Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1.[CH3:29]I.O>C1COCC1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([O:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@H:4]2[O:3][CH3:29])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
Reaction under nitrogen atmosphere. Sodiumhydride (0.3 mol) was added to a solution of 1,1-dimethylethyl trans-3-hydroxy4-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c)] (0.27 mol) in THF (1300 ml). The mixture was stirred for 30 minutes. Methyliodide (0.54 mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. The solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1,1-dimethylethyl trans4-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-3-methoxy-1-piperidinecarboxylate (intermediate 49).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].C(Cl)Cl.O.[NH2:16][NH2:17]>>[C:1]([C:3]1[CH:10]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:17][N:16]=[CH:8]2)#[N:2]
Reactant: NN
Reactant: N#Cc1ccc(F)c(C=O)c1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Reaction time: 8 h

Procedure:
5-Cyano-2-fluorobenzaldehyde (512 mg, 3.43 mmol) was dissolved in hydrazine hydrate (25 mL) at room temperature and the solution left to stand overnight. To this reaction mixture was added methylene chloride (30 mL). The mixture was purified by filtration through a pad of silica eluting with methylene chloride, concentrated in vacuo to afford a white solid:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.S([O-])(O)=O.[Na+].CN(C=O)C>O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: O=Cc1ccccc1F
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccccc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 153 °C
Yield: 30.2 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.91 g), 2-fluorobenzaldehyde (1.86 g), sodium hydrogen sulfite (1.56 g), and DMF (10 ml) was stirred with heating under reflux at 153° C. for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.89 g of 2-(2-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound (1E)-F1).
Reaction SMILES: [CH:1]1([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.C(N(S(F)(F)[F:28])CC)C.C([O-])(O)=O.[Na+]>>[CH:1]1([CH:6]([F:28])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(c2ccc(C(F)C3CCCC3)cc2)CC1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
1-{4-[Cyclopentyl(hydroxy)methyl]phenyl}cyclopropanecarbonitrile (600.0 mg, 0.002486 mol) was dissolved in methylene chloride (10 mL, 0.2 mol), cooled to −78° C., and to the solution was added diethylaminosulfur trifluoride (0.328 mL, 0.00249 mol) (DAST). The resulting reaction mixture was warmed to rt and stirred at rt for 18 h. The reaction mixture then was poured into ice-water containing NaHCO3 and the resulting mixture was extracted with CH2Cl2 (3×). The combined organic phase was dried over Na2SO4, and concentrated to afford the product.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: COC(=O)/C=C/c1ccc(CN)cc1
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(/C=C/C(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenz-aldehyde and methyl (2E)-3-[4-(aminomethyl)phenyl]acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 20/80 to 50/50 for about 30 min.) as a white solid (73%). 1H NMR (CDCl3) δ: 7.56 (d, 1H, J=16.2 Hz), 7.36 (d, 2H, J=8.3 Hz), 7.23 (m, 4H), 7.12 (m, 2H), 6.29 (d, 1H, J=15.8 Hz), 3.69-3.63 (m, 7E), 2.26 (m, 2H), 1.56-1.40 (m, 2H), 1.38-1.10 (m, 10H), 0.76 (m, 3H). M+ (ESI): 418.3. HPLC, Rt: 4.5 min (purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][OH:25])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
1.00 g (3.30 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 0.49 g (3.92 mmol) of 2-bromoethanol were dissolved in 10 ml of acetone, and 0.55 g (3.98 mmol) of potassium carbonate was added to the mixed solution. The mixture was stirred at room temperature for 15 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of chloroform and methanol in the volume ratio 20:1 as the eluent. The desired fraction was concentrated under reduced pressure to give 0.64 g (56%) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethanol as an oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(C)OCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCCCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 73 %

Procedure:
A suspension (70 ml) of 1.81 g of 60% sodium hydride in N,N-dimethylformamide was cooled to −18° C. with ice-sodium chloride bath, and 21 ml of a solution of 8.67 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added slowly. After 1-hour-stirring, 21 ml of a solution of 14.10 g of ethyl 2-(6-iodohexyloxy)-2-methylpropionate in N,N-dimethylformamide was added dropwise slowly. The bath was removed and the mixture was stirred for additional 18 hours at room temperature. The reaction solution was, after addition of ice-cold water, extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 12.20 g of the objective compound as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:30][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:28])([F:29])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:30]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C(C)O)c1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of 149 (764.1 mg, 1.894 mmol) in THF (18.9 ml) 78° C. was added drop-wise a solution of methyl magnesium bromide (1.579 ml, 4.74 mmol). The temperature was allowed to slowly warm to 0° C. and the reaction was stirred an additional hour at 0° C., then it was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated and the residue was purified by chromatography (Biotage, 20 to 70% EtOAc in hexane) to afford 153 (646 mg, 1.54 mmol, 87%) as peach oil. LRMS (ESI): (calc.) 419.2 (found) 442.2 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13](=[O:51])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18](=[O:32])[CH:17]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36](C(OC(C)(C)C)=O)[N:35]=4)[C:16]3=[O:50])[C:6]=2[CH:5]=[C:4]([CH3:52])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13](=[O:51])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18](=[O:32])[CH:17]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][N:35]=4)[C:16]3=[O:50])[C:6]=2[CH:5]=[C:4]([CH3:52])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)N(C(=O)CN1C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc31)CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)N(C(=O)CN1C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc31)CCCC2
Reaction time: 3 h
Yield: 12.8 %

Procedure:
A solution of tert-butyl 3-({1-[2-(6,8-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate (64 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 3 hours then concentrated to dryness. The residue was chromatographed on silica gel (Hexane:Ethyl Acetate. The residue was triturated with Ethyl Ether and filtered to yield the title compound as an off-white solid (7 mg).
Reaction SMILES: I[C:2]1([O:9][CH3:10])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH2:3]1>CC(C)=O.O.[Pd].[Zn]>[CH3:10][O:9][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[O:9][CH3:10]
Reactant: COC1(I)C=C(C)C=CC1
Agent: [Pd]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C)ccc1-c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Bdb was synthesized according to FIG. 15. Briefly, 1-iodo-5-methylanisole (100 mg, 0.4 mmol) was added in to a mixture of 10% Pd on carbon (100 mg) and zinc powder (100 mg, 1.5 mmol) suspended in 5.2 mL of acetone/water (1:1), and the mixture was stirred at room temperature overnight. The solution was extracted with diethyl ether and the ether layer was collected and dried over anhydrous Na2SO4. The ether was removed under reduced pressure and the residue was applied to a flash column chromatography to afford 2,2′-dimethoxy-4,4′-dimethyl biphenyl as a yellow solid (42 mg, 46%). The conversion of 2,2′-dimethoxy-4,4′-dimethyl biphenyl to 4,4′-bis-bromomethyl-2,2′-dimethoxy-biphenyl was accomplished by following a previously reported procedure and resulted in a 31% yield.
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:29]C(F)(F)C1C=C(F)C=CC=1C(Cl)=O>>[CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][C:21]([F:29])=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Product: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccc(F)cc1C(F)(F)F

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-trifluoromethyl-4-fluorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride. Data: LCMS (M/Z): 430 (M+23); 1H NMR (acetone) δ: 9.64 (br. s., 1H), 8.14 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.5, 5.4 Hz, 1H), 7.71 (dd, J=8.2, 2.0 Hz, 1H), 7.50-7.64 (m, 2H), 7.39 (d, J=8.2 Hz, 1H), 5.13 (d, J=4.8 Hz, 1H), 2.25-2.37 (m, J=8.2, 8.2, 8.2, 8.2, 4.8 Hz, 1H), 1.82-1.92 (m, 1H), 1.62-1.74 (m, 2H), 1.44-1.59 (m, 3H), 1.30-1.40 (m, 1H), 1.10-1.19 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccccc1[Mg]Br
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 2.0 M 2-methylphenylmagnesium bromide in THF (0.15 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:28])[CH2:26][N:25]([CH3:30])[CH3:24])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
55 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine was reacted with N,N-dimethylglycine via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 3 mg of 152. MS (Q1) 514 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+].O>CN1C(=O)CCC1>[F:12][C:13]([F:18])([F:17])[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 160 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
To a solution of 2-bromo-4-nitrotoluene (23.2 mmol) in NMP (200 mL) was added sodium trifluoroacetate (8.5 g, 62.5 mmol) and Cul (8.75 g, 46 mmol) and the reaction mixture was stirred at 160° C. for 4 hours. The solution was cooled and water (300 mL) was added. The solution was filtrated and the solid was washed with ethyl ether (250 mL×3). The organic phase was washed with water and brine, dried, filtered, concentrated and purified through column chromatography to give 2-(trifluoromethyl)-4-nitrotoluene (3.12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: N#CCBr
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.2 %

Procedure:
4-Methyl-3-nitrophenol (5.0 g) (TCl America, Portland, Oreg.) and 4.70 g of bromoacetonitrile were dissolved in 30 ml of 2-butanone; then 13.5 g of potassium carbonate was added and the mixture was stirred and heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate, washed with water, dried, and evaporated to give 6.1 g of (4-methyl-3-nitrophenoxy)-acetonitrile as a brown oil. ##STR74##
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:2]#[CH:3]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 530 mg (98%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:1])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(OC(F)(F)F)ccc1O
Yield: 100 %

Procedure:
A mixture of 4.53 g of 4-trifluoromethoxy-2-nitrophenol, 35 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 1.7 hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 3.92 g of 2-amino-4-trifluoromethoxy phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=O)[C:8]=1[CH2:9][C:10]([OH:12])=O.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([N:19]1[C:10](=[O:12])[CH2:9][C:8]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:13]1=[O:15])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: COc1cccc(C(=O)O)c1CC(=O)O
Product: C=CCN1C(=O)Cc2c(OC)cccc2C1=O

Procedure:
A mixture of 6-methoxyhomophthalic acid (9.7 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) is heated by an oil bath until molten for 40 minutes. The mixture solidifies upon cooling and is recrystallized from isopropanol, giving 2-allyl-5-methoxyisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2>>[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:26][CH:25]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(O)c1cccc(-c2cc3nccc(Cl)c3s2)n1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(C(C)(C)O)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-[6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-propan-2-ol and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.05 (d, 1H), 7.83 (s, 1H), 7.75 (m, 2H), 7.53 (d, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.95 (d, 1H), 6.56 (d, 1H), 6.10 (s, 1H), 2.40 (s, 3H), 1.54 (s, 6H); RP18-HPLC RT: 5.05 minutes; API MS: 415 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].[F-].[K+].C1(C)C=CC=CC=1>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.O>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2ncccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 55.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.076 g) was added to a deoxygenated mixture of 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.69 g), 4-isobutylphenylboronic acid (0.47 g), potassium fluoride (0.38 g), toluene (15 ml) and water (2.5 ml) and the mixture was stirred and heated under reflux for 24 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extracts were washed with saturated sodium chloride solution and then combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with dichloromethane/hexane (1:1-1:0 v/v) then dichloromethane/hexane/ethyl acetate (10:9:1 v/v) through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-nitrophenyl 2-(4-isobutylphenyl)pyridine-3-sulphonate (0.50 g), m.p. 123°-124° C.; 1H NMR (d6 -DMSO): 0.9 (d, 6 H), 1.9 (m, 1 H), 2.55 (d, 2 H), 7.2-7.3 (m, 4 H), 7.5 (d, 2 H), 7.7 (dd, 1 H), 8.2 (d, 2 H), 8.4 (dd, 1 H), 9.0 (dd, 1 H); mass spectrum (+ve FAB, NBA/DMSO): 413 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnoc1-c1ccccc1
Reactant: C1CCNC1
Product: O=C(c1cnoc1-c1ccccc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(phenyl)isoxazole-4-carboxylic acid (9.5 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (12.9 mg). MS (pos) m/z 243.2 (M+H).