Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.[K].C(=O)([O-])[O-].Br[CH2:44][CH2:45][CH2:46][Cl:47]>CN(C=O)C>[Cl:47][CH2:46][CH2:45][CH2:44][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=2)[C:8]1=[O:13]
Reactant: ClCCCBr
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.00 g, 2.04 mmol), potassium, carbonate (564 mg, 4.08 mmol), 1-bromo-3-chloropropane (962 mg, 6.12 mmol), and DMF (100 ml) was stirred for four hours at a bath temperature of 60° C. The solvent of the reaction mixture was removed under reduced pressure. Water was then added to the mixture, and the mixture was extracted with chloroform-methanol (10:1). The thus-obtained organic phase was dried over magnesium sulfate anhydrate, and the solvent was removed under reduced pressure. The organic phase was then subjected to silica gel column chromatography (developer: chloroform-methanol (100:1)), purified, and crystallized from a chloroform-diethylether mixture, to thereby obtain the title compound (546 mg, 0.963 mmol, 47.2%) as pale yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[CH2:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
A solution of triphenylphosphine (212 mg, 0.81 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (144 mg, 0.81 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (250 mg, 0.73 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (279 mg, 1.61 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate), to afford N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (121 mg, 33%) as a white foam: mp 80-83° C. (foam to gel); FAB-HRMS m/e calcd for C20H22BrN3O5S (M+H)+ 496.0542, found 496.0543.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: O=C(O)c1cc(F)ccc1-n1ccnn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1ccnn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-fluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 9; 66 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[C:4]([CH3:19])=[C:3]1[Si:20]([CH3:23])([CH3:22])Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[C:4]([CH3:19])=[C:3]1[Si:20]([CH3:23])([CH3:22])[NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC(C)(C)N
Reactant: CC1=C([Si](C)(C)Cl)C(C)c2c1c1ccccc1c1ccccc21
Solvent: ClCCl
Product: CC1=C([Si](C)(C)NC(C)(C)C)C(C)c2c1c1ccccc1c1ccccc21

Procedure:
To a 500 ml round bottom flask containing 2.420 g (0.00718 mole) of (1,3-dimethyl-1H-cyclopenta[l]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of methylene chloride was added 1.331 g (0.0180 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 2.120 g (79.0 percent). 1H NMR analysis indicated the predominant isomer was substituted at the 2 position.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH3:22]>C(Cl)(Cl)Cl>[NH2:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OCC(C)C
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ccc(N)nn2)cc1OCC(C)C
Yield: 53.8 %

Procedure:
7.0 g (24 mmol) of 3-chloro-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazine are reacted as described in Example 1 in 40 ml of ammonia-saturated ethylene glycol. The crude product obtained by precipitation with water is dissolved in chloroform, the solution is dried with potassium carbonate, and the product is precipitated with petroleum ether (b.p. 50°-70° C.). 3.5 g (53.8%) of the title compound of m.p. 187° C. are obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32](Cl)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate (500 mg), cyclopropylboronic acid (188 mg), potassium phosphate (1.12 g) in toluene (6.2 mL) and water (0.31 mL) was purge with nitrogen. Tricyclohexylphosphine tetrafluoroborate (79 mg) and palladium acetate (24 mg) were added. The mixture was heated at 90° C. for 16 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated. The residue was purified with flash chromatography (0-30% EtOAc/heptane) to give the product (276 mg).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.COC1C=C(NC=C(C(OCC)=O)C(OCC)=O)C=CC=1>>[OH:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate. To a solution of boiling Dowtherm™ (100 mL) was added diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate (20.0 g, 68.3 mmol). After 15 minutes the reaction was cooled to ambient temperature and poured into hexanes (500 mL). The precipitate was collected by filtration and dried under high vacuum to yield the title compound as a brown solid (15.2 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.09 (d, J=5.9 Hz, 1H), 8.47 (d, J=6.7 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.25 (t, J=7.2 Hz, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: CN1CCN(CC(O)c2ccccc2)CC1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CC(Oc2ccc(F)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethanol (38) (2.0 g, 9.09 mmol) was dissolved in 50 mL of THF. 4-fluorophenol was added to the solution and then triphenylphosphine. After complete dissolution, the mixture was cooled to 0° C. and after 10 minutes DIAD was added dropwise. Ice-bath was removed and the reaction mixture was stirred at room temperature for 48 hours. The product was purified using flash chromatography, eluting pure ethyl acetate to recover any starting materials. Polarity of the solvent was then increased using 30:70 methanol/ethyl acetate. The product 13a (2.18 g, 6.94 mmol, 76%) was afforded as a orange-brown oil. 1H-NMR (CDCl3): δ 7.33 (5H, m), 6.80 (4H, m), 5.21 (1H, dd, J=3.08, 3.07 Hz), 3.00 (1H, dd, J=8.49, 8.48), 2.67 (5H, b), 2.45 (4H, b), 2.27 (3H, s).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])[CH2:17][CH2:16]2)=[CH:7]1.[CH2:33](Br)[CH:34]=[CH2:35]>CN(C=O)C>[CH2:35]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])[CH2:19][CH2:20]2)=[CH:7]1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCO)c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
To a suspension of 0.012 g (0.04 mmol) of a dispersion of 60% NaH in 0.5 mL of DMF, a solution of 0.042 g (0.01 mmol)of 2-(2-{4-[1-(2-hydroxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid in 0.5 mL of DMF was added. After stirring at room temperature for 30 minutes as solution of 0.014 g (0.12 mmol) of allyl bromide in 0.3 mL of DMF was added. The crude mixture was stirred at room temperature for 15 hours. The solvent was evaporated at reduced pressure and the crude mixture was dissolved in 1 mL of ethanol. 0.2 mL of an aqueous 2N NaOH solution were added and the mixture was heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and after addition of 1 mL of water, the mixture was neutralised with 2N HCl and extracted with chloroform. The crude was purified by chromatography over silica gel affording 0.015 g (33% of yield) of the desired product.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)C.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH2:5][C:4](=[O:16])[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Yield: 77.5 %

Procedure:
Using General Procedure A; ethyl-4-methoxybenzoylacetate (7.00 g, 27.8 mmol, 1.1 equ.) in ethanol (100 mL) was treated at 0° C. with phenylhydrazine (2.50 mL, 25.3 mmol, 1.0 equ.) to give 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (5.21 g, 19.6 mmol, 78%) after crystallization (ethanol) as a light yellow solid. 1H-NMR (400 MHz) CDCl3: 7.99-7.97 (d, 1H), 7.66-7.64 (d, 2H), 7.44-7.40 (t, 2H), 7.22-7.18 (t, 1H), 6.94-6.92 (d, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 13C-NMR (100 MHz) CDCl3: 170.1, 161.5, 154.4, 138.2, 128.8, 127.5, 125.0, 123.5, 118.8, 114.2, 55.3, 39.6; LC/MS-MS: 267.0→77.2 m/z; GS1 and GS2 at 30, DP=81, CE=65, CXP=4, tR=4.15 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].N1CCCC1.[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:18])[CH3:17]>CO>[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29]3([CH2:9][C:8](=[O:10])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:1]3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1C(C)(C)C
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)ccc1C(C)(C)C
Temperature: 80 °C
Yield: 93.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (260 μL, 2.2 mmol) was added portion-wise at room temperature to pyrrolidine (370 μL, 4.4 mmol) followed by portion-wise addition of 1-(4-tert-butyl-3-methoxy-benzoyl)piperidin-4-one (630 mg, 2.2 mmol). Anhydrous methanol (140 μL) was added and the slurry was heated at 80° C. for 3 h. The mixture was then partitioned between ethyl acetate and 1M aqueous HCl. The layers were separated and the aqueous layer was discarded. Saturated aqueous sodium bicarbonate was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to give 1′-(4-tert-butyl-3-methoxybenzoyl)spiro[chroman-2,4′-piperidin]-4-one (840 mg, 94%) as a light yellow solid. ESI-MS m/z calc. 407.2. found 408.2 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15]O>Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
4-Hydroxy-3-(trifluoromethyl)benzoic acid (2 g, 9.7 mmol) was dissolved in methanol (40 mL) and 12N HCl (10 drops) was added thereto. The reaction mixture was stirred at 90° C. for 48 hours, cooled to room temperature and concentrated, and then ethyl acetate (100 mL) was added thereto. The reaction mixture was washed with sat. NaHCO3 Solution, and the organic layer was dried with Na2SO4, filtered and concentrated to obtain the title compound (2.07 g, 91%) without further purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[N:7]=1.[ClH:19].Cl.NCCCC1N=C(N)NC=1>>[ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][C:16]([Cl:19])=[C:17]([Cl:1])[CH:18]=2)=[O:13])[N:7]=1
Reactant: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: Nc1nc(CCCNC(=O)c2cc(Cl)c(Cl)[nH]2)c[nH]1
Yield: 65 %

Procedure:
Using the same general procedure as used for the synthesis of 1H-pyrrole-2-carboxylic acid [3-(2-amino-1H-imidazol-4-yl)-propyl]-amide hydrochloride 17, 0.200 g of 4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 afforded 0.204 g (65%) of the title compound 20 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.32 (t, 1H, J=4.8 Hz), 6.91 (s, 2H), 6.53 (s, 1H), 3.21 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=7.2 Hz), 1.72 (tt, 2H, J=7.5, 14.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 159.15, 147.11, 127.31, 125.14, 114.75, 109.82, 108.99, 107.77, 37.83, 28.03, 22.04; HRMS (ESI) calcd for C11H14Cl2N5O (MH+) 302.0569, found 302.0569.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][O:36][CH2:37][CH2:38]Br.[OH-].[Na+]>CN(C=O)C>[CH3:35][O:36][CH2:37][CH2:38][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: COCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (500 mg, 1.2 mmol) in 12 mL of DMF was added Hunig's base (790 mg, 6.1 mmol) and 2-bromoethyl methyl ether (850 mg, 6.1 mmol). The solution was stirred at room temperature for 5 days. The solution was poured onto 2.5 N NaOH and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over Na2SO4 and was filtered. The solvent was removed under reduced pressure to leave a solid. The solid was triturated and filtered to leave the title compound: 1HNMR (CDCl3) δ8.63 (d, J=4.23 Hz, 2 H), 7.28 (m, 4 H), 7.14 (d, J=4.43 Hz, 2 H), 3.57 (t, J=5.24 Hz, 2 H), 3.38 (s, 3 H), 3.14 (bd, J=10.1 Hz, 2 H), 2.79 (m, 1 H), 2.68 (t, J=5.04, 2 H), 2.08 (m, 4 H), 1.92 (m, 2 H). MS (M+H): 397 (base peak).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O)#[CH:2].CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14]1[NH:26][C:27]2[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=2[N:33]=1)#[CH:2]
Reactant: C#Cc1ccc2cncc(CC(=O)O)c2c1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolved in DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml, 1.03 mmol) are added, followed by a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified by flash column chromatography (30:1 dichloromethane-methanol elution). The intermediate is dissolved in methanol (2 ml) and water (2.75 ml) added, followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction is heated at 40° C. for 2 hours, then stirred for 16 hours at ambient temperature. The solvent is evaporated and the crude product purified by flash column chromatography (30:1 dichloromethane-methanol elution) to afford 8-(6-ethynyl-isoquinolin4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 388.
Reaction SMILES: [Cl:1][CH:2]([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N+](=[CH2:17])=[N-]>C(Cl)Cl>[Cl:1]/[C:2](=[C:12](/[O:13][CH3:17])\[CH3:14])/[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)C(Cl)C(=O)Nc1ccccc1
Solvent: ClCCl
Product: CO/C(C)=C(/Cl)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
52.9 g of α-chloroacetoacetanilide in 500 ml of methylene chloride was held at 0° C for 4 hours and then 725 ml of methylene chloride solution titrating 17.4 g/l of diazomethane were added. The mixture was stirred for 16 hours at 0° C and then 1 hour at 20° C and was concentrated to dryness under reduced pressure. The residue was added to isopropyl ether and the precipitate formed was recovered by vacuum filtration and was crystallized from isopropyl ether to obtain 12 g of 2-chloro-3-methoxy-crotonanilide melting at 100° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7](N)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].N([O-])=O.[Na+].[BrH:16]>>[Br:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: Br
Reactant: CC(C)Cc1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-isobutylphenylamine (3.80 g) in 48% hydrobromic acid (10 ml) was added aqueous sodium nitrite (2.11 g, 2 ml) below 10° C. over 20 minutes. The reaction mixture was added to a solution of cuprous bromide (7.3 g) in 48% hydrobromic acid(5 ml) at 25° C. After stirred at 25° C. for 1 hour, the mixture was extracted with hexane two times. The extracts were combined, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (150 g) eluting with hexane to give 1-bromo-3-isobutylbenzene (2.61 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12].P(Cl)(Cl)(Cl)=O.[CH2:19](C1C(O)=C([N+]([O-])=O)C(=O)NC=1C)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:19])[NH:5][C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCc1c[nH]c(=O)c([N+](=O)[O-])c1Cl
Reactant: CCc1c(C)[nH]c(=O)c([N+](=O)[O-])c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1c(C)[nH]c(=O)c([N+](=O)[O-])c1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
As described for compound 6b in example 7, phosphorus oxychloride (8.3 ml, 88.8 mmoles) was added to a solution of compound 5c (4.00 g, 20.2 mmoles) and benzyltriethylammonium chloride (18.40 g, 80.8 mmoles) in acetonitrile (80 ml). The mixture obtained was agitated at 40° C. for 30 minutes and heated under reflux for 1 hour. After evaporation of the solvent, 150 ml of water was added and the mixture agitated at ambient temperature for 48 hours. The brown precipitate was collected, washed with cyclohexane (3×10 ml) and recrystallised in ethanol to give compound 6c (1.5 g, 34%) in the form of pale yellow crystals: NMR-1H (DMSO-d6) δ 12.98 (1H, s, NH-1), 2.58 (2H, q, L=7.5 Hz, CH2CH3), 2.38 (3H, s, CH3 -6), 1.08 (3H, t, J=7.5 Hz, CH2CH3 ).