Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CCO
Product: CNCC(O)COc1ccccc1

Procedure:
To a solution of 1,2-epoxy-3-phenoxypropane (15 g), in ethanol (50 ml) was added 25-30% methylamine in water (50 ml) and the mixture heated under reflux for 1 h. The ethanol was removed in vacuo and the residue acidified with 2 N hydrochloric acid. The aqueous solution was extracted with ethyl acetate then made alkaline with 2 N sodium hydroxide and extracted into ether. The combined ethereal extracts were dried (Na2SO4), filtered and evaporated to give a semi-solid (14.8 g). The product was distilled in vacuo to give the title compound as white crystals b.p. 110°/0.07 mm, m.p. 74°-77° (9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].C[O-].[Na+]>CO.C(Cl)Cl>[NH2:31][C:30]1[N:32]=[CH:18][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=3[C:6]=2[N:29]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 8 h

Procedure:
A stirred suspension of 16 g (0.047 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 12.5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room temperature, under argon, with 7.5 g (0.14 mol) of sodium methylate in one portion. Methylene chloride (290 ml) was added after 10 min. and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 460 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from ethanol/methylene chloride solution gave off-white crystals: mp 245°-248° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH3:18])[CH:8]=1)=O.Cl.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:31]=[C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[N:30]=2)=[CH:8]1)[CH2:17][CH3:18]
Reactant: N=C(N)Nc1ccc(O)cc1
Reactant: CCCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Agent: Cl
Product: CCCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one with 1-(4-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 0.88 (t, 3H, J=7.2 Hz, CH3), 1.90 (t, 2H, J=7.6 Hz, CH2), 4.30 (t, 2H, J=6.8 Hz, CH2), 6.74 (m, 2H, Ph-H), 7.16 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.20 (t, 1H, J=4.8 Hz, Ar—H), 7.51 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.35 (m, 1H, Ar—H), 8.52 (s, 1H, Ar—H), 8.88 (d, 1H, J=7.6 Hz, Ar—H), 9.05 (s, 1H, NH), 9.11 (s, 1H, OH). MS (ESI+) m/z 346.1659 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:17][N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: CN1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-1-methyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.00 g) in the mixture solvent of MeOH and EtOAc was added a catalytic amount of 20% Pd(OH)2/C. The reaction mixture was stirred for 2 h at room temperature under H2. The resulted mixture was filtered and the filtrate was concentrated to in vacuo to give the crude product, which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 141.2 (M+1).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]1([OH:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
Phosphorus oxychloride (1.94 mL, 1 equiv) and α-naphthol (Aldrich, 3 g, 1 equiv) were stirred in anhydrous diethyl ether (20 mL). Anhydrous triethylamine was added (2.90 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow oil (4.88 g, 90%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:45]=[O:46])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:45]([OH:46])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: COCOc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 96.2 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (8.07 g, 27.0 mmol) was dissolved in THF (320 mL), and the solution was treated with TMEDA (13.0 mL, 85.4 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 87.1 mL, 86.3 mmol) and DMF (4.60 mL, 59.3 mmol), followed by purification by slurry using hexane to obtain 4-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (8.50 g, yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])C=C[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CC(C)=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][SH:8]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7]1)[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(C[SH]1C=CC(Cl)=C1)OCC
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A three-neck round bottom flask was charged with 3-chloro-thiophenol (20.0 g, 0.138 mol) and potassium carbonate (21 g, 0.15 mol) in acetone (220 ml) and treated with a dropwise addition of bromoacetaldehyde diethyl acetal. After stirring for 17 hours at 23° C., the slurry was filtered through a small plug of celite, the filtrate evaporated under reduced pressure and the residue diluted with diethyl ether and water. The organics were washed with brine, dried over sodium sulfate, and evaporated to a rust-colored oil weighing 35.1 g (97%). FDMS m/e=260 (M+).
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1.CO[CH:16]([O:19]C)[CH2:17][NH2:18]>>[F:13][C:7]1[CH:8]=[C:9]2[C:4]([NH:3][C:16](=[O:19])[C:17]3[N:10]2[CH:11]=[CH:2][N:18]=3)=[CH:5][CH:6]=1
Reactant: Fc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: COC(CN)OC
Product: O=c1[nH]c2ccc(F)cc2n2ccnc12

Procedure:
By reacting 2,3-dichloro-6-fluoroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 8-fluoroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.) and, subsequently, 4-chloro-8-fluoroimidazo[1,2-]quinoxaline. By reacting this product with cyclopentyl amine according to the method described in example 3, there is obtained 4-cyclopentylamino-8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=85.7° C.(onset); IR (KBr): 3255, 2964, 1551 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,m), 7.7÷7.35 (1H,dd, JHF =16 Hz), 7.5 (1H,d, J=2 Hz), 7.6÷7.25 (1H,dd, JHF =16 Hz), 7.05 (1H,dd), 6.0 (1H,d), 4.55 (1H,m), 2.35÷1.3 (8H,m); UV (EtOH): λmax =226, 268, 285, 296, 323, 336 nm. Elementary analysis for C15H15FN4 (m.w. 270.31): calcd. C 66.65, H 5.59, N 20.73%; found C 66.36, H 5.66, N 20.86%.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O>ClC1C=CC=CC=1Cl>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCCCC(=O)O
Yield: 233.3 %

Procedure:
A solution is formed by mixing 28.8 grams of trimellitic acid anhydride and 132.5 grams of p,p'diphenyl methane diisocyanate and 212.4 grams of o-dichlorobenzene by heating the mixture. At approximately 170°C. a clear, homogeneous solution is obtained. Once clarity is obtained 51.1 grams of adipic acid is added slowly. The temperature of the mixture is raised to approximately 170°C. and slow reflux is maintained. After approximately 30 minutes, a yellow viscous resin is obtained and 283.2 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 200 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 30% weight resin.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][C@H:2]12.C(=O)([O-])[O-].[K+].[K+].I[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>[Cu](I)I.CN(C)C=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][C@H:2]23)=[CH:19][CH:20]=1
Reactant: O=C1CN2C(=O)CC[C@@H]2N1
Reactant: Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2C(=O)CN3C(=O)CC[C@@H]32)cc1

Procedure:
In a 100 ml round bottomed flask fitted with a magnetical stirrer and a reflux condenser are placed 10 ml of dimethylformamide, 1.2 g of (R)-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione, 0.456 g of copper iodide, 1.2 g of potassium carbonate and 4.0 g of 1-iodo-4-methyl-benzene. The well stirred reaction mixture is heated at reflux for 4 hours. After cooling, the solvent is removed under vacuum (50° C., 7 mbar) and the residue is treated with 70 ml of ethyl acetate and the insoluble is filtered off. The organic solvent is then washed with 20 ml of saturated NaCl solution, dried over Na2SO4, filtered and evaporated under vacuum. The residue is triturated with 30 ml of diethyl ether and then crystallized with 20 ml of isopropanol, obtaining 0.92 g (y=47%) of the title compound as an off-white powder.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7]1)C.[OH-].[K+]>CO.CO.O>[CH3:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:16])=[O:3])[CH:7]=1
Reactant: CCOC(=O)Cn1cc(C)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The residue, 3-methyl-indole-1-acetic acid ethyl ester, is dissolved in 900 ml of methanol, potassium hydroxide (90 g) in 400 ml of 1:1 methanol-H2O is then added. The mixture is stirred at room temperature for 11/2 hours. The methanol is evaporated under reduced pressure. The residue is diluted with water (800 ml) and extracted (3x) with ether. Acidification with 6NHCl of the aqueous phase yields 3-methyl-indole-1-acetic acid, m.p. 174°-176°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH3:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH:18]=[CH:22][N:23]([CH3:25])[CH3:24])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine (1.0 g, 3.93 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred and heated at reflux for 17 h. The mixture was cooled to room temperature and the volatiles evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluded with 1% MeOH/CH2Cl2) to afford the title compound as an orange solid, 0.830 g (68%). 1H NMR (CDCl3) 88.50 (d, 1H, J=6.9 Hz), 8.39 (d, 1H, J=9.0 Hz), 7.83 (d, 2H, J=12.6 Hz), 7.73 (m, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.93 (m, 1H), 5.13 (d, 1H, J=12.5 Hz), 3.10 (s. 3H), 2.56 (s, 3H). MS (+ve ion electrospray) 310 (90), (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Yield: 75.5 %

Procedure:
A 250 mL one-necked round-bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3-(4-chlorophenyl)-3-ketopropionaldehyde (18.3 g, 0.1 mol ), 4-sulfonamidophenylhydrazine hydrochloride (11.2 g, 0.05 mol) and 100 mL of absolute ethanol. The solution was heated to reflux for 15 hour and then diluted with 100 mL of water and allowed to stand whereupon a white solid formed that was isolated by filtration on a Buchner funnel and air dried to provide 12.6 g, 76% of 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide, mp 185°-187° C. 1H nmr (CDCl3 /300 MHz) 7.89(d, J=8.7 Hz, 2H), 7.76(d, J=1.8 Hz, 1H), 7.43(d, J=8.7 Hz, 2H), 7.34(d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.53 (d, J=1.8 Hz, 1H), 4.93 (brs, 2H), mass spectrum MH+ =334.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,3-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 46%).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH:18]([C:23]3[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=3)[C:26]#[N:27])[C:19]([F:22])([CH3:21])[CH3:20])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:15][CH:16]([CH:18]([C:23]3[CH:24]=[C:25]([C:26]4[NH:34][N:33]=[N:32][N:27]=4)[CH:28]=[C:29]([F:31])[CH:30]=3)[C:19]([F:22])([CH3:21])[CH3:20])[CH2:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(F)C(c1cc(F)cc(C#N)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(F)C(c1cc(F)cc(-c2nnn[nH]2)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 16 h

Procedure:
A mixture of 1.17 g (2.81 mmol) of 3-{1-[(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzonitrile, 914 mg (14.06 mmol) of sodium azide, and 715 mg (14.05 mmol) of ammonium chloride in 15 mL of DMF was stirred for 16 h. Then it was concentrated to remove solvents. The residue was purified by silica gel chromatography with CH2Cl2/MeOH/NH3 (2M) in MeOH to afford the title compound as a white solid;
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][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.[O:20]=[C:21]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:33][C:34](O)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:34](=[O:35])[CH2:33][N:22]2[CH2:23][CH2:24][CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][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: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To 1-benzhydrylpiperazine (0.238 g, 0.943 mmol), the product from Example 91D (0.200 g, 0.857 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.358 g, 0.943 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (0.225 mL, 1.286 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was concentrated and loaded onto a silica gel column (SF25-25, Analogix®, Burlington, Wis.) and eluted using a gradient of 0.5% to 5% methanol/dichloromethane. The product was isolated along with a slightly lower Rf spot. The mixture was rechromatographed over silica gel using a gradient of 5% to 100% ethyl acetate/hexanes to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.43 (m, 4H), 7.14-7.34 (m, 11H), 4.43 (d, J=15.6 Hz, 1H), 4.24 (s, 1H), 4.00 (d, J=15.6 Hz, 1H), 3.70 (dd, J=7.7, 6.0 Hz, 1H), 3.61-3.66 (m, 2H), 3.52-3.59 (m, 1H), 3.44-3.49 (m, 2H), 3.41 (dd, J=11.6, 5.8 Hz, 1H), 2.37-2.43 (m, 4H), 2.15-2.28 (m, 1H), 1.90-2.03 (m, 2H), 1.77-1.89 (m, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:10]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:27]([C:29]([F:31])([F:32])[F:30])([C:33]([F:34])([F:36])[F:35])[OH:28])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(homopiperazin-1-yl]-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]4[CH2:29][CH2:28][N:27]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(C3CCNC3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c2cc(C3CC3)c(N(C3CCN(S(C)(=O)=O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pyrrolidin-3-yl)amino]-2H-indazole-3-carboxamide in DCM at 0° C. was added DIPEA (4 μL, 0.023 mmol), followed by methanesulfonyl chloride (3 μL, 0.039 mmol) and the mixture was stirred at RT for 20 min. The mixture was concentrated to dryness and purified by preparative LCMS (5-40-100% ACN in 0.1% aqueous formic acid) to afford Compound (52) as a white solid (1.4 mg, 36%). ESI-MS m/z calculated for [M+H]+: 610.1/612.1; found: 610.0/612.0; 1H NMR (400 MHz, CDCl3) δ 7.72 (2×s, 1H), 7.70-7.64 (m, 2H), 7.51-7.44 (m, 2H), 7.36 (2×s, J=2.6 Hz, 1H), 5.75 (2×d, J=5.0 Hz, 1H), 4.92-4.68 (m, 1H), 3.88-3.68 (m, 1H), 3.54-3.37 (m, 1H), 3.38-3.16 (m, 2H), 3.10 (d, J=4.6 Hz, 3H), 3.00 (2×d, 3H), 2.79 (2×s, 3H), 2.43-2.17 (m, 2H), 2.17-1.82 (m, 1H), 1.21-0.95 (m, 3H), 0.80-0.62 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].Br[CH2:7][CH2:8][CH2:9][CH:10](Br)[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:7][C@H:8]1[CH2:9][CH2:10][CH2:11][N:1]1[C@@H:2]([CH3:5])[CH2:3][OH:4]
Reactant: CC(Br)CCCBr
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)N1CCC[C@@H]1C
Temperature: 100 °C
Yield: 8.8 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (12.5 g, 0.166 mol), 1,4-dibromopentane (42 g, 0.18 mol) and Na2CO3 (53 g, 0.51 mol) in EtOH (800 mL) was heated at 100° C. for 24 h. The mixture was filtered, and the filter cake was washed with EtOH (50 mL). The combined filtrate was concentrated under reduced pressure, and the crude product was purified on a silica gel column (NH4OH/MeOH/DCM=1/6/300) to give (S)-2-((S)-2-methylpyrrolidin-1-yl)propan-1-ol (2.1 g) as a colorless oil and a crude mixture containing (S)-2-((R)-2-methylpyrrolidin-1-yl)propan-1-ol. 1H NMR (DMSO-d6): δ 4.22 (br s, 1H), 3.36 (dd, 1H), 3.22 (dd, 1H), 2.82 (m, 1H), 2.65 (m, 2H), 2.42 (q, 1H), 1.78 (m, 1H), 1.60 (m, 2H), 1.25 (m, 1H), 0.95 (d, 3H), 0.84 (d, 3H); LCMS: 144 (M+H)+.