Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:24])[C:10]([S:22][CH3:23])=[CH:11][CH:12]=[C:13](N(C)C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.C([OH:28])C>>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:24])[C:10]([S:22][CH3:23])=[CH:11][CH:12]=[C:13]([OH:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(O)c(O)c1)N(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(O)c(O)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
The procedure is as in Example 4, starting with ethyl 6-(3,4-dihydroxyphenyl)-2-dimethylamino-5-methylthio-6-oxo-2,4-hexadienoate (1.9 g) and 1N aqueous hydrochloric acid solution (10.8 cc) in ethanol (10.8 cc). The mixture is heated to boiling for 5 minutes, and then cooled to a temperature in the region of 20° C. After purification by crystallization in isopropyl ether (100 cc), ethyl 6-(3,4-dihydroxyphenyl)-2-hydroxy-5-methylthio-6-oxo-2,4-hexadienoate (0.6 g), m.p. 156° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:35]([N:39]=[C:40]=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([NH:39][C:40](=[O:41])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
N-({1-[4-(4-Amino-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 15, 100 mg, 0.21 mmol) in DMF (2 mL) was treated with t-butyl-isocyanate (Aldrich, 25 mg, 0.25 mmol) at room temperature for 48 hours. The reaction mixture was directly purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a suspension of 3-bromo-5-iodo-benzoic acid (6.5 g, 20 mmol) in 25 mL of methanol was added SOCl2 (1.14 mL, 40 mmol) dropwise at 0° C. The mixture was then warmed to room temperature and stirred at room temperature for 2 days. The precipitates formed were collected by filtration to afford the desired product as white solid 5.12 g (75%). LC/MS m/e calcd. for C8H6BrIO2: 341, observed (M+H)+: 342.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH:6]=2.C(=O)([O-])O.[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>O1CCCC1.O>[C:31]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([OH:1])[C:3]([C:23]([OH:25])=[O:24])=[CH:4]2)=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:33])[CH3:32]
Reactant: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(Cc1ccc2cc(O)c(C(=O)O)cc2c1)c1ccc(C(C)C)cc1
Yield: 79.5 %

Procedure:
3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic acid (25 mg, 0.07 mmol) (example 363) was suspended in tetrahydrofuran (200 μL). A solution of sodium hydrogencarbonate (23 mg, 0.27 mmol) in water (200 μL) was added followed by acetic anhydride (14 μL, 15 mg, 0.15 mmol). The reaction mixture was stirred vigorously for 65 hours at room temperature before 6 N hydrochloric acid (4 mL) was added. The precipitate was filtered off and rinsed with water (3×1 mL) to yield the title compound (21 mg). No further purification was necessary.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[S:33][CH2:32][CH:31]([CH3:34])[NH:30][C:29]3[N:35]([CH2:44][CH3:45])[N:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[C:28]2=3)=[C:23]([CH3:46])[CH:22]=1.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>CN(C=O)C.[Cu]I.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>[CH2:44]([N:35]1[C:29]2[NH:30][CH:31]([CH3:34])[CH2:32][S:33][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])=[CH:22][C:23]=3[CH3:46])[C:28]=2[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:36]1)[CH3:45]
Reactant: C#CC(C)(C)O
Reactant: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(C#CC(C)(C)O)cc1C
Temperature: 150 °C
Yield: 59.4 %

Procedure:
To a microwave vial was added CuI (2.7 mg, 0.014 mmol), PdCl2(PPh3)2 (0.040 g, 0.056 mmol), PPh3 (0.059 g, 0.23 mmol), 4-(4-bromo-2-methylphenyl)-1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine (0.500 g, 1.13 mmol, prepared using B from Example #2, step A with ethyl hydrazine oxalate, J with 4-bromobenzaldehyde and 1-sulfanylpropan-2-one [Enamine] and K with Na(OAc)3BH) as a solution in DMF (3.76 ml), 2-methylbut-3-yn-2-ol (0.197 ml, 2.26 mmol) and TEA (2.36 ml, 16.9 mmol). The vial was sealed and the solution was sparged with N2 for about 15 min. The mixture was heated in a microwave (300 W, pressure limit 250 atm) at 150° C. for 6 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; heptane/EtOAc 1:0 to 0:1) to give 4-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)-2-methylbut-3-yn-2-ol (0.3 g, 59% yield); LC-MS (Table 1, Method g) Rt=2.52 and 2.55 min.; MS m/z: 447.17 and 447.17 (M+H)+.
Reaction SMILES: ClCCC1C=CC(OC)=CC=1.[BrH:12].Br.N1CCC([NH:20][C:21]2[N:25](CC3N=CSC=3)[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)CC1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[BrH:12].[BrH:12].[NH:22]1[C:23]2[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=2[N:25]=[C:21]1[NH2:20]
Reactant: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1cscn1
Agent: Br
Agent: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2ccccc2[nH]1

Procedure:
A mixture of 4.7 parts of 1-(2-chloroethyl)-4-methoxybenzene, 14 parts of N-(4-piperidinyl)-1-(4-thiazolylmethyl)-1H-benzimidazol-2-amine dihydrobromide.monohydrate, 15 parts of sodium carbonate, 0.3 parts of sodium iodide and 90 parts of N,N-dimethylacetamide was stirred overnight at 80° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was converted into the hydrobromide salt in ethanol. The salt was filtered off and dried, yielding 9 parts of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1-(4-thiazolyl)-methyl)-1H-benzimidazol-2-amine dihydrobromide. dihydrate; mp. 239.2° C. (compound 17).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 510 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine, 200 mg of (3R)-3-ethynyl-3-quinuclidinol, 139 mg of tetrakis (triphenylphosphine) palladium (0), 11 mg of cuprous iodide, 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 281 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:19]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([C:20]1[CH:25]=[CH:24][C:23](/[CH:17]=[CH:16]/[CH2:15][CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:18])=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Ic1ccc(Cc2ccccc2)cc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (0.380 g, 1.233 mmol) in acetonitrile (4 mL) was added to a flask containing 1-benzyl-4-iodo-benzene (0.3649 g, 1.233 mmol) and cesium carbonate (0.4102 g, 1.233 mmol). Palladium(II) acetate (0.030 g, 0.1233 mmol) was added and the reaction was heated to 85° C. and stirred overnight. The reaction was then cooled and submitted to standard aqueous workup followed by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:20].CI.[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[CH:6]=2)[C:2]([CH3:21])([CH3:1])[C:3]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccccc3)ccc21
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)c2ccc(C(=O)Nc3ccccc3)cc21

Procedure:
2.8 g. (10 mmol) 2,3-Dihydro-3,3-dimethyl-N-phenyl-2-oxo-(1H)-indole-6-carboxamide, 2.8 g. (20 mmol) methyl iodide and 2.5 g. (20 mmol) potassium carbonate were stirred in 50 ml. dimethylformamide for 3 hours at 70° C. After cooling, the reaction mixture was mixed with water, decanted and again mixed with water. The residue was purified by column chromatography (RP-18, methanol:water:ammonium hydroxide 80:20:1 v/v/v). Pure fractions were evaporated until the commencement of crystallisation, subsequently filtered off with suction and washed with water. There were obtained 2.3 g. (78% of theory) of the title compound; m.p. 184-186° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].[SH:30][CH2:31][CH2:32][CH2:33][OH:34]>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: OCCCS
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCCO)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)-cyclohexanecarboxamide (101 mg) and potassium carbonate (73 mg) were weighed into a 5 mL vial fitted with a stir bar and cap. Dimethylformamide (1 mL) and 3-mercapto-1-propanol (45 μL) were added. The vial was flushed with nitrogen and sealed with a cap. After stirring the reaction mixture at 100° C. for 6 h, the reaction mixture was allowed to cool to room temperature and stirred overnight. The reaction mixture was diluted with acetonitrile (4 mL) and filtered to remove solids. Concentration of the filtrate followed by chromatography of the crude residue on C-18 reverse-phase HPLC provided the desired product as a white solid. 1H NMR (DMSO-d6): δ=8.56 (1H, t), 7.68 (2H, m), 7.46 (2H, m), 4.05 (2H, d), 3.49 (2H, t), 3.14 (3H, m), 2.92 (1H, d), 2.2 (1H, m), 2.0 (2H, m), 1.8 (2H, m), 1.7 (3H, m), 1.3 (1H, m), 1.13 (3H, m). MS [ESI, (M−H)−] m/z=409.3 amu
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:20][CH2:21][CH3:22])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>[OH-].[Na+]>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:20][CH2:21][CH3:22])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCO
Agent: [Na+]
Agent: [OH-]
Product: CCCn1nc2c(N)nc3c(c2c1CCCCO)CCCC3
Reaction time: 24 h
Yield: 600.4 %

Procedure:
4-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol (prepared as described in Example 593, 0.118 g, 0.396 mmol) was hydrogenated for 1.8 days using the method described in Example 59. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to yield an oil that was dissolved in 6 M aqueous sodium hydroxide (20 mL). The mixture was stirred for 1 day, then a white solid was isolated by filtration, washed with water, and dried at 70° C. under vacuum to provide 0.719 g of 4-(4-amino-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol as a white powder, mp 194.0-200.0° C.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[CH2:1][CH:2]([CH3:4])[CH3:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC(C)C)c(C#N)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 33 %

Procedure:
Isobutyl bromide (56.1 mL, 512 mmol) was added to a suspension of the ethyl 3-cyano-4-hydroxybenzoate crude product (51.4 g) and potassium carbonate (70.8 g, 512 mmol) in dry DMF (200 mL), stirred at 100° C. for 10 hours, and cooled to room temperature. Ice-water (500 mL) was then added to the cooled suspension. The aqueous mixture was extracted with ethyl acetate (200 mL×2). The ethyl acetate portion was washed successively with water (500 mL×2) and aqueous saturated brine (200 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4). The resulting crystalline product was dissolved in ethyl acetate (50 mL) under heating. The mixture was kept hot, while hexane (100 mL) was added to the mixture. The hexane solution was stirred and cooled to room temperature, and further stirred for 10 min. under cooling with ice. The precipitated crystalline product was collected by filtration, washed successively with ethyl acetate/hexane (1/5, 60 mL) mixture and hexane (500 mL), and dried in air, to give 20.8 g (yield 33%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+]>ClCCl.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanol (from Example 36 supra) (33 g, 0.098 mol) in dichloromethane (300 mL) was added water (30 mL), NaHCO3 (3.8 g, 0.045 mol), TEMPO (156 mg, 1 mmol) and Bu4NI (1 g, 2.7 mmol) successively. The mixture was cooled to 0° C. and then aqueous NaClO (146 mL) was added dropwise. The resulting mixture was stirred for another two hours. The organic phase was separated and washed with water (100 mL), brine (100 mL) and dried over Na2SO4. The drying agent was removed by filtration and the residue was evaporated to give crude (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanone as yellow solid. (Yield 30.2 g, 92%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:41]=[CH:40][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:20][C:19]=3[N:31](C)[C:32](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.Cl.O1CCOCC1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:40]=[CH:41][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[N:31]([CH3:32])[C:19]=2[CH:20]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccn2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccn3)cc21
Yield: 67.9 %

Procedure:
Using 0.37 g of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-yloxy)phenyl}-N-methylcarbamate and 20 ml of a 4N hydrochloric acid/dioxane solution, reaction and purification were carried out in a similar manner to that described in Example (2-2a), whereby 0.20 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(O)[C:11]3[CH:10]=[C:9]4[C:23]5[C:28]([C:29]([CH3:31])([CH3:30])[C:8]4=[CH:7][C:6]=3[C:5]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(O)[C:4]=2[CH:3]=1)=[CH:27][CH:26]=[CH:25][CH:24]=5.[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:6]3[CH:7]=[C:8]4[C:29]([CH3:30])([CH3:31])[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:9]4=[CH:10][C:11]=3[C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(O)(c1ccccc1)c1cc(Br)ccc1C3(O)c1ccccc1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3c(-c4ccccc4)c4ccc(Br)cc4c(-c4ccccc4)c3cc21
Reaction time: 5 h
Yield: 73.6 %

Procedure:
9-bromo-13,13-dimethyl-6,11-diphenyl-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (4.19 g, 0.0075 mol), potassium iodide (12.45 g, 0.075 mol), and sodium hypophosphite (6 g, 0.037 mol) were placed in a flask, and were suspended in acetic acid (200 ml). The reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed with distilled water, filtered, and purified by column chromatography to give 9-bromo-13,13-dimethyl-6,11-diphenyl-13H-indeno[1,2-b]anthracene (2.9 g, yield=74%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[N:20]=1)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH:4]3[CH2:9][CH2:8][N:7]([C:10]4[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=4)[CH2:6][CH2:5]3)=[CH:26][CH:25]=2)[N:20]=1)[CH3:18]
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: CCc1nc(-c2ccc(O)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1nc(-c2ccc(OCCC3CCN(c4ccc(C)nn4)CC3)cc2)no1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
A mixture of 3.12 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine, 2.47 parts of 4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol, 1.38 parts of sodium carbonate and 94 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed with water and dissolved in trichloromethane. This solution was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.7 parts (33.2%) of 3-[4-[2-[4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy]ethyl]-1-piperidinyl]-6-methylpyridazine; mp. 125.3° C. (comp. 6).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:39]=[CH:38][C:30]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:34]([NH:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:39][CH:38]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 51.2 %

Procedure:
A solution of 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (1.0 g, 1.83 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 10 mL, 10 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-benzamide (380 mg, 51.1%) as a white solid: LC/MS m/e calcd for C25H28FN3O [M+H]+ 406.52, observed 406.0.