Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:40]([F:43])([F:42])[F:41])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][CH:14]=3)[C:6]=2[CH:39]=1.[H-].[Na+].[CH3:46]I.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:40]([F:43])([F:41])[F:42])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([O:12][CH3:46])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:18]=3)[C:6]=2[CH:39]=1
Reactant: CI
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 4, 590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg, 1.13 mmol). Then the mixture was added MeI (0.08 ml, 1.23 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was added water (30 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3:1) to afford 550 mg (91%) of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1Cl)=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])(=[O:14])[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[C:10]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccc(O)c(F)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)c(F)c1

Procedure:
2-Fluoro-4-aminophenol (0.8 g, 6 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.5 g, 5.7 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, sodium hydrogen oarbonate solution and brine then dried and evaporated. The residue was recrystallised from methanol-water to afford 3-butyryl-4-(3-fluoro-4-hydroxyphenylamino)-8-methoxyquinoline, m.p. 266°-268°.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:24])[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([Cl:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:24])[CH2:21][C:22]#[N:23])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([Cl:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[Cl:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(CC#N)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 1e from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-cyanomethyl-amino]-4-methylamino-5-amino-benzoic acid amide (48 mg, 0.125 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (40 mg, 0.125 mmol), DIC (19 μL) and DMF (2.0 mL).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2cccnc2)n(CCO)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2cccnc2)n(CCOS(C)(=O)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.70 ml) is added dropwise to a solution of 7.5 g 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole and 10.34 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated NaHCO3 solution, dried over MgSO4 and evaporated in vacuo. There is obtained 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole which is used directly in the above reaction.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([I:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.N1C2C=CC=C(O)C=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][C:6]2[C:5]([I:12])=[CH:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[CH:7]=2)[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COC(=O)c1cc(I)c(CC(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5-fluoro-2-iodo-4-(methoxycarbonyl)phenyl)acetic acid (100 mg, 0.30 mmol), 1-benzhydrylpiperazine (82 mg, 0.33 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol), 1H-benzo[d][1,2,3]triazol-4-ol (61 mg, 0.45 mmol) and triethylamine (91 mg, 0.90 mmol) in DCM (5.0 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (20 mL), washed with HCl (2M, 10 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (60%-70% CH3CN in 0.1% HCOOH) to afford methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate (70 mg, 41%) as a white solid. LCMS (ESI): m/z: 572.8 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: O=C1NCCN1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CCNC1=O
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 1-(2-hydroxyethyl)imidazolidin-2-one (100 mg; 0.77 mmol) and Et3N (81 mg; 0.80 mmol) in dry DCM (10 mL) was added MsCl (137 mg; 1.20 mmol) under nitrogen. The reaction mixture was stirred overnight, diluted with DCM (20 mL), washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, concentrated to afford 72 mg (44%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:10]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:23][O:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:26]=1[NH2:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:10]1([C:20]([NH:27][C:26]2[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=2[O:24][CH3:23])=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC1(C(=O)Cl)CCc2ccccc2C1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(OC)cc(OC)cc2OC)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according to the procedure described in Example 65, except that 422 mg 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride, 247 mg (1.3 mmole) 2,4,6-trimethoxyaniline, and 165 mg (1.3 mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirred at room temperature for 20 hours. There was obtained 421 mg product (68% yield). IR(CHCl3) 1670 cm-1. 1H NMR: δ 0.87 (t, 3H); 1.25 (c, 12H); 1.5 (c, 3H); 1.85 (c, 2H); 2.21 (c, 1H); 2.8 (c, 2H); 3.0 (c, 1H); 3.3 (d, 1H); 3.66 (s, 6H); 3.75 (s, 3H); 6.06 (s, 2H); 6.56 (s, 1H); 7.1 (s, 4H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:5][N:4]([CH2:3][N:9]=[CH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:6]
Reactant: COC(OC)N(C)C
Reactant: NCC1CCNCC1
Solvent: Cc1ccccc1
Product: CN(C)CN=CC1CCNCC1

Procedure:
N,N-Dimethylformamide dimethyl acetal (23.3 ml) was added to 4-aminomethylpiperidine (20.0 g) in toluene (20 ml) and the mixture was boiled under reflux for 3 hours removing the water formed using a Dean and Stark apparatus to give a solution of 4-(dimethylaminomethyliminomethyl)piperidine. The mixture was cooled to ambient temperature and 2-bromoethyl phenyl ether (22.1 g) then triethylamine (24.3 ml) were added. The mixture was boiled under reflux for 10 hours and then evaporated to dryness. The residue was dissolved in 2M hydrochloric acid (200 ml) and heated on a steam bath for 24 hours. The mixture was cooled to ambient temperature and washed with dichloromethane. The aqueous layer was basified with 6M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 186°-242° C. at 0.8 mbar. The distillate was dissolved in methanol (50 ml) and treated with concentrated aqueous ammonia solution (20 ml, specific gravity 0.88) and then left at ambient temperature for 18 hours. The solution was concentrated by evaporation and water (200 ml) was added. The mixture was extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride. A solid was collected by filtration and recrystallised from propan-2-ol/IMS to give 4-aminomethyl-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 212°-214° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.N#N.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH:31]=1.C([O-])(O)=O.[Na+]>ClCCl>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([NH:22][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:31][C:27]=2[CH:28]=[N:29]1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2oncc2c1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oncc3c2)cc1
Yield: 72 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (171 mg, 0.783 mmol) in dichloromethane (4 mL).was added pyridine (150 μL, 1.86 mmol) and the mixture was stirred under. N2 for 5 min, after which time 5-amino-1,2-benzisoxazole (100 mg, 0.746 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (170 mg, 72%), single spot at Rf 0.68 (1:1 hexane:ethyl acetate). mp 130.0-130.6° C., HPLC purity 99+% (tR 2.44 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.62 (1H, d, J=1.0 Hz), 7.60 (2H, d, J=8.4 Hz), 7.48 (2H, m), 7.19 (3H, m), 6.86 (1H, s, N−H), 2.58 (2H, t, J=7.5 Hz), 1.58 (2H, sextet, J=7.4 Hz), 0.88 (3H, t, J=7.4 Hz). LCMS: 315.14 (M−). FAB-MS (MH+, C16H16N2O3S): calcd 317.0960, found 317.0962.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[CH3:28][C:29]1[O:33][N:32]=[C:31]([C@:34]([OH:38])([C:36]#[CH:37])[CH3:35])[CH:30]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:37]#[C:36][C@:34]([C:31]4[CH:30]=[C:29]([CH3:28])[O:33][N:32]=4)([OH:38])[CH3:35])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(C(C)(C)O)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a pressure tube was added 2-[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]propan-2-ol followed by piperidine (2.5 mL), tetrakis(triphenylphosphine)palladium (102.88 mg, 0.09 mmol), copper(I) iodide (16.96 mg, 0.09 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (269.16 mg, 1.78 mmol). The reaction was capped and stirred at 65° C. for 1.5 hr and then concentrated in vacuo. DCM (5 mL) was added to the reaction mixture and the concentration was repeated (×2). The crude product was purified by flash chromatography (Biotage, 1-10% methanol in DCM) gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.63 (6H, s), 1.85 (3H, s), 2.41 (3H, s), 5.57 (1H, s), 6.41 (1H, s), 6.56 (1H, s), 7.00 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.33 (1H, dd, J=8.3, 1.2 Hz), 8.13 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=5.2 Hz), 8.88 (1H, s); LC-MS: m/z=+419.10 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)#[CH:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C.CN(C=O)C>[Cu]I.CO>[NH:16]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]3[CH:9]=[CH:10][N:11]=[C:5]3[CH:4]=2)[N:18]=[N:17]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccn2ccnc2c1
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: c1cn2ccc(-c3c[nH]nn3)cc2n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
Combine 7-ethynyl-imidazo[1,2-a]pyridine (1.10 g, 7.74 mmol), copper (I) iodide (0.074 g, 0.387 mmol), and trimethylsilyl azide (1.53 mL, 11.61 mmol) in a 9:1 mixture of DMF:methanol (13.8 mL) in a pressure flask. Seal the flask with a Teflon screw cap and heat the reaction mixture to 100° C., stir overnight (15 hours), and cool to room temperature. Concentrate the mixture to dryness in vacuo. Slurry the resulting solid into dichloromethane and filter through Celite® 521. Concentrate the solution in vacuo to an orange solid. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→8% methanol in dichloromethane) to afford product (0.82 g, 57%). MS(ES), m/z 186 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O.C(=O)([O-])O.[Na+]>C(O)CC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:15]=[C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]4)=[CH:14][N:13]3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Temperature: 80 °C
Yield: 135.8 %

Procedure:
5.0 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 5.30 g of 2-bromo-1-(4-chlorophenyl)ethanone are placed in 150 ml of n-propanol in a round-bottomed flask. 2.67 g of sodium hydrogencarbonate are added. The mixture is heated at 80° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. 10.93 g of compound are obtained, which compound is used as is in the following stages.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([C:13](=O)[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[BH3-]C#[N:20].[Na+]>CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([CH:13]([NH2:20])[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1ncc(Oc2ccc(F)cc2)cn1
Yield: 94.3 %

Procedure:
1-(5-(4-fluorophenoxyl)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH3CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.26 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[CH:23][C:14]=1[N:9]1[CH2:10][CH2:11][C:6]2([NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5]2)[CH2:7][CH2:8]1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1CCCC2(CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of 1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (800 mg, 4.76 mmol) in 10 mL DMF, 2-chloroquinoxaline (937 mg, 5.71 mmol) and K2CO3 (3.3 g, 23.8 mmol) were added and the reaction mixture was stirred for 18 h at 80° C. under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (eluent: 3% methanol in chloroform) to yield the title compound (1.0 g, 71%). [LCMS RtF=0.37 min, [M+H]+=297.2]
Reaction SMILES: [CH2:1](N(CC)CC)C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([N:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32][OH:33])[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.CI>CN(C=O)C>[CH3:1][N:28]1[CH2:27][CH2:26][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:31][CH2:32][OH:33])[C:23]=2[CH2:29]1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
Triethylamine (0.038 ml, 0.27 mmol) was added to 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.058 g, 0.14 mmol, Example 1) in DMF (2 mL). Methyl iodide (9.28 μl, 0.15 mmol) was added and the reaction mixture was stirred for 1 h at 25° C. The solution was concentrated under reduced pressure and the product purified by preparative HPLC to give 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.022 g, 36.7%). MS (ESI+)/(ESI−) m/z 443/441
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>C(OCC)(=O)C>[CH2:16]([O:15][C:8]1([O:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[CH3:17]
Reactant: O=C1CCCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC1(OCC)CCCCC1
Reaction time: 1 h

Procedure:
In a 200-ml three-neck flask, 4.45 g (45.2 mmol) of cyclohexanone, 7.05 g (47.5 mmol) of triethyl orthoformate, 0.04 g of p-toluenesulfonic acid (monohydrate), 4.15 g (90 mmol) ethanol and 95 ml of ethyl acetate were heated to 100° C. and kept at this temperature for 1 hour (reflux). Thus, 1,1-diethoxycyclohexane was formed. Then 4.0 g (22.7 mmol) of D-isoascorbic acid was added and the first heterogeneous mixture was refluxed for 5 hours, and a clear solution was formed. Then 2 g of aluminum oxide was added, the suspension was stirred for 1 more hour at room temperature and filtered over Celite®, which was rewashed three times with ethyl acetate. The filtrate was concentrated by evaporation at 35° C./30 mbars to 20.5 g, and a viscous pulp was formed. The product was completely precipitated by addition of 20 ml of hexane, filtered off and dried. The yield was 5.05 g (86.8 percent). The product had a melting point: 177° to 178.5° C. The product had the following properties:
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C@@H:10]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=O)(C)(C)C.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][C:40]2[N:43]=[C:44](C([O-])=O)[S:45][C:39]=2[CH2:38]1.[Li+]>O1CCOCC1>[ClH:34].[C:17]([NH:16][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])[C@H:9]([NH:8][C:6]([C:44]2[S:45][C:39]3[CH2:38][N:37]([CH3:36])[CH2:42][CH2:41][C:40]=3[N:43]=2)=[O:5])[CH2:14]1)=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)NC(C)(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.