Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=O.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[N:24]=[N:23][C:22]([C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH:14]3[CH2:16][CH2:15]3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1)=[O:8]
Reactant: COC(=O)c1ccccc1C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: COC(=O)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use phthalic acid monomethyl ester in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a light yellow solid (97% yield). 1H NMR (300 MHz, CDCl3) δ 8.02-8.06, 7.96, 7.88, 7.60, 7.48, 7.30, 6.98, 3.72-4.02, 3.54, 3.33, 1.49, 0.74, 0.45, 0.08. MS (ES+) m/z 438 (M+1).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1)(=O)C.[Li+].[OH-].O.CO>C1COCC1>[OH:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.16 g, 3.08 mmol) in 12 mL THF was added 3M LiOH (2.57 mL, 7.70 mmol) and 3 mL H2O. The reaction mixture was stirred at room temperature for 15 hours, after which H20 was added, and the mixture was extracted with 3×75 mL EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 40S) first with 1:1 to 1:6 DCM:EtOAC gradient, followed by 20:1 DCM:MeOH to give (R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.556 g, 54.0% yield) as a 1:1 mixture of diastereomers as a brown foam. MS (APCI+) m/z 335 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21]I>CC(N(C)C)=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N(C)C1CCCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene (Example 1) in 10 ml of DMA was added dropwise under argon to a suspension of 0.12 g (4.1 mmol) of 80 percent sodium hydride in 5 ml of DMA. After stirring at RT for 3 h, 0.63 g (4.5 mmol) of methyliodide was added dropwise and the mixture was stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 0.64 g of 3-fluoro-5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene was obtained.
Reaction SMILES: [CH2:1]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:46]([O:53][NH2:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:46]([O:53][NH:54][C:21](=[O:23])[CH2:20][N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCCCCCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCCCCCN(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.6 %

Procedure:
[Octyl-(toluene-4-sulfonyl)amino]-acetic acid (4.0 g, 0.012 mol) was taken up in DMF (150 ml) and treated at room temperature with NMM (1.55 ml, 0.014 mol) followed by EDC (2.92 g, 0.015 mol). The reaction mixture was allowed to stir for 15 minutes at room temperature before the addition of HOBt (2.1 g, 0.016 mol). The reaction mixture was left to stir for a further 20 minutes before a mixture of O-benzylhydroxylamine hydrochloride (1.87 g, 0.012 mol) and NMM (2.6 ml, 0.024 mol) in DMF (50 ml) was added. The reaction mixture was allowed to stir at room temperature for a further 48 h. The DMF was removed under reduced pressure and the resulting crude oil was dissolved in ethyl acetate (200 ml). The solution was washed consecutively with 1M HCl, 0.5M Na2CO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give an oil which was further purified by flash chromatography (silica gel, 20% ethyl acetate in hexane) to give the title compound as a white solid (1.91 g, 37%). 1H NMR: δ (CDCl3), 9.39 (1H, br s), 7.65 (2H, d, J=8.2 Hz), 7.45-7.20 (7H, m), 4.91 (2H, s), 3.67 (2H, br s), 3.07 (2H, dd, J=7.5, 7.9 Hz), 2.40 (3H, s), 1.50-1.33 (2H, m), 1.31-1.10 (10 H, m) and 0.86 (3H, t, J=6.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3-chloro-4-fluorophenyl)methanol (95 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:1])=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: COc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)CCN2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 21 %

Procedure:
N-Chlorosuccinimide (0.15 g) was added at room temperature to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline (0.39 g) in methylene chloride (5 ml) and the resultant mixture was stirred for 20 min. Then a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (methylene chloride/ethanol system) followed by conversion into a hydrochloride to give the hydrochloride (0.10 g) of the title compound as apale red powder (yield: 21%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:11]>[Pd].C(O)C.O1CCCC1>[ClH:11].[F:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ncc(F)cc1F
Yield: 100 %

Procedure:
A mixture of 3,5-difluoropicolinonitrile (1.4 g, 10 mmol), conc.HCl (12 ml) and 10% Pd—C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture was filtered and the ethanol removed in vacuo. The remaining solution was lyophilized to afford an off-white solid (2.16 g, 100% yield). LCMS (M+H) calcd for C6H7F2N2: 145.06. found: 145.12.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.C[O:18][C:19](=O)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:18]=[C:19]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CC1CCCCC1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CC1CCCCC1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 31.2 g (0.20 mole) methylcyclohexylacetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatenous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H 2 O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 160°-162° (0.2 mm) to give dimethyl 2-oxo-3-cyclohexylpropylphosphonate (2h).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C=O.[C:30](=O)([O-])[O-:31].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH2:30][OH:31])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Yield: 93.3 %

Procedure:
In a solution of 7.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 in 70 mL of 1,4-dioxane, 1.82 g of 37% formalin, 7.00 g of potassium carbonate and 15 mL of water were added at room temperature with stirring, and stirred at the same temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted by adding 200 mL of ethyl acetate, washed with water (50 mL×1), and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, filtered through silica gel, and the solvent was distilled off under reduced pressure to obtain 7.00 g of the crude product as white crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]([O:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][O:18][C:17]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccccc1OCCOc1nc2ccccc2nc1Cl
Product: Clc1ccccc1OCCOc1nc2ccccc2nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
Piperazine (0.580 g, 6.65 mmol) was added to the crude material from Step 1 and the resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the crude mixture was dissolved in DMSO and precipitated with water. The precipitate was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (40:3:3:2) as eluent to afford 0.100 g (22%) of the title compound as a yellow oil. HRMS m/z calcd for C20H21ClN4O2 (M)+ 384.1353, found 384.1334.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>CO.CCCCC>[Cl:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1c(F)cc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCC
Product: OCc1c(F)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to an ice-cooled solution of 2-chloro-4,6-difluorobenzaldehyde (6.70 g, 38.0 mmol) in methanol (56 ml); once addition was complete the reaction was warmed to rt over 1 h and then concentrated in vacuo. The residue was partitioned between ether and saturated sodium bicarbonate solution, the phases were separated and the aqueous phase extracted with more ether. The combined organic phases were washed with H2O, dried with MgSO4 and concentrated in vacuo to yield the crude product as an oil which was diluted with pentane (20 mL) and allowed to stand in a freezer overnight. The liquors were decanted from the resultant white crystals which were then dried in vacuo to yield the title compound (5.60 g, 31.4 mmol).
Reaction SMILES: [C:1]([CH:4]1CCC[N:5]1[CH3:9])(=O)[CH3:2].C1(C)C(S(C[N+:20]#[C-])(=O)=O)=CC=CC=1.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+].O>COCCOC.C(O)(C)(C)C>[CH3:9][N:5]1[CH2:4][CH2:1][CH2:2][CH:23]1[CH:24]([CH3:27])[C:25]#[N:20]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: CC(=O)C1CCCN1C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C#N)C1CCCN1C
Temperature: -78 °C

Procedure:
2-Acetyl-N-methylpyrrolidine 0.979g (7.7 mmol) and toluenesulfonylmethyl isocyanide 2.3 g (11.5 mmol) are dissolved in 50 mL of dry DME and cooled to −78° C. while stirring under N2. To this mixture is added dropwise a solution of potassium t-butoxide 1.75 g (15.4 mmol) in 15 mL of hot t-butanol. The reaction mixture is stirred at −78° C. for 3 h then poured into 50 mL of H2O and extracted with 150 mL of dichloromethane and 150 mL of EtOAc. The organic layers are combined, washed with saturated NaHCO3 and saturated NaCl, dried and concentrated in vacuo. Purification by chromatography gives the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester LIX (648 mg, 2.04 mmol) in THF (20 ml) was added Red-Al (65% w, 1.96 ml, 6.87 mmol) dropwise. The mixture was stirred at 0° C. for 3 hours, at room temperature for 30 minutes, and the reaction was quenched by addition of H2O (7 ml). The resulting mixture was stirred for 10 minutes and H2O (5 ml) and EtOAc (8 ml) were added. The mixture was then stirred overnight at room temperature. The solid was filtered off and washed with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 4-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX as a white solid (377 mg, 67% yield).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[C:16]([O:28]C)[N:17]2[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:13]([NH2:30])[N:12]=1)[CH2:7][CH2:8][CH3:9].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:30][C:13]1[N:12]=[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:28])[N:17]2[CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:26][CH2:27]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCCC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 12.3 %

Procedure:
1-Iodobutane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (0.418 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was heated at 50° C. for 18 hours. An additional portion of 1-iodobutane (15 μl) and DIPEA (20 μl) was added and heating continued for a further 18 hours. DMSO (200 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to a 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (4.8 mg).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-iodobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[CH:10][N:9]=[N:8]1.CN(C=O)C.Cl[C:18]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1>O>[N:7]1[N:8]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[N:9]=[CH:10][CH:11]=1.[N:7]1([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[CH:11]=[CH:10][N:9]=[N:8]1
Reactant: Nc1ccnc(Cl)c1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccnc(-n2ccnn2)c1
Product: Nc1ccnc(-n2nccn2)c1
Temperature: 180 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (1.9 g) and 1H-1,2,3-triazole (540 mg) were added to a tube containing a DMF (2 ml) solution containing 2-chloropyridin-4-amine (500 mg) and the tube was sealed, followed by stirring at 180° C. for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:3 to 0:1), and a white solid of 2-(2H-1,2,3-triazol-2-yl)pyridin-4-amine (75.7 mg) and brown oily matter of 2-(1H-1,2,3-triazol-1-yl)pyridin-4-amine (25.1 mg) was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=O)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)=[CH:28][CH:27]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(CNc3ccc(N4CCOCC4)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-formyl-1H-indole-6-carboxylic acid methyl ester (500 mg, 2.46 mmol), 4-morpholinoaniline (482.3 mg, 2.71 mmol) and dibutyltin dichloride (76 mg, 0.25 mmol) in THF was added phenylsilane (334 μl, 2.71 mmol). The mixture was stirred at room temperature overnight under nitrogen, THF was evaporated off the mixture and the residue was purified by flash chromatography (hexane/EtOAc, 20/80) to afford the title compound 123 (881 mg, 98%). 1H-NMR (DMSO) δ: 8.00 (d, J=1.0 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H); 7.58 (dd, J=8.4, 1.6 Hz, 1H); 7.52 (d, J=2.0 Hz, 1H); 6.70 (d, J=9.0 Hz, 2H); 6.59 (d, J=9.0 Hz, 2H); 5.48 (t, J=5.8 Hz, 1H); 4.31 (d, J=5.7 Hz, 2H); 3.83 (s, 3H); 3.68 (t, J=4.7 Hz, 4H); 2.86 (t, J=4.7 Hz, 4H).