Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH:4][CH2:2][CH3:3]
Reactant: O=Cc1cccs1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNCc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a 0° C. chilled round bottom flask was added ethyl amine hydrochloride (4.58 g, 56.17 mmol) and thiophene-2-carbaldehyde (5.0 mL, 53.50 mmol) in methanol (20.0 mL), followed by triethylamine (7.83 mL, 56.17 mmol) and the reaction was stirred for 30 minutes. Sodiumtriacetoxyborohydride (15.87 g, 74.90 mmol) was added in one portion under vigorous stirring. The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo. The reaction mixture was quenched by adding 1 N NaOH, and the product was extracted with dichloromethane. The organic extract was washed with brine and dried over MgSO4. The volatiles were evaporated to give the crude free base N-(thiophen-2-ylmethyl)ethanamine (5.85 g, 41.42 mmol, 77%), which resulted of a purity grade >97% by 1H-NMR analysis, therefore it was used in the next step without any further purification. 1H NMR (400 MHz, CDCl3) δ 1.13 (t, J=7.1 Hz, 3H), 2.71 (q, J=7.2 Hz, 2H), 4.00 (d, J=0.7 Hz, 2H), 6.90-6.97 (m, 2H), 7.21 (dd, J=5.0, 1.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:13][C:15]([Cl:17])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)c(F)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a dichloromethane solution (200 mL) containing 3,4-difluorophenyl propionic acid (30.45 g, 163.6 mmol) and 2 drops of dimethylformamide was added oxalyl chloride (41.4 g, 327.1 mmol) over 20 min. The resulting solution was stirred for 24 hours at which time the solvent was removed in vacuo. The residual oil was then evaporated with toluene (˜100 mL) yielding 33.4 g of 3-(3,4-difluorophenyl)propanoyl chloride as a yellow liquid, which was taken directly into the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH:12]1[CH2:21][CH:20]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:33]([O-:35])=[O:34])[CH:18]=2)[NH:13]1)([CH3:11])[CH3:10])(C)(C)C.Cl>O1CCCC1>[NH2:7][CH2:8][C:9]([CH:12]1[CH2:21][CH:20]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:33]([O-:35])=[O:34])[CH:18]=2)[NH:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)C1CC(N2C(=O)c3ccccc3C2=O)c2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CN)C1CC(N2C(=O)c3ccccc3C2=O)c2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
The compound of Example 2 (200 mg) was dissolved in 2 ml of tetrahydrofuran, and 2 ml of 2N hydrochloric acid was added. After overnight stirring at room temperature, the reaction mixture was filtered under reduced pressure. The resulting solid was dried in a vacuum to obtain 119 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[I:22][C:23]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:24]=1[CH2:25]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:23]=5[I:22])[CH2:18][CH2:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCc1cc(I)ccc1I
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Product: Ic1ccc(I)c(CN2CCN(C3CC=C(c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.25 g, 0.87 mmole) and 2,5-diiodobenzyl chloride (0.33 g, 0.87 mmole) by the method described in example 45 to give the product (82%, mp: 174-175° C.). Calc'd for C24H26I2N2O2 : C, 45.89%; H, 4.18%; N, 4.46%. Found: C, 45.58%; H, 4.13%; N, 4.35%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH:1]=[CH:16]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2ccc([N+](=O)[O-])cc2)n[nH]1

Procedure:
15 g of 4-nitroacetophenone are converted into the pyridazinone in accordance with with GWP 1.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH2:14]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1csc(N2CCC(O)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(c2nc(C(N)=O)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (1.93 g, 8.49 mmol) (obtained as described in Reference Example 15(2)) in methylene chloride (100 ml) were added methanesulfonyl chloride (10.0 ml, 129 mmol) and triethylamine (18.0 ml, 129 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 24 hours. After checking the completion of the reaction, methanol was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (1.59 g, yield 61%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:10]=2)[C:6]([CH3:14])([CH3:15])[C:7]1=[O:13])[CH3:12]
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: CC(=O)OC(C)=O
Product: CCN1C(=O)C(C)(C)c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.05 g, 24.72 mmol) in acetic anhydride (80 ml) was stirred at room temperature for 4 h. The mixture was poured onto ice water (150 ml), allowed to warm to room temperature and was stirred again for 2 h. After extraction with ethyl acetate (3×100 ml), the combined organic layers were washed with sat. NaHCO3-solution (3×100 ml), brine (100 ml) and dried over sodium sulfate. After removal of the solvent the crude product was purified by column chromatography on silica gel (ethyl acetate/n-heptane 1:1) yielding 5.6 g (91%) N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide as light yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])=[O:16].Cl>C(O)C.O>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(C(=O)C=Cc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 3-formylbenzoic acid (2.0 g, 13.3 mmol) and sodium hydroxide (1.32 g, 33 mmol) in 400 mL of ethanol/water (1:1) is added 2,5-dimethoxyacetophenone (2.4 g, 13.3 mmol) and the resulting solution is stirred overnight at room temperature. The mixture is acidified with concentrated hydrochloric acid and the resulting solid is collected by filtration after diluting the mixture with water (200 mL) to provide 2.9 g of the title compound; mp 152°-155° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[CH2:9][CH2:10][CH:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[CH2:12]1>CN(C)C=O>[N:3]1([CH2:9][CH2:10][CH:11]2[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]3[CH:20]=[CH:21][CH:22]=[N:23][C:13]=3[CH2:12]2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(CCn2cccn2)Cc2ncccc2C1=O

Procedure:
To a suspension of sodium hydride in dimethylformamide (DMF) is added a solution of pyrazole in DMF. This solution is then added to a solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in DMF. After reaction has occurred, DMF is removed by evaporation (80° C., vacuum pump) and the residue is taken up in chloroform. The chloroform solution is washed with dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The residue is subjected to high pressure liquid chromatography using a suitable solvent on a silica gel column.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][O:13]CC2C=CC=CC=2)=[C:8]([CH2:10][CH3:11])[CH:9]=1)([O-])=O.[H][H]>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][OH:13])=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: [H][H]
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1COCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(N)c(=O)[nH]c1CO
Reaction time: 84 h
Yield: 90 %

Procedure:
A solution of 3-nitro-5-ethyl-6-benzyloxymethylpyridin-2(1H)-one (576 mg, 2.0 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) containing 10% palladium/charcoal (130 mg) was hydrogenated at an atmospheric pressure of hydrogen, monitoring the progress by tlc. Additional catalyst was added in 100 mg portions after day 2 and day 3. After 3-4 days, the catalyst was filtered and the solvents evaporated. The catalyst was vigorously washed with methanol/chloroform and combined solvents evaporated. The residue was triturated with methylene chloride and product collected by filtration to give 136 mg of 90% pure product. This material was used as is.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[Cl-].[NH4+]>C(O)(C)C.[Fe]>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc([N+](=O)[O-])c(NC(=O)c2ccccc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: Cc1ccc(N)c(NC(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
To a suspension of N-(5-methyl-2-nitrophenyl)benzamide (3 mmol) in isopropanol (150 mL) was added iron powder (2 g) and ammonium chloride (0.3 mmol). The reaction mixture was heated at 100° C. for 12 h. The hot mixture was filtered off and the filtrate was evaporated. The residue was subjected to flash chromatography on silica gel using a mixture of hexanes and CH2Cl2 (9:1) as eluent to afford N-(2-amino-5-methylphenyl)benzamide as a white-gray solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CNCCO
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N(C)CCO)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), N-methylethanolamine (750 mg) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 ml), dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-[N-(2-hydroxyethyl)-N-methylamino]-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (108 mg, 26%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[Cl:23][C:24]1[CH:49]=[CH:48][C:27]([CH2:28][S:29]([N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[C:42]([F:44])[C:41]([O:45]C)=[CH:40][C:39]=3[F:47])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:49]=[CH:48][C:27]([CH2:28][S:29]([N:32]2[CH2:33][CH2:34][N:35]([C:38]3[CH:43]=[C:42]([F:44])[C:41]([OH:45])=[CH:40][C:39]=3[F:47])[CH2:36][CH2:37]2)(=[O:30])=[O:31])=[CH:26][CH:25]=1
Reactant: COc1cc(F)c(N2CCN(S(=O)(=O)Cc3ccc(Cl)cc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=S(=O)(Cc1ccc(Cl)cc1)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 98.3 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-(4-chlorobenzylsulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)-piperazine (400 mg), to provide crude 1-(4-chlorobenzylsulfonyl)-4-(2,5-difluoro-4-hydroxyphenyl)piperazine (380 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 90 mg, 0.185 mmol), pyrimidin-5-ylboronic acid (22.9 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0092 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.26 min, m/z=448.1 [M+H]+, m/z=446.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:42][C:43]([F:51])([F:50])[CH2:44]OS(C)(=O)=O>CS(C)=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][N:25]([CH2:44][C:43]([F:51])([F:50])[F:42])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1N=C(N2CCCN(CC(F)(F)F)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.051 g, 0.098 mmol) in DMSO (2.2 mL) was treated with potassium carbonate (0.045 g, 0.32 mmol) and methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.06 g, 0.32 mmol). Reaction mixture was stirred at 70° C. for 1 hour and partitioned between dichloromethane and water. The dichloromethane layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified using semi-preparative reverse phase HPLC (YMC ODS A, 100×30 mm, 50 μM I.D., 0.05% TFA acetonitrile/0.05% TFA water=30/70 to 100/0) to yield the title compound as a flocculent solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C>[CH3:11][S:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of 2.0 g (9.85 mmol) 2-bromo-5-nitropyridine dissolved in 8 mL DMF was added 690 mg (9.85 mmol) of sodium thiomethoxide. The mixture was stirred at room temperature for 1 h, and partitioned between ethyl acetate and water, dried over MgSO4 and concentrated to obtain 1.13 g of 2-methylthio-5-nitro-pyridine, pure by 1H NMR.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][CH:22]([OH:27])[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1.[C:30](OCC)(=[O:34])[C:31]([CH3:33])=[CH2:32].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([N:19]3[C:20]([CH3:29])([CH3:28])[CH2:21][CH:22]([O:27][C:30](=[O:34])[C:31]([CH3:33])=[CH2:32])[CH2:23][C:24]3([CH3:25])[CH3:26])[N:8]=2)[CH2:5][CH2:6]1
Reactant: CC1(C)CC(O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: C=C(C)C(=O)OCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
10.2 g of 2,4-dimorpholino-6-(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 34) are heated to 120° together with 6.9 ml of ethyl methacrylate, 0.04 g of 2,6-bis-tert-butyl-p-cresol and 0.04 ml of tetrabutylorthotitanate (monomer), some liquid slowly being removed by distillation. The mixture is allowed to react for 50 hours, some ethyl methacrylate and catalyst subsequently being added periodically. After the reaction has ended, the product is filtered through bleaching earth and evaporated. The residue is dissolved in toluene/acetone and purified chromatographically on an SiO2 column, the above product being obtained as a colorless resin.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]([CH3:25])[CH2:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:16][NH2:17]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:14][CH:13]([CH3:25])[CH3:12])=[O:6]
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH+): m/z=364.9, tR (minutes, Method A)=1.43
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH2:27])=[C:25]([CH3:32])[CH:24]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:20]#[N:21])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 125 °C
Yield: 81.8 %

Procedure:
Following the procedure of Example 11, a mixture of 75.8 mg (0.25 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 51.5 mg (0.30 mmol) of 4-chloro-5-methoxy-2-methylaniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at 120-130° C. for 2 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 88.7 mg (82.1%) of the pure product as a yellow solid, mp 171-173° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[N:11]1([CH2:10][CH2:9][OH:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCCCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCCN1CCCCCCC1
Yield: 37 %

Procedure:
A solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azocane (9.13 g, 33.7 mmol) and TBAF (1M in THF, 36 mmol) was stirred at room temperature overnight. The mixture was concentrated and purified on a silica gel column (eluting with DCM/MeOH=30/1˜50/1) to afford 2-(azocan-1-yl)ethanol (1.96 g, 37%). 1H NMR (DMSO-d6): δ 4.33 (br s, 1H), 3.45 (t, 2H), 2.53 (m, 6H), 1.54 (m, 10H); LCMS: 158 (M+H)+.
Reaction SMILES: [BH3-]C#N.[Na+].[NH2:5][CH2:6][CH:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:11][CH:10]=[CH:9][C:8]1=2.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC(O)=O.CO>[CH:27]1([NH:5][CH2:6][CH:7]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12]([O:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=4)=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Add NaBH3CN (63 mg, 1.00 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol) and cyclohexanone (98 mg, 1.00 mmol) dissolved in 5% AcOH/MeOH (5 ml) and stir at ambient temperature for 16 hours. Concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 145 mg of the title compound as a white foam. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.79 (br. s, 2H), 2.99 (m, 1H), 2.96-2.79 (m, 2H), 2.63-2.41 (m, 3H), 1.91 (m, 2H), 1.85-1.67 (m, 6H), 1.31-1.04 (m, 6H).