Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22]O)=[CH:20][N:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22][NH:39][CH:36]5[CH2:38][CH2:37]5)=[CH:20][N:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC1CC1
Reactant: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2cccc(-n3nncc3CNC3CC3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 7-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 63) (218 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF as described in Example 47. Obtained as a light yellow solid (130 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:12])[C:5]=2[N:13]=1>[Pd].CO>[CH3:1][C:2]1[N:3]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:12])[C:5]=2[N:13]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)c2nc(C)n(CCOCCCc3ccccc3)c2c1C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
2,6,7-Trimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine (0.55 g, 1.645 mmol) from Part I of Example 7 was combined with 10% palladium on carbon (0.10 g) in a Parr reactor. Methanol (30 mL) was added to the resulting mixture under a nitrogen purge, and then the mixture was placed under hydrogen at a pressure of 310 kPa for 4 hours. The resulting reaction mixture was filtered through a layer of Celite™ filter agent, and the filtrate was concentrated under reduced pressure to a clear oil. The oil was dissolved in 5% methanol in diethyl ether (˜50 mL), and 1M hydrochloric acid in diethyl ether (1.7 mL) was added to the resulting solution. Volatiles were removed under reduced pressure, and the resulting solids were dissolved in water. The aqueous solution was stirred for 10 minutes when the product oiled out of solution. The aqueous portion was washed with dichloromethane (3×). The combined organic portions were washed with water (2×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated to a glassy oil under reduced pressure. The oil was triturated with diethyl ether. The solids that formed after 10 minutes of stirring were filtered off and dried for 18 hours to provide 0.3185 g of 2,6,7-trimethyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 118.1-119.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:50][CH2:49][CH:46]1[O:45][C:44]2[CH:51]=[C:40]([O:39][CH3:38])[CH:41]=[CH:42][C:43]=2[O:48][CH2:47]1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(F)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
5-Fluoroindole-3-butyric acid (1.2 g, 5.4 mmole), 1-hydroxybenzotriazole hydrate (0.88 g, 6.5 mmole) and 1,3-diisopropylcarbodiimide (2.0 ml, 13.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 5.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (56%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3-yl)-butanamide, as an oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(Cl)Cl.CCOCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:32]=[O:33]
Reactant: COc1cc(CO)ccc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (3 gm, 7.07 mmol) was added to (3-methoxy-4-methylphenyl)methanol (1 gm, 6.57 mmol) in CH2Cl2 (35 ml) at 0° C. After stirring at 0° C. for 0.5 h, some of the CH2Cl2 was removed, reaction mixture was diluted with ether, washed with sodium bicarbonate solution, sodium thiosulfate solution and water. Organic layer was dried and evaporated to obtain 3-methoxy-4-methylbenzaldehyde in quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:5]([CH3:31])[CH:4]=1)#[N:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[C:10]2[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:5]([CH3:31])[CH:4]=1)(=[O:33])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C#N)cc1C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred suspension of ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28B) (120 mg, 0.28 mmol) and potassium carbonate in DMSO (0.2 mL) was added dropwise 30% H2O2 at 0° C. The mixture was allowed to warm to room temperature and stirred 3 h. After water (2 mL) was added, some precipitate appeared, which was separated by centrifuge, rinsed with water (0.5 mL) and dried in vacuum to afford ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28C) as a white solid (100 mg, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:18][C:19]([SH:22])=[N:20][N:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:18][C:19]([SH:22])=[N:20][N:21]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: Sc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: CCCc1c(CSc2nnc(S)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a mixture of 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.24 g of 2,5-dimercapto-1,3,4-thiadiazole, 0.20 g of anhydrous potassium carbonate and 4 ml of methyl ethyl ketone was added a catalytic amount of tetra-n-butylammonium bromide. The mixture was stirred at 60° C. for 1 hour. After the reaction solution was rendered neutral by adding diluted hydrochloric acid thereto, it was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from isopropyl alcohol to give 0.20 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1,3,4-thiadiazole.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:27][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[C:16]([NH2:18])[N:15]4[N:19]=[C:20]([C:22]5[O:23][CH:24]=[CH:25][CH:26]=5)[N:21]=[C:14]4[N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1.CO.[BH4-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:21]=[C:14]2[N:13]=[C:12]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:27][CH:3]([CH2:2][NH:1][CH2:34][C:31]5[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=5)[CH2:4][CH2:5][CH:6]4[CH2:11]3)[N:17]=[C:16]([NH2:18])[N:15]2[N:19]=1
Reactant: NCC1CCC2CN(c3nc(N)n4nc(-c5ccco5)nc4n3)CCN2C1
Reactant: O=Cc1ccncc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(N2CCN3CC(CNCc4ccncc4)CCC3C2)nc2nc(-c3ccco3)nn12
Reaction time: 1 h

Procedure:
A solution of (7RS,9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see Example 9 above) and pyridine-4-carbaldehyde (1 eq.) in anhydrous THF was treated with titanium (IV) isopropoxide (1.7 eq.) at around 60° C. for 5 hours. To the mixture was added anhydrous methanol, and followed by the careful addition of NaBH4 (1.5 eq). After one hour, the reaction was completed as indicated by HPLC analysis. The solvent was removed and the residue was purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aRS)-2-furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine as a white powder: 1H NMR (400 MHz, CD3OD) δ 1.77-2.11 (m, 4H), 2.66 (m, 1H), 3.78-3.05 (m, 1H), 4.46 (bs, 2H), 6.65 (dd, J=1.8, 3.4 Hz, 1H), 7.18 (d, J=3.4 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.88 (d, J=6.0 Hz, 2H), 8.81 (d, J=6.0 Hz, 2H). MS m/z: 461 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1>C(#N)C.O>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:29]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (25 mg, 0.085 mmol, EXAMPLE 1 Step 3), indole-2-carboxylic acid (15 mg, 0.093 mmol), triethylamine (0.060 mL, 0.43 mmol), and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (48 mg, 0.13 mmol) in acetonitrile (1 mL) was stirred at room temperature for 4 h. The mixture was poured into water, and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual solid was washed with methanol to give 22 mg (71%) of the title compound as a white solid.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][CH:44]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23](=[O:41])[N:24]([CH2:30][C:31]([O:33]CC2C=CC=CC=2)=[O:32])[C:25]([CH3:29])=[C:26](Cl)[N:27]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>[Pd].CO>[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][CH:44]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23](=[O:41])[N:24]([CH2:30][C:31]([OH:33])=[O:32])[C:25]([CH3:29])=[CH:26][N:27]=1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: Cc1c(Cl)nc(NCCc2cccc(OCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(NCCc2cccc(OCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
10% Palladium on charcoal (125 mg), followed by ammonium formate (553 mg, 8.77 mmol) were added to a solution of benzyl 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy})phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 129) (500 mg, 0.88 mmol) in methanol (10 ml), and the reaction stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fibre, NaOH solution (8.77 ml, 1N, 8.77 mmol) was added to the filtrate, and the solution evaporated under reduced pressure. The residue was triturated with a 10% methanol:dichloromethane solution, the suspension filtered, the filtrate dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white solid, (289 mg, 69%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.[CH2:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Reactant: c1ccc(CCC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)n1nc(CN2CCC(CCc3ccccc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (0.50 g, 1.98 mmol) in CH2Cl2 (25 mL) was treated with 4-phenethylpiperidine hydrochloride (0.893 g, 3.96 mmol) and Hunig's base (0.78 g, 5.94 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (0%→10% EtOAc in hexane) to give 1-acetyl-3-(4-phenethylpiperidin-1-ylmethyl)-1H-indazole as a colourless oil (98 mg, 14%). This was dissolved in CH2Cl2 /methanol (1:1, 10 mL), treated with NaOMe (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue recrystallised from EtOAc/hexane to give the title compound (55 mg, 69%) as colourless crystals; mp 153°-155° C. (from EtOAc/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 12.75 (bs, 1H, NH), 7.84 (d, J=8.1 Hz, 1H, indazole), 7.46 (d, J=8.4 Hz, 1H, indazole), 7.31 (t, J=6.7 Hz, 1H, indazole), 7.27-7.12 (m, 5H, Ph), 7.07 (t, J=7.1 Hz, 1H, indazole), 3.78 (s, 2 H, Ar--CH2N), 2.85 (m, 2 H, aliphatic), 2.56 (m, 2 H, aliphatic), 1.94 (m, 2H, aliphatic), 1.65 (m, 2H, aliphatic), 1.47 (m, 2H, aliphatic), 1.16 (m, 3H, aliphatic); MS (CI+) m/e 320 (M+H+); Anal. calcd for C21H25N3 : C, 78.96; H, 7.89; N, 13.15. Found: C, 78.94; H, 7.96; N, 12.89.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[S:41](Cl)(=[O:43])=[O:42].O>C(OCC)C.C(O)C>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:41]([C:32]3[CH:33]=[CH:34][C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:31]=3)(=[O:43])=[O:42])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCCCCCCCCCCOc1ccc(-n2ccnc2)cc1
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCCCCCCCOc1ccc(-n2ccnc2)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 2.5 g of 10-[4-(1H-imidazol-1-yl)phenoxy]decaneamine (Example 66) in 250 ml of diethyl ether containing 3 ml of triethylamine is stirred while 2.0 g of 2-naphthalenesulfonylchloride is added. The reaction mixture is stirred at room temperature for 72 hours and 50 ml of H2O added. The solvents are decanted, leaving a viscous solid. The solid is dissolved in 100 ml of 50% aqueous ethanol. Careful concentration under a gentle stream of air gives a crystalline solid. The solid is collected washed with water and dried in vacuo at room temperature; m.p. 112°-115° C.; yield, 0.2 g.
Reaction SMILES: CS(C)=O.[N+:5](/[CH:8]=[CH:9]/[C:10]1[S:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)([O-:7])=[O:6].C(O)(=O)C.[BH4-].[Na+]>O>[N+:5]([CH2:8][CH2:9][C:10]1[S:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)([O-:7])=[O:6]
Reactant: Cc1ccc(Oc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(CC[N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a dimethyl sulfoxide (30.0 mL) solution of 2-((E)-2-nitro-vinyl)-5-p-tolyloxy-thiophene (2.50 g, 9.57 mmol) described in Manufacturing Example 48-1-3 and acetic acid (2.50 mL) was added sodium borohydride (610 mg, 20.6 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (1.20 g, 47.6%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:9]=C[C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=1)C(O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[C:1]([CH:9]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Temperature: 50 °C

Procedure:
Oxalyl chloride (1.23 ml, 14.24 mmol) was added dropwise to a solution of 5-fluoro 2-trifluoromethyl benzoic acid (1 gm, 4.81 mmol) in HPLC grade DCM (15 ml), containing DMAP. The reaction mixture was heated to 50° C. for 40 min. The reaction mass was cooled to room temperature and solvent evaporated to dryness under a nitrogen atmosphere to get crude 5-fluoro 2-trifluoromethyl benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19]Cl)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[N:3]=1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: COc1cc2c(C)nn(CCCCl)c(=O)c2cc1OC
Solvent: CO
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCN(CCCn2nc(C)c3cc(OC)c(OC)cc3c2=O)Cc2ccccc2)cc1OC

Procedure:
1-[4-Methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-[N-benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]propane was prepared analogous to Example 1 (a) by reaction of 1-[4-methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-benzylamine in chlorobenzene. Rf -value (chloroform/methanol = 9/1) : 0.9.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>[Cu]I.O1CCOCC1>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]
Reactant: O=C1CCCN1
Reactant: Ic1cccs1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccs1
Temperature: 110 °C
Reaction time: 23 h
Yield: 100 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %) and K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), 2-iodothiophene (115 μL, 1.04 mmol), 2-pyrrolidinone (94 μL, 1.24 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 1:1; 20 mL fractions). Fractions 9-15 provided 174 mg (100% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 6.95 (dd, J=5.5, 1.3 Hz, 1H), 6.90 (dd, J=5.5, 3.7 Hz, 1H), 6.55 (dd, J=3.7, 1.3 Hz, 1H), 3.92 (t, J=7.4 Hz, 2H), 2.66 (t, J=7.4 Hz, 2H), 2.27 (p, J=7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 172.4, 140.9, 124.2, 118.4, 110.9, 49.2, 31.7, 18.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH2:28])=[N:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])[CH2:16][CH2:15]2)=[CH:7][CH:8]=1.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]3[CH2:2][NH:1][C:30](=[O:31])[NH:28][C:4]=3[N:5]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc1N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A mixture of 3-aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-ylamine (0.260 g, 0.61 mmol) in THF (10 mL) was treated with 4-nitrophenyl chloroformate (0.160 g, 0.79 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. and treated with LDA (0.9 mL, 3.8 mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% MeOH/EtOAc) to afford the title compound as a light yellow solid (0.071 g, 25%). mp 166–167° C.; 1 H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.19–7.14 (m, 2H), 7.14–7.09 (br s, 1H), 6.99–6.94 (m, 1H), 6.32 (d, 1H), 5.57–5.51 (br s, 1H), 4.45 (s, 2H), 4.24 (t, 2H), 3.16–3.02 (m, 4H), 2.75–2.58 (m, 4H), 2.49 (t, 2H), 1.84–1.64 (m, 4H). MS ES: m/z=450.03, 452.02.