Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: Cc1ccc2cc(O)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 72 h

Procedure:
To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), c is 4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol; Supplier=Aldrich) in tetrahydrofuran (100 mL, 1 mol; Supplier=Acros), cooled in an ice bath, was added diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol; Supplier=Acros) in Tetrahydrofuran (10 mL, 0.1 mol; Supplier=Acros). The reaction mixture was stirred for 72 h allowing to reach room temperature. The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to give the title compound in 56% yield. ESI-MS (M+H+): 298.3.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N)[CH2:23][NH2:24]>CN(C=O)C.O>[C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12]([C:23]#[N:24])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: CC(C)(C)O/N=C(\c1ccccn1)c1cc(Br)ccc1O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)O/N=C(\c1ccccn1)c1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(5-bromo-2-hydroxybenzoyl)pyridine O-t-butyloxime (12.7 g) was dissolved in DMF (100 ml). To the solution was added cuprous cyanide (4.64 g), and the mixture was heated, under argon atmosphere, for 3 hours under reflux. To the reaction mixture was added a solution of ethylenediamine (30 ml) in water (20 ml). The mixture was stirred for 30 minutes at room temperature, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography, eluting with ethyl acetate/hexane, to give (Z)-2-(5-cyano-2-hydroxybenzoyl)pyridine O-t-butyloxime (4.31 g) (Compound 76).
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([N:10]=[N+]=[N-])[CH3:9])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([NH2:10])[CH3:9])([CH3:2])[CH3:3]
Reactant: CC(COc1ccccc1C(C)C)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(N)COc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
12.3 g of 2-(2-isopropylphenoxy)-1-methylethylazide was dissolved in 150 ml of ether and added portionwise with small amount of lithium aluminium hydride up to 18 g and stirred at room temperature for 2.5 hr. Then 1.8 ml of water, 1.8 ml oif 15% aqueous solution of sodium hydroxide and 5.4 ml of water were added one after another in order to decompose the residual lithium aluminium hydride. Crystals thus isolated were filtered off and washsed with ether; the ether layer was washed consecutively with water and saturated saline and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and yielded 9.8 g of 2-(2-isopropylphenoxy)-1-methylethylamine. Physical properties of this substance are as the following:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.[ClH:40].C(OCC)C.B(Br)(Br)Br>ClCCl>[ClH:40].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=1)[CH:7]=[CH:6]2
Reactant: CNS(=O)(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.03 h
Yield: 85 %

Procedure:
In a round bottom flask place the product of Example 69 (85 mg, 0.146 mmol), dichloromethane (5 mL) and a solution of 1.0 M hydrochloric acid in diethyl ether (0.150 mL, 0.150 mmol). Shake this solution at ambient temperature for 2 minutes and then evaporate it in vacuo. After drying in vacuo, add dichloromethane (6 mL) and place this solution in an ice bath with stirring. Add a solution of 1.0 M boron tribromide in dichloromethane (0.32 mL, 0.32 mmol) and stir the reaction for 2-3 hours, keeping the temperature between 0° C.-10° C. Quench the reaction over saturated aqueous sodium bicarbonate then extract it into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, water and brine; then dry (sodium sulfate) and evaporate in vacuo. Purify the crude solid on a Chromatotron (silica gel; 6%-10% MeOH gradient in CH2Cl2). Dissolve the purified material in methanol (5 mL) and add a solution of 1.0 M hydrochloric acid in diethyl ether (0.30 mL). Shake the resulting solution for two minutes at room temperature then evaporate in vacuo to give 71 mg of the title compound (85%). MS (IS+) m/e 533 (M+1-HCl).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BrH:17].BrBr>CC(O)=O>[Br:17][CH:3]1[CH2:4][CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[S:9][C:10]=2[C:2]1=[O:1]
Reactant: Br
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Agent: BrBr
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Temperature: 45 °C
Yield: 166.9 %

Procedure:
A solution of 1-(7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 4 (1.00 g, 4.18 mmol) and 48% HBr (aq) (0.24 mL, 2.09 mmol, 0.5 eq) in AcOH (18 mL) was treated dropwise with a solution of Br2 (0.23 mL, 4.39 mmol, 1.05 eq) in AcOH (1 mL) with stirring. The reaction mixture was heated at about 45° C. with stirring for about 16 hours with a condensor on top of the reaction flask. An orange colored suspension was obtained. The solid was filtered off and washed with AcOH (5 mL), toluene (2×3 mL) and Et2O (2×5 mL). After drying under vacuum, 1.11 g (83%) of the desired compound 7 was obtained. 1H NMR (DMSO) δ 11.15 (br s, 1H, NH), 6.73 (br s, 1H, NH), 4.87 (t, 1H, J=4.6 Hz, CH), 3.17 (m, 2H, CH2), 2.87 (dd, 2H, J=7.2, 4.4 Hz, CH2), 2.61–2.54 (m, 1H, CH2), 2.39–2.33 (m, 1H, CH2), 1.08 (t, 3H, J=7.2 Hz, CH3); LC/MS 318 (MH+); RP-HPLC RT 2.68 minutes.
Reaction SMILES: C1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:19]([OH:20])=[C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:17]([CH3:30])=[N:16]1.[C:31](Cl)(=[O:33])[CH3:32]>O>[CH3:14][N:15]1[C:19]([O:20][C:31](=[O:33])[CH3:32])=[C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:17]([CH3:30])=[N:16]1
Reactant: CC(=O)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1c(C(=O)c2ccccc2Cl)c(C)nn1C
Yield: 82.2 %

Procedure:
In a mixture of 20 ml. of benzene and 0.51 g. of triethylamine is dissolved 1.25 g. of 1,3-dimethyl-4-(2-chlorobenzoyl)-5-hydroxypyrazole and 0.4 g. of acetyl chloride is added dropwise at room temperature with stirring. After completion of the dripwise addition, the mixture is stirred at room temperature for 3 hours. After completion of the reaction, water is added to the reaction mixture to dissolve the salts and an organic layer is separated. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting oily substance is recrystallized from n-hexane to give crude crystalline substance. The substance is recrystallized from methanol to give 1.20 g. of the desired product as colorless prisms melting at 78°-79° C. Yield 82.2%.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=2)=[N:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(-c2nc(=O)n(Cc3ccccc3)c3ccc(O)cc23)cc1
Reaction time: 4 h

Procedure:
A solution of 470 mg (1.22 mmol) of 1-benzyl-4-(4-isopropyl-phenyl)-6-methoxy-1H-quinazolin-2-one in 5 ml anhydrous THF is treated at 0° C. dropwise with 2.44 ml 1.0 M (2.44 mmol; 2 eq.) boron tribromide solution (in methylene chloride). After complete addition, the mixture is allowed to come to rt and stirred for 4 h. The yellow-red solution is poured into water and extracted with CH2Cl2. Concentration in vacuo afforded a yellow solid. yield: 360 mg (80%). m.p.>270° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCCCCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCC1CCCCCCCCCC1)C(=O)OCC

Procedure:
4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 7.6 g of (3-cycloundecylpropyl)-malonic acid ethyl ester, 0.84 g of paraformaldehyde, 7 ml of pyridine and 0.3 ml of piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1.[CH:14]1([C:17]2[CH:21]=[C:20]([NH2:22])[N:19]([CH2:23][CH3:24])[N:18]=2)[CH2:16][CH2:15]1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][NH:22][C:20]2[N:19]([CH2:23][CH3:24])[N:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:21]=2)=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: CCn1nc(C2CC2)cc1N
Reactant: COc1nc(Cl)c(C=O)c(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nc(C2CC2)cc1NCc1c(Cl)nc(OC)nc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-2,6-dimethoxypyrimidine-5-carbaldehyde (2.4 g, 11.8 mmol), and 3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine (2.15 g, 14.2 mmol) in THF was heated at 50° C. for 3 h. The flask was then removed from the heating bath and cooled in an ice bath and EtOH (13 mL) was added followed by NaBH4 (0.896 g, 23.7 mmol). The resulting mixture was left to gradually warm to rt and stir for 18 h. The excess NaBH4 was quenched slowly with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc (2×250 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified via FCC (20-75% EtOAc/heptane) to give the title compound N-((4-chloro-2,6-dimethoxypyrimidin-5-yl)methyl)-3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine. MS (ESI+) m/z 338.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:20][CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH2:20][CH3:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1nn(Cc2ccccc2)c2cccc(N)c12
Temperature: 85 °C
Yield: 97 %

Procedure:
A mixture of 1-benzyl-3-ethyl-4-nitro-1H-indazole (46.0 mg, 0.164 mmol), iron powder (91.3 mg, 1.64 mmol) and ammonium chloride (4.4 mg, 0.082 mmol) was stirred in a 4:1 mixture of ethanol and water (5 mL) with heating to 85° C. for 60 minutes. The solvent was removed under reduced pressure. Ethyl acetate (4 mL) and triethylamine (1 mL) was added and the mixture was heated for 15 minutes at 85° C. After cooling, the mixture was filtered through glass fiber filter paper, rinsing with methanol, dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure to provide 1-benzyl-3-ethyl-1H-indazol-4-amine as an oil (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH2:18]Br.[C-:21]#[N:22].[Na+]>CS(C)=O.O>[C:21]([CH2:18][C:5]1[C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:22]
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 2-bromomethyl-5-isopropoxy-isophthalic acid dimethyl ester (Cpd C, 17.4 g, 50.5 mmol) in DMSO (200 mL) was added NaCN (3.71 g, 75.7 mmol) in H2O (20 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (500 mL), and extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine (1×300 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-40%, EtOAc/heptanes) to give Dimethyl 2-(cyanomethyl)-5-(propan-2-yloxy)benzene-1,3-dicarboxylate (Cpd D, 12.8 g, 87% yield) as a clear oil which solidified upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+]>C(O)(C(F)(F)F)=O.CC(O)=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N+:6]([O-:16])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 60 °C
Yield: 42 %

Procedure:
A solution of 4-bromo-2,6-difluoroaniline (4.75 g, 22.8 mmol) in TFA (50.2 mL) and AcOH (50.2 mL) was charged with sodium perborate tetrahydrate (16.0 g, 104 mmol). The reaction was warmed to 60° C. and heated for 24 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield a yellow solid. The material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 2.28 g (42% yield). 1H NMR (CDCl3, 400 MHz): δ=7.31-7.35 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=C(C)S[C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3COC)[N:9]=2)=[CH:4][CH:3]=1.Cl[C:30]1C=CC(C2C3C=CC=CC=3NC(=O)C3(N=2)CC3)=C[CH:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:19][CH:30]=[CH:31][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:24][CH2:25]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reactant: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)=NC12CC2
Product: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NC21CC1

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that 5-(4-chlorophenyl)spiro[benzo[e][1,4]diazepine-3,1′-cyclopropan]-2(1H)-one was used as starting material. LRMS (M+H)+: 335 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.74-7.79 (m, 2H), 7.46-7.58 (m, 5H), 7.32 (d, J=7.55 Hz, 1H), 2.58 (s, 3H), 1.67-1.77 (m, 1H), 1.34-1.44 (m, 1H), 0.67-0.83 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Cl>ClCCl.ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:34][CH2:33][O:32][CH3:31])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (2.03 g, 6.41 mmol) and dimethylformamide (50 mL). Cool in an ice-bath. Add sodium hydride (0.28 g, 60% n in oil, 7.0 mmol). After 20 minutes, add 2-chloroethyl methyl ether (0.7 mL, 7.66 mmol). Heat to 85° C. After 18 hours, cool to ambient temperature and dilute with dichloromethane, and extract with water, a saturated aqueous sodium bicarbonate solution, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated ammonium hydroxide 95/5/0.05 to give 1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:19]>>[ClH:19].[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:18])=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(c1ccc(F)cc1)C1CCNCC1

Procedure:
A solution of 70.6 of 1-acetyl-4-(4-fluorobenzoyl)piperidine in 200 ml of 6N HCl is refluxed for 2 hours. The cooled solution is extracted twice with ether, the aqueous solution basified with sodium hydroxide and then extracted with benzene. The benzene extracts are dried, filtered and the filtrate is concentrated under reduced pressure. The residual oil is dissolved in ether and HCl gas is bubbled into the solution with stirring. The salt is collected by filtration, washed with ether and dried. The salt is recrystallized from isopropanol to give the solid product of 4-(4-fluorobenzoyl)piperidine hydrochloride, mp 222°-224° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[NH2:67]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:62]3[CH2:63][CH2:64][CH2:65][CH2:66][CH:61]3[CH3:60])=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: CC1CCCCC1N
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCCC1NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 2-Methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (192 mg) as a light yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:10][CH2:9][CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCOCCO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Into a reaction vessel, 3.29 g (22.5 mmol) of 2-hexyloxyethanol and 5.33 g (67.5 mmol) of pyridine were charged, and 4.72 g (24.7 mmol) of p-toluenesulfonic acid chloride was added thereto in an ice bath, which were then stirred for 1 hour and thereafter further stirred at room temperature for 3 hours. After the reaction was completed, 3N HCl was added to make the reaction mixture acidic, followed by extraction with toluene twice. The extract obtained was washed with water, and thereafter sodium sulfuric anhydride was added to effect drying. After the solvent was evaporated off, the resultant mixture was purified by silica gel chromatography (eluting solvent: toluene/ethyl acetate=10/1) to obtain 6.45 g (21.5 mmol) of 2-hexyloxyethyl p-toluenesulfonate. Yield: 95%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:27])=[C:21]([F:26])[CH:22]=2)[N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:27])[N:17]=[C:16]([NH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[CH:25]=[N:24]2
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2ncc(NC[C@@H]3CCCCN3)nc2cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.460 g) was dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a pale yellow foam (0.286 g), MH+ 279.