Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH:17](OC)([O:20][CH3:21])[O:18]C.[CH3:24][C:25]1[CH:26]=[CH:27][C:28](S(O)(=O)=O)=[CH:29][CH:30]=1>C1(C)C=CC=CC=1.CO>[C:17]1([C:26]2[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:21][O:20]1)=[O:18]
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1occc2ccccc12
Temperature: 25 °C

Procedure:
To a stirred solution of the isocaumarin from step 3 above (9.4 mg, 0.4 mmol) in 8 ml of toluene was added dropwise a solution of DIBAL-H (1M, 0.50 ml, 0.50 mmol) at -78° C. under argon. The resulting mixture was stirred at -78° C. for 1.5 hour before Na2SO4 10 H2O (100 mg, 0.31 mmol). After the reaction was warmed to room temperature, it was filtered to remove the solids, and washed with acetone. The filtrate was evaporated to give an oily residue which contained the corresponding lactol. Without further purification, the residue was treated with 5 ml of CH3OH, 1 ml of CH(OMe)3, and PTSA (30 mg, 0.16 mmol) at room temperature for 10 minutes. The solvents were removed by rotavapor and the residue was purified by flash chromatography with hexane and ethyl acetate (7:3) to give pure title isocoumarin (65 mg, 0.26 mmol) in 65% overall yield. 1H NMR (CDCl3) δ:2.47 (1H, dd, J=17.2, 12.0 Hz), 2.85 (1H, dd, J=17.2, 3.6 Hz), 3.56 (3H, s), 3.78 (3H, s), 3.82 (3H, s), 4.63 (1H, m), 5.24 (1H, dt, J=10.6, 1.4 Hz), 5.43 (1H, dt, J=17.3, 1.4 Hz), 5.63 (1H, s), 6.05 (1H, m), 6.70 (1H, d, J=8.9 Hz), 6.76 (1H, d, J=8.9 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=O)[CH3:2].P(Cl)(Cl)(Cl)=O.C(OC([S-])=[S:37])C.[K+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=[S:37])[CH3:2]
Reactant: CCOC(=S)[S-]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At -20° C., 5.79 g of 1,1-diethyl-3-(6-methyl-12-methylthio-8α-ergolinyl)urea (15 mmol) is dissolved in a mixture of 4.13 g of freshly distilled phosphorus oxychloride (45 mmol) and 50 ml of anhydrous methylene chloride and the temperature is allowed to rise within 4 hours to +10° C. The mixture is stirred overnight at room temperature and then another 2 hours at 40° C.,and the solvent is subsequently distilled off under vacuum. The residue is dissolved in 50 ml of anhydrous acetonitrile, cooled to -10° C., combined with 7.2 g of potassium ethylxanthate (45 mmol), and stirred at room temperature for 20 hours. The solvent is exhaustively removed by distillation; then the mixture is distributed between ethyl acetate and saturated sodium carbonate solution; the organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate, yielding 82%.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18]C)=O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(O)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:16](=[O:18])[C:7]3[N:8]=[N:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:6]=3[NH:30]2)=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1nnc2ccccc2c1O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=c1c2nnc3ccccc3c2[nH]n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (326 g, 200 ml) was added dropwise under inert atmosphere to methyl 4-hydroxycinnoline-3-carboxylate (10.0 g, 49 mmol). The mixture was heated to reflux for 2.5 h, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (100 ml) was added to the residue and removed under vacuum. This procedure was repeated with further toluene (100 ml). A brown semi-solid material was obtained and taken up in ethanol (200 ml). 4-Nitrophenylhydrazine (5.99 g, 39.2 mmol) was added portionwise. The mixture was stirred at room temperature overnight. The mixture was heated to 40-45° C. for 1 h and cooled to room temperature. The solids were collected by filtration, triturated with ethanol (100 ml) and dried under vacuum. The title compound was isolated as a brown solid (8.42 g, 27.4 mmol, 70%). LCMS: m/z 308 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)=[N:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)C1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 60.7 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)pyrrolidin-3-ylcarbamate (418 mg, 1.5 mmol) to afford the desired product (336 mg, 61%) as a yellow solid: ESI MS m/z 553 [C26H29BrN6O3+H]+.
Reaction SMILES: N1CCCCC1.C(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:20])(O)=O.Cl>C1(C)C=CC=CC=1>[O:20]=[C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])/[CH:18]=[CH:15]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1ccccc1)Nc1ccccc1C(=O)O
Yield: 96.1 %

Procedure:
Piperidine (0.42 mL, 4.2 mmol) was added to a suspension of benzaldehyde (0.43 mL, 4.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.83 g, 3.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[(1-oxo-3-phenyl-2-propenyl)amino]benzoic acid (0.95 g, 96%) was obtained as a pale yellow crystalline solid; mp 188-189° C., lit. [23] 196-197° C.; δH (500 MHz, DMSO-d6) 6.88 (d, J=16.0 Hz, 1H, CH═CHCO), 7.18 (t, J3,4=J4,5=8.0, 1H, H4), 7.41-7.45 (m, 3H, H3′, H4′, H5′), 7.62 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.62 (d, J=16.0 Hz, 1H, CH═CHCO), 7.72-7.74 (m, 2H, H2′, H6′), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.59 (d, J5,6=8.0 Hz, 1H, H6), 11.32 (s, 1H, NH).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[N:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(c1cnc(-n2ccnc2)nc1)N(C1CCNCC1)C1CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-imidazol-1-yl-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.40 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C@H:35]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][CH:46]=1)[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:57][C:55]1[CH:54]=[CH:53][C:52]([F:58])=[C:51]([C:48]2[CH:47]=[CH:46][C:45]([CH2:44][C@@H:35]([NH:34][C:7]([C:4]3[O:3][C:2](=[O:1])[NH:6][CH:5]=3)=[O:9])[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39])=[CH:50][CH:49]=2)[CH:56]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1c[nH]c(=O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.4 %

Procedure:
2-Oxo-2,3-dihydrooxazole-5-carboxylic acid (7.1 mg, 55 μmol) and HATU (21 mg, 55 μmol) were combined in DMF (0.3 mL) and stirred at room temperature for 5 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF (0.5 mL) and DIPEA (29 μL, 164 μmol) were added, and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3 mg). MS m/z [M+H]+ calc'd for C23H22ClFN2O6, 477.12. found 477.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH2:20])[CH2:13]2>C1(C)C=CC=CC=1.C1COCC1>[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH:20][C:10]([NH:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)=[O:11])[CH2:13]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorophenyl isocyanate (1.88 g, 10 mmol) in toluene (20 ml) was added at 0° to 1-azabicyclo[2.2.2]octan-3-amine (3-aminoquinuclidine) (1.26 g, 10 mmol) in THF (40 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was partitioned between ether and dilute hydrochloric acid. The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate. The dried (Na2SO4)ethyl acetate phase was evaporated and the residue (1.64 g) converted to the 1:1 oxalate, quarter hydrate, mp 208°-209° C. (dec).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(Cn2nc(-c3ccncc3)nc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-Bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mol) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1 g., 0.024 mol.) and the mixture is heated 45 minutes at reflux. The suspension is concentrated to a solid, N,N-dimethylformamide (70 ml.) and benzyl chloride (2.8 g., 0.022 mol.) are added. The mixture is stirred 0.5 hour at ambient temperature followed by 4 hours at steam bath temperature. The solution is concentrated to a gum, water is added and the material solidifies. After recrystallization from methylcyclohexane 1.4 g. of 1-benzyl-3,5-bis(4-pyridyl)-1,2,4-triazole, melting at 136-138° C. is obtained.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]=[CH:5]1>C1C=CC=CC=1.C(O)C>[CH3:1][NH:2][CH:6]1[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4](=[O:3])[CH2:5]1
Reactant: O=C1C=CCCc2ccccc21
Reactant: CN
Solvent: c1ccccc1
Solvent: CCO
Product: CNC1CCc2ccccc2C(=O)C1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A solution of 22.7 g of monomethylamine in 160 ml of benzene was added to a solution of 40 g of 5-oxo-8,9-dihydro [5H] benzocycloheptene in 400 ml of ethanol and the mixture was stirred for 2 1/2 hours and was evaporated to dryness to obtain 47.5 g of 7-methylamino-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 7.0 mL of 4-methoxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p.159°-162° C. (dec.)). 1H NMR (CDCl3) δ 2.91 (dd, 2 H), 3.57 (dd, 2 H), 3.83 (s, 3 H), 5.66 (dd, 1 H), 6.93-6.97 (m, 2 H), 7.30-7.34 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:27]([O:31][CH2:32]C)[O:28][CH2:29]C)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:27]([O:28][CH3:29])[O:31][CH3:32]
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(Br)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(Br)c(C(OC)OC)c1
Yield: 53 %

Procedure:
Step AH (2): 2-Bromo-5-methoxybenzaldehyde (1069 mg, 4.975 mmol) was dissolved in a mixture of methanol (20 mL) and triethylorthoformate (20 mL). p-Toluenesulfonic acid monohydrate (180.0 mg, 0.946 mmol) was added and the reaction mixture was stirred under reflux for 5 h. The reaction was quenched with aqueous NaHCO3 and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum at the temperature, not exceeding 35° C. The residue was purified by silica gel chromatography to give 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (688.5 mg, 53%) as colorless oil. LC-MS (M+H)+=261.00. 1H NMR (CDCl3, 500 MHz) δ 7.42 (d, J=7.0 Hz, 1H) 7.16 (d, J=3.0 Hz, 1H) 6.76 (dd, J1=10 Hz, J2=3.0 Hz, 1H) 5.50 (s, 1H) 3.80 (s, 3H) 3.39 (s, 6H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=O)(C)(C)C.Cl.[CH3:22]O>C(OCC)C>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([CH2:17][C:18]([O:20][CH3:22])=[O:19])[CH2:9]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CC(=O)O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C[C@@H]1CNc2ccccc21
Temperature: 5 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(+)-(S)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (14.2 g, 0.05 mol) was dissolved in methanol (600 mL), cooled (5° C.) and a saturated solution of HCl in diethyl ether (150 mL) was added. The resulting mixture was stirred at room temperature for 16 h, concentrated in vacuo to about 50 mL and poured onto an ice/water mixture. The aqueous phase was extracted with ethyl acetate and diethyl ether, and the combined organic phases were washed with aqueous ammonia and brine. The organic phase was dried and concentrated in vacuo to give the title compound (9.8 g, 100%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CCOCC>[Pd].C(O)C>[ClH:1].[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN1CCc2ccc(N)cc2C1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A suspension of 3.98 g (17.5 mmol) of 7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and 0.4 g of 10% palladium on carbon in 200 ml of ethanol was hydrogenated at 50 psi for 2 h. The catalyst was filtered and washed with a small amount of water. The filtrate was concentrated yielding an aqueous solution. Absolute ethanol was added and evaporated driving off the excess water until a solid was produced. This solid was dissolved in hot ethanol (60 ml) and ether was added slowly to induce crystallization. The product was collect to give 3.38 g (97%) of the title compound as an off-white solid, m.p. 114°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:6]1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:6]1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Temperature: 40 °C

Procedure:
To a solution of methyl 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (2000 mg 5.123 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (430 mg 10.246 mmol, 2 eq.) and water (10 mL) and the clear solution was warmed to 40° C. for 3 hours. THF was removed under vacuum and 1 M HCl added (10.3 mL 10.3 mmol, 2 eq.). The crude product was extracted into EtOAc (3×30 mL), then DCM:MeOH 100:5 (3×30 mL). The organics were dried (Na2SO4), volatiles were removed in vacuo to give the title product as a cream colored powder 1563 mg (82%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, ESI, +mode): RT—0.91 min, m/e=377.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ=3.42 (s, 3H), 3.46 (m, 2H), 3.60 (m, 2H), 4.69 (s, 2H), 5.66 (s, 2H), 7.07 (m, 1H), 7.36 (m, 2H), 7.82 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14].O1CCOCC1>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][C:4]([F:10])=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:14]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(F)c(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution comprising 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5M, 7.5 mmol) was stirred at room temperature for 3 hours to give a fine white precipitate. The mixture was diluted with an equal volume of water to dissolve the white precipitate and give yellow crystals. The crystals were isolated were collected and dried to provide 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yellow needles; m.p. 66° C.; 1H NMR (CDCl3) δ 6.4 (1H, m), δ 6.0 (2H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[C:18]1([S:24]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCOc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25, 3.67 g, 11.5 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (506.0 mg, 12.65 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then benzenesulfonyl chloride (26, 1.614 mL, 12.65 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (27, 4.50 g). MS (ESI) [M+H+]+=460.0.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([NH2:21])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][C:19]#[N:21])=[CH:24][CH:25]=1
Reactant: CC(C)(CC(N)=O)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(CC#N)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
2.7 g of 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutanamide are dissolved in 50 ml of chloroform. 2.3 ml of phosphorus oxychloride are added and the mixture is refluxed for 5 hours. After cooling, the solvents are evaporated off under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum to give an oil which crystallizes from ether. The crystals are filtered off, washed with ether and then dried to give 2.5 g of 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutyronitrile in the form of crystals melting at 110° C.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=CC=1C#N)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide (328 mg, 7.83 mmol) in water (20 m) was added dropwise to a stirred solution of (2-cyanophenyl)methyl 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 34; 350 mg, 0.78 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 18 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The residual water phase was extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 160 mg.