was converted to the hydrobromide and this salt was recrystallized from isopropyl alcohol-ethylacetate-diethylether to yield 4.9 g (55%) of tan needles, m.p. 152°-3° C.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7](=[O:33])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:29](=[CH:30][CH:31]=1)[O:28][C:15]1([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23]C(C)(C)C)=O)[CH2:16]1)[CH2:14][C:13]2=[O:32]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:33])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:29](=[CH:30][CH:31]=1)[O:28][C:15]1([CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:23])[CH3:1])[CH2:16]1)[CH2:14][C:13]2=[O:32]
Reactant: CC(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Acetyl chloride (168 mg, 2.14 mmol) was added dropwise to a stirred solution of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (Intermediate 2, 600 mg, 1.78 mmol) and TEA (0.742 ml, 5.33 mmol) in DCM (30 ml). The resulting mixture was stirred overnight at RT, then washed with 5% NaHCO3, brine and dried over Na2SO4. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (609 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCN2CCOCC2)ccc1Br
Yield: 70 %

Procedure:
To a mixture of 2-bromo-5-hydroxybenzaldehyde (62; 3 g, 15 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (120; 5.6 g, 30 mmol) in DMF (75 mL) was added K2CO3 (10.3 g, 74.6 mmol). After reaction 2 h at 120° C. for 3 h, the reaction mixture was quenched by addition of water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography afforded 2-bromo-5-(2-morpholinoethoxy)benzaldehyde 121 (3.3 g, 72%) as a brown solid.
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH:10]1C=CC=C[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)C>O>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][CH:10]([CH3:11])[O:4][CH2:3]1
Reactant: O=[N+]([O-])C(Br)(CO)CO
Reactant: c1ccccc1
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1OCC(Br)([N+](=O)[O-])CO1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Forty grams (0.2 mole) of 2-bromo-2-nitropropane-1,3-diol were suspended in 200 ml. of benzene and about 0.3 g. of p-toluene sulfonic acid was added. The mixture was cooled in an ice-water bath and a condenser attached to the reaction vessel. About 13.5 g. (0.3 mole) of acetaldehyde were slowly added through the condenser and the reaction mixture was stirred for 30 minutes. A Dean-Stark trap was connected and the mixture warmed slowly, then heated to reflux until water no longer was evolved. (About 4 ml. of water was evolved in 1.5 hours). The solution was filtered and evaporated on a rotating evaporator at about 45° C. A dark oil residue was obtained, which was vacuum distilled at 0.25 mm. Thirty-six and one-half grams (85% yield) of 5-bromo-2-methyl-5-nitro-1,3-dioxane were obtained having a boiling range at 0.25 mm. of from 72°-74° C. The NMR and IR were consistent with the structure, and an elemental analysis disclosed the following percentage composition:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:22]([O:24][C:25](=[O:30])[CH:26]=[C:27](Cl)[CH3:28])[CH3:23]>O1CCCC1>[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](/[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)\[CH3:28])[CH3:23]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1ccccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1OCc1ccccc1
Temperature: 23 °C
Yield: 73 %

Procedure:
Potassium t-butoxide (5.60 g, 0.05 mol) was added to a stirred solution of 2-benzyloxy-phenol (5.00 g, 0.025 mol) in tetrahydrofuran (50 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 3.70 g, 0.025 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-benzyloxy-phenoxy)-but-2-enoic acid ethyl ester (5.70 g, 73%) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C:28]1[C:29]([CH3:31])=[N:30][C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:26][CH:27]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)N2CC3CN(c4ncc(F)c(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288-step B, 33 mg, 0.10 mmol), 2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10 mmol) and DIPEA (54 μL, 0.3 mmol) in ACN (1 mL) were heated in a microwave reactor for 2 h at 200° C. Then the reaction mixture was concentrated and purified via prep HPLC (Agilent, basic) gave the title compound as a clear oil. MS (ESI) mass calcd. C21H22FN7O2, 423.45; m/z found 424.2 [M+H]+. 1H NMR (CDCl3): 8.06 (d, J=1.8 Hz, 1H), 7.74 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd, J=11.4, 5.2 Hz, 1H), 3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t, J=4.9 Hz, 3H).
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:25])[C:13](=[O:24])[C:14]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:20]([C:14]1([CH2:22][CH3:23])[C:13](=[O:24])[CH:12]([CH3:25])[NH:11][C:15]1=[O:16])[CH3:21]
Reactant: CCOC(=O)C(CC)(CC)C(=O)C(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)C(=O)NC(C)C1=O
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-{[benzyloxy)carbonyl]amino}-3-oxopentanoate (3.0 g) in acetone (50 mL) were added potassium carbonate (2.83 g) and iodoethane (2.45 mL), and the mixture was refluxed overnight. After allowing to room temperature, potassium carbonate (2.83 g) and iodoethane (2.45 mL) were added, and the mixture was refluxed for 1 day. After allowing to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→3:2) to give ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-diethyl-3-oxopentanoate as a colorless oil (yield: 1.91 g, 53%). To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-diethyl-3-oxopentanoate (1.91 g) in methanol (15 mL) was added 10% palladium carbon (containing 50% water, 1.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (yield: 920 mg, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
20 g (93.8 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6 -one in 100 ml of dimethylformamide are treated with 17.5 g (98 mmol) of N-bromosuccinimide and stirred at room temperature for 35 minutes. The solution is poured into water and extracted twice with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. After recrystallization from ethyl acetate, the residue yields 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 196°-198°.
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[NH:19][C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]([CH3:1])[C:18]2=[O:27])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
MeI (0.377 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and NaH (0.362 g) in DMF (20 mL) at 20° C. The mixture was stirred at 20° C. under a dry atmosphere for 1 h. The mixture was diluted with sat. NaHCO3 at 20° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g). This product was subjected to the next reaction without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.OS(O)(=O)=O>O>[CH2:8]([NH:15][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC1CCc2ccccc21
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CNC2CCc3ccccc32)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
A mixture of 272 ml of toluene and 199.5 g benzylamine was prepared and heated to 90° C. The chlorindan was added dropwise to the mixture over a 30 minute period. The reaction mixture was heated to 115° C. for ten hours. The reaction mixture was cooled to ambient temperature and 300 ml of water was added. The resulting heterogeneous mixture was then brought to pH2.2 by the addition of 33% H2SO4. The phases were separated and the organic layer discarded. The pH of the aqueous layer was adjusted to pH6.0 prior to extraction with 300 ml of toluene. A further 100 ml of toluene was then added and the aqueous phase discarded. The toluene was removed under vacuo from the combined organic layer leaving 104.3 g racemic N-benzyl-1-aminoindan base as an oil (72.5 % yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred solution of 0.50 g (3.10 mmol) 1H-indole-3-carboxylic acid in 5 ml DMF was added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromide was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 0.61 g (78%) of 1-benzyl-1H-indole-3-carboxylic acid as a white solid. ES-MS m/e (%): 250 (M−H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:22][O:23][CH2:24][CH2:25]Br.[Cl-].[NH4+]>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:25][CH2:24][O:23][CH3:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: COCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCC1(C(=O)OC)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of diisopropylamine (21 mL, 150 mmol) in THF (100 mL) was added dropwise a solution of n-butyl lithium (58 mL, 145 mmol) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of methyl cyclopentane carboxylate (12.8 g, 100 mmol) in THF (20 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 30 min at −50 to −60° C. Then, a solution of 2-methoxy ethyl bromide (12.5 g, 90 mmol) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 30 min at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (250 mL) and was extracted with ether (2×100 mL). The combined extracts were washed with a saturated solution of sodium chloride (100 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum to afford 16.55 g of crude product as a black liquid. Distillation at 70-75° C./1.5 mm Hg afforded 7.98 g of a colorless oil and a further 2.76 g as a light yellow oil for a total yield of 10.74 g (64%). HR MS (C10H18O3): Obs. mass, 186.1257. Calcd. mass, 186.1256 (M+).
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=1)(C)(C)C.[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:28])=[O:5])=[CH:12][CH:11]=1)=[O:25]
Reactant: COC(=O)CCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCCCCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(11-Methoxycarbonylundecyl)benzoic acid tert-butyl ester (185 mg, 0.47 mmol) was dissolved in THF (2 ml), and 1 N NaOH (0.497 mmol) was added over 1 min. The mixture was stirred for 16 h at rt. AcOEt (50 ml) was added and the solution was washed with 5% AcOH (2×25 ml), dried over MgSO4 and concentrated under vacuum to the product (153 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])C=C.[CH2:20]1[CH:29]2C(CCCC2)CC[CH2:21]1>>[CH2:29]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc(F)cc1-c1c(Cl)cccc1Cl
Reactant: C1CCC2CCCCC2C1
Product: C=CCc1cc(F)cc(-c2c(Cl)cccc2Cl)c1O
Yield: 84 %

Procedure:
A solution of 2-allyloxy-2′,6′-dichloro-5-fluorobiphenyl (11.02 g, 37 mmol) in decahydronaphthalene (100 mL) was refluxed for 38 h. The solvent was removed under vacuum. Chromatography with 0–20% ethyl acetate in hexanes afforded 9.26 g (84%) of 3-ally-2′,6′-dichloro-5-fluorobiphenyl-2-ol as a light yellow oil. MS (ES) m/z 295.0 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:14][CH:13]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1)#[N:2].Cl.[NH2:39][OH:40].C(N(CC)CC)C>C(O)C>[NH2:2][C:1](=[N:39][OH:40])[C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:34][CH:35]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1
Reactant: NO
Reactant: N#Cc1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
The compound (20 mg, 0.04 mmol) of Example 54 was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (14 mg, 0.21 mmol) and triethylamine (0.058 mL, 0.42 mmol) were added thereto, and stirred at room temperature for 2 hours. After that, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:8][CH:9]=1)([O-])=O.Cl>C(O)C.O>[C:20]1([C:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]#[C:10][C:7]3[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:15][CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reaction time: 0.5 h

Procedure:
A solution of 1,2,3,6-tetrahydro-1-[4-(5-nitro-2-pyridinyl)-3-butynyl]-4-phenylpyridine (Example 9) (2.0 g, 0.006 mol), reduced iron (3.1 g), and 0.10 mL of concentrated hydrochloric acid in 30 mL of 95% ethanol and 10 mL of water is heated at 80° C. with vigorous stirring for 30 minutes. The hot solution is filtered through diatomaceous earth (Celite), and the filter cake is washed with 300 mL of hot ethanol. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 135.5°-137° C.
Reaction SMILES: I[Si](C)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26]C)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11].CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][OH:26])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
Iodotrimethylsilane (5.61 mL, 39.39 mmol) was added to 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (2.5 g, 7.88 mmol) in acetonitrile (25 mL) and the reaction stirred at RT for 20 hours. Methanol (15 mL) was added and stirred for 1 hour then a saturated solution of sodium thiosulphate (10 mL) was added and stirred for a further 20 mins. The volatiles were removed in vacuo and the aqueous residue extracted into ethyl acetate (2×150 mL). The organics were washed with water (100 mL), brine (100 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a white solid (2.03 g). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.48 (s, 3H), 3.44-3.59 (m, 2H), 4.50 (sextet, 1H), 4.87 (t, 1H), 6.53 (t, 1H), 6.98 (s, 1H), 7.11 (s, 1H), 8.36 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H), 10.89 (s, 1H); m/z 304 (M+H)+