Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=C1NCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1NCCc2ccc(OCCCCBr)cc21
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of intermediate 19 (196 mg, 1.2 mmol), 1,4-dibromobutane (0.43 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.22 mmol) was dissolved in EtOH (4 mL) and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=3:1) to give 7-(4-bromobutoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 21) (230 mg, 63%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1C
Yield: 73.2 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-methyl-4-(methyloxy)phenyl]boronic acid (740 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), pyridine (0.36 mL, 4.46 mmol) and powdered molecular sieves (400 mg) in DCM (75 mL) were stirred at room temperature in the presence of air. After 41 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.17 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 0 to 30% in hexane to afford 562 mg of title compound (D34) containing an impurity.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH3:22])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc2c(=O)c(C(=O)c3ccccc3)cn(C)c2n1

Procedure:
25.3 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.1 mol.), 15.5 g. of methyl iodide (0.11 mol.) and 21 g. of potassium carbonate (0.15 mol.) are heated in 150 ml. of dimethylformamide with stirring at 80° for 10 hours. After this time, the inorganic precipitate is filtered off and the filtrate evaporated to dryness. The remaining 5-benzoyl-2,7-dihydro-2,7-dimethyl-4H-pyrazolo[3,4-b]pyridin-4-one is recrystallized from butanol, yield 18 g. (67%); m.p. 272°-274°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:9]2[CH2:27][NH:28][C@@H:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:48](=O)([O:54]C(C)(C)C)[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>ClCCl>[C:50]([O:49][C:48]([N:28]([CH2:27][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[O:15])[CH2:10]1)[C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 37 h
Yield: 47.8 %

Procedure:
To a solution of 888 mg of 4-(methoxycarbonyl)phenyl 4-(4-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidine-1-carboxylate in 9 mL of dichloromethane were added 0.7 mL of triethylamine and 868 mg of di-tert-butyl carbonate, followed by stirring at room temperature for 37 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 503 mg of 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as a pale yellow foamy substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 3-(diethylamino)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[CH:6]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH3:24])[S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH:6]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C)S(=O)(=O)c2ccccc2C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 2-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1.O>CS(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Trimethylsulfoxonium iodide (7.92 g, 36.0 mmol) in dimethyl sulfoxide (40 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 1.57 g, 36.0 mmol) under cooling with ice, stirred at room temperature for 1 hour and then stirred with (E)-ethyl 3-(4-fluorophenyl)acrylate (5.83 g, 30.0 mmol) for 18 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the title compound as a colorless oil (793 mg, yield 13%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[N:17]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2CC=C(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (43 mg) and potassium carbonate (13 mg) were suspended in N,N-dimethylformamide (1 ml), and ethyl bromoacetate (9.6 μl) was added to the suspension. After the reaction mixture was stirred at room temperature for 13 hours, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation from the organic layer to give 44 mg of the title compound. δ: 1.19 (s, 9H) 1.23–1.51 (m, 3H) 1.48 (s, 9H) 1.74 (s, 6H) 3.14–3.20 (m, 4H) 3.52–3.58 (m, 4H) 4.17–4.27 (m, 2H) 4.68–4.72 (m, 2H) 4.75 (s, 2H) 5.37–5.42 (m, 1H) 6.03 (s, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(O)ccc2c1=O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCCCN3CCOCC3)ccc2c1=O
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
7-Hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (750 mg, 2.7 mmol) was suspended in methylene chloride (40 ml) at 5° C. and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added. The mixture was stirred for 5 minutes and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes at 5° C. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The solution was then purified directly by column flash chromatography eluting with methylene chloride, and then ethyl acetate, acetonitrile/ethyl acetate (20/80), and acetonitrile/ethyl acetate/ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 7-(3-morpholinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin4-one (745 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][CH:24]=2)[C:5]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.Cl[Mg][CH2:28][CH3:29]>>[Cl:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][CH:24]=2)[C:5]([C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[C:6]([C:8](=[O:9])[CH2:28][CH3:29])[CH:7]=1
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)c1cc(Cl)c2cnc(C)n2c1-c1cc(F)cc(F)c1
Product: CCC(=O)c1cc(Cl)c2cnc(C)n2c1-c1cc(F)cc(F)c1
Yield: 39 %

Procedure:
The desired compound was prepared by the procedure of Example 1, step J using 8-chloro-5-(3,5-difluorophenyl)-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide and chloro(ethyl)magnesium as the starting materials in 39% yield. LCMS calculated for C17H14ClF2N2O (M+H)+: m/z=335.1. found: 334.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.Cl.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:30][CH:29]=2)=[N:6][CH:5]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (216 mg, 1.0 mmol) and 4-benzyloxyaniline hydrochloride (280 mg, 1.2 mmol) in MeOH (10 mL) was added iPr2NEt (0.35 mL, 2.0 mmol). The resulting mixture was stirred at rt overnight, a red solid precipitated from the mixture, which was collected by filtration. MS (ES, Pos.): m/z 380 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.94 (s, 3H), 5.10 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.38-7.46 (m, 5H), 7.50 (d, J=8.8 Hz, 2H), 9.01 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 10.2 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[N:8]=1.C=O.[BH4-].[Na+].[CH2:40](Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:40])[CH2:22][CH2:23]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:27][CH2:28]3)[CH2:25]2)[N:8]=1
Reactant: ClCCl
Reactant: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCNCC2)cc1Cl
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCN(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 65 %

Procedure:
In methanol (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-N-(2-(piperazin-1-yl)ethyl)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (250 mg, 0.5 mmol). Formalin (37%, 61 mg, 0.75 mmol) was added. The reaction was conducted at ambient temperature for 1 h. Sodium borohydride (28 mg, 0.75 mmol) was added. The reaction was continued for 8 h, followed by addition of DCM (50 mL). The reaction mixture was washed with water for three times (50 mL at a time). The organic phase was dried and concentrated to give 4-((3-chloro-4-methoxybenzyl)amino)-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (168 mg, 65% yield). The product was dissolved in methanol (5 mL). Hydrochloric acid (0.1 mL) was added. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed by evaporation to give the hydrochloride salt of the compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ncccn2c1-c1ccccn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ncccn2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamine (800 mg, 3.34 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (520 mg 3.34 mmol) in n-butanol (5 mL) was added DIEA (1.7 mL, 10.04 mmol) at rt. The reaction mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-30% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamino]-pyrimidine-5-carbonitrile: 1H NMR: (DMSO-d6, 400 MHz) δ 1.547 (d, J=6.4 Hz, 3H), 5.807-5.841 (br s, 1H), 7.150-7.176 (m, 1H), 7.289 (br s, 2H), 7.429-7.466 (m, 2H), 7.847-7.867 (m, 1H), 7.998 (s, 2H), 8.653 (s, 1H), 8.789 (s, 1H), 9.419 (d, J=6.4 Hz, 1H); LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:14]([C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:19])=[C:13]([Cl:28])[CH:12]=[CH:11][C:10]=3[N:9]=2)[CH2:3]1.[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:28][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:3]3)[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:19]
Reactant: N[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a) using 2-[(3S)-3-amino-1-piperidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 51) (200 mg), activated 3 Å molecular sieves (0.20 g), (tert-butyldimethylsilyloxy)acetaldehyde (0.085 mL), dichloromethane (5.0 mL) and sodium triacetoxyborohydride (210 mg). Purification (SiO2, ethyl acetate:isohexane 1:1) gave the sub-titled compound (190 mg).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][C:29]=2[OH:31])[N:24]=[CH:23][N:22]=1.O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][C:29]=2[O:31][CH2:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:24]=[CH:23][N:22]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC)cc(O)c23)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC)cc(OCCCN4CCOCC4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
Di-tert-butyl azodicarboxylate (0.208 g) was added dropwise to a stirred mixture of 4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (0.2 g), 4-(3-hydroxypropyl)morpholine (Bull. Soc. Chim. Fr., 1962, 1117; 0.131 g), triphenylphosphine (0.237 g) and methylene chloride (3 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.12 g); NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 3.1 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.68 (t, 2H), 3.8 (s, 3H), 4.0 (d, 2H), 4.02 (s, 3H), 4.6 (t, 2H), 6.93 (s, 1H), 7.05–7.15 (m, 2H), 7.5 (s, 1H), 7.57 (d, 1H), 8.87 (s, 1H); Mass Spectrum: M+H+ 459 and 461; Elemental Analysis: Found C, 60.0; H, 6.0; N, 12.1; C23H27ClN4O4 requires C, 60.19; H, 5.93; N, 12.2%.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[B:31]2[O:35]C(C)(C)C(C)(C)[O:32]2)[CH2:18]1>C1COCC1>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[B:31]([OH:32])[OH:35])[CH2:18]1
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4ccccc4B4OC(C)(C)C(C)(C)O4)C3)c(C)o2)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4ccccc4B(O)O)C3)c(C)o2)c1
Temperature: 25 °C

Procedure:
1 ml of 1 N HCl is added to 300 mg of (1S,3R)-5-methyl-4-{3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyloxy]cyclohexyloxymethyl}-2-m-tolyloxazole in 5 ml of THF, and the mixture is stirred at RT until the reaction has gone to completion. The solvent is removed under reduced pressure and the compound is purified by RP-HPLC. This gives (1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzeneboronic acid as a colorless oil. C25H30BNO5 (435.33), MS (ESI): 436 (M+H+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10].C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.O>[O:3]=[C:4]1[C:8](=[CH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1CCCC1=O
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCC(=CCCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.9 %

Procedure:
To a suspension of 60% NaH (1.2 g, 30 mmol) in anhydrous THF (30 mL) in an ice bath is added a solution of methyl 2-oxocyclopentanecarboxylate (4.26 g, 30 mmol) in 10 mL of THF dropwise over 5 minutes. The mixture is stirred at room temperature for 20 minutes. The mixture is cooled to -25° C. and 2.5 M n-butyllithium is added over 5 minutes (12 mL, 30 mmol). After stirring for 5 minutes, 1-bromo-3-phenylpropane (4.6 mL, 30 mmol) is added. The mixture is stirred at room temperature for 3 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (6:1 hexane:ethyl acetate) to afford methyl 2-oxo-3-(3-phenylpropyl-1-yl)cyclopentanecarboxylate (1 g, 13%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.22-1.50 (m, 2H), 1.62-1.90 (m, 4H), 2.12-2.38 (m, 4H), 2.58-2.69 (m, 2H), 3.75 (s, 3H), 7.10-7.32 (m, 5H); MS (EI) m/e 260 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[C@H:44]12[CH2:50][C@H:47]([NH:48][CH2:49]1)[CH2:46][O:45]2>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:48]3[CH2:49][C@@H:44]5[CH2:50][C@H:47]3[CH2:46][O:45]5)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3C[C@@H]4C[C@H]3CO4)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-methoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene, diisopropylethylamine and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. LCMS (Method F): 552 (M+H)+, Retention time 4.7 minutes.