Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH2:43][CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:43]([C:30]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:44]
Reactant: CCOC(=O)CC(CC)(CCCBr)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)CC(CC)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1

Procedure:
Prepared from 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-ylamide and ethyl 5-bromo-2-ethyl-2-phenyl-pentanecarboxylate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:22]([NH2:24])=[O:23])=[C:13]([NH:15][C:16]2[CH:17]=NC=[CH:20][CH:21]=2)[N:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.IC1C=C[N:117]=[C:116]2[N:120]([CH3:123])[N:121]=[CH:122]C=12>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:22]([NH2:24])=[O:23])=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:117]=[C:116]3[N:120]([CH3:123])[N:121]=[CH:122][C:17]=23)[N:14]=1
Reactant: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccnc1
Reactant: Cn1ncc2c(I)ccnc21
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1ncc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)ccnc21

Procedure:
The title compound was prepared in the same procedure as described in Example 3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide. However, here Pd(OAc)2 and BINAP were substituted for Pd2(dba)3 and Xantphos. Additionally, dioxane was used as the solvent. The coupling partner, 4-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine, was synthesized as seen below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccncc2)nc(N2CCOCC2)n1
Temperature: 120 °C
Yield: 19.9 %

Procedure:
A mixture of 0.048 g (0.51 mmol) of 4-aminopyridine and 0.095 g (0.26 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (1.5 mL) was heated at 120° C. for 1 hr. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration and washed with water to give 0.022 g (20% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyridinyl)-1,3,5-triazin-2-amine: mp (MeOH) 222-224° C.; 1H NMR (DMSO-d6) δ 10.30 (br s, 1H), 8.59-8.46 (m, 3H), 7.91-7.86 (m, 4H), 7.55-7.44 (m, 2H), 3.88 (br s, 4H), 3.77-3.76 (m, 4H); HRMS (FAB+) MNa+ Calcd. for C20H18F2N8NaO: m/z 447.1466. Found: m/z 447.1464; HRMS (FAB+) MH+ Calcd. for C20H19F2N8NO: m/z 425.1644. Found: m/z 425.1629.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Add methanesulfonyl chloride (1.8 mL, 23.5 mmol) to a solution of (5-fluoro-pyridin-2-yl)-methanol (2.5 g, 19.7 mmol) and triethylamine (8.2 mL, 59.0 mmol) in DCM (150 mL) at 0° C. under nitrogen. Stir the mixture for 30 min and concentrate in vacuo. Dilute with water (20 mL) and extract the mixture with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to obtain the desired intermediate (2.2 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][O:13][CH:12]1[C:20]([F:23])([F:22])[F:21].[SiH](CC)(CC)CC>C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:12][C:20]([F:23])([F:22])[F:21])[C@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:14][OH:13]
Reactant: CC(C)C[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Yield: 43.4 %

Procedure:
To a solution of (4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine (4.8 g, 14.3 mmol) and Et3SiH (21.6 g, 186 mmol) in 60 mL chloroform was added BF3OEt2 (14.2, 60 mmol, added in portions) The reaction was heated at reflux for 1 d After cooling, the reaction was poured in water (200 mL) and extracted with chloroform (3 ×150 mL). The organic layers were combined, washed sequentially with water (200 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to a brown oil. Flash chromatography (gradient elution, hexanes:ethyl acetate 95:5 to 3:1) afforded 2.1 g (44%) of (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol, an orange oil. Data for (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol: Rf0.8 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J=9.3, 2.4), 7.94 (dd, 1H, J=12.9, 2.5), 7.40 (dd, 1H, J=8.7, 8.7), 4.21–4.10 (m, 1H), 3.89–3.78 (m, 1H), 3.79–3.65 (m, 3H), 1.96–1.89 (m, 1H), 1.67–1.54 (m, 1H), 1.55–1.44 (m, 1H), 1.32–1.22 (m, 1H), 0.91 (d, 3H, J=6.6), 0.77 (d, 3H, J=6.6).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH:9]([OH:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 3-allyloxycarbonylamino-4-hydroxy-5-phenyl-pentanoic acid tert-butyl ester, 107, (0.8 g, 2.23 mmol) in CH2Cl2 (10 mL) is added to a solution of Dess-Martin reagent (1.05 g, 2.47 mmol) in CH2Cl2 (10 mL). After 1 hour the reaction solution is diluted with ether (50 mL) and the solution poured into a 1.3 M solution of NaOH (20 mL). Stir for 1 hour and decant the organic layer. Dry the organic layer over Na2SO4, concentrate in vacuo to afford a crude residue that is purified over silica to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]2=O.C[Si]([C:24]#[N:25])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)#[N:25]
Reactant: COc1cccc2c1CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(c1ccccc1)C=C2C#N
Temperature: 60 °C

Procedure:
To a suspension of 8.8 g (35 mmol) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, the product of Example 1, is added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture is heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture is reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct is dehydrated by treatment with 15 mL of trifluroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture is cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C([O:42][CH2:43][C:44](Cl)=[O:45])(=O)C.[OH-].[Na+]>C(Cl)Cl.CO>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:43](=[O:42])[CH2:44][OH:45])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3C(=O)CO)cc2c1=O
Reaction time: 1 h

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (0.20 g), triethylamine (0.133 ml), and acetoxyacetyl chloride (0.077 ml) were stirred in methylene chloride (2 ml) under argon at room temperature for 30 minutes. A solution of 2N NaOH (2 ml) and methanol (2 ml) was added to the reaction mixture and stirring continued for 1 hour at room temperature. The reaction mixture was diluted with methylene chloride and washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 5% methanol/ethyl acetate to give the title compound (0.113 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.83-2.10 (m, 4H), 2.14 (s, 3H), 2.86 (m, 1H), 3.40 (m, 2H), 4.05 (m, 3H), 4.25 (m, 1H), 4.32 (m, 1H), 4.52 (t, 1H), 7.53 (m, 2H), 7.60 (s, 1H), 7.74 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1M, 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:21][CH2:20]3)[CH2:13]2)[CH2:9]1.[CH3:36][C:37](OC(C)=O)=[O:38]>C(Cl)Cl>[C:37]([N:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:23][CH2:24]3)[CH2:13]2)[CH2:11]1)(=[O:38])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CN(C3CNC3)CCO2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(N2CCO[C@@H](CN3CCN(C(=O)Nc4ccc(Cl)c(Cl)c4)CC3)C2)C1
Reaction time: 3 h

Procedure:
Triethylamine (61 uL) was added to a stirring solution of 4-{[(25)-4-azetidin-3-ylmorpholin-2-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (125 mg) in DCM (5 ml) followed by Ac2O (30 uL) and the reaction was stirred for 3 h. The reaction was then quenched by addition of 1M NaOH (aq.) (10 ml) and DCM (15 ml). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography 5-10% MeOH:DCM afforded the title compound (31 mg) as a white foam.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Reactant: Nc1ccccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.080 mL, 0.6 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (193 mg, 0.50 mmol) in DCM (10 mL) and stirred at RT for 30 minutes. 2-Aminopyridine (57 mg, 0.6 mmol) and pyridine (0.082 mL, 1 mmol) were added and the reaction stirred for a further 16 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (50 mL). The organic phase was washed with water (2×20 mL), 1N citric acid (10 mL), water (10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (100 mL), then dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-80% ethyl acetate in isohexane, to give the desired compound as a white foam (42 mg). 1H NMR δ (CDCl3): 1.28 (d, 3H), 2.31 (quin, 2H), 3.34 (s, 3H), 3.43-3.56 (m, 2H), 4.19 (t, 2H), 4.57 (q, 1H), 4.62 (t, 2H), 6.90 (s, 1H), 7.03 (t, 1H), 7.20 (s, 1H), 7.36 (s, 1H), 7.71 (t, 1H), 8.23 (d, 1H), 8.28 (s, 1H), 8.30 (d, 1H), 8.64 (s, 1H), 8.79 (s, 1H); m/z 464 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-ethanol (0.582 g, 3.09 mmol, from step (iii) above) in methylene chloride (8 mL) was cooled to 0° C. Triethylamine (0.52 mL, 3.7 mmol) was added followed by a solution of methanesulfonyl chloride (0.26 mL, 3.4 mmol) in methylene chloride (2 mL) and the reaction mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with methylene chloride (40 mL) and the organic phase was washed with water (2×30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give 0.78 g (95%) of the title compound as a colourless oil.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:6]=1)C.[OH-].[Li+].O1CCCC1.Cl>O>[CH2:15]([S:12]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:18])=[O:3])(=[O:13])=[O:14])[CH2:16][CH3:17]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(propane-1-sulfonylamino)-benzoic acid ethyl ester (75, 1.60 g, 5.90 mmol) in water was added lithium hydroxide (1.0 g, 4.2 mmol) and tetrahydrofuran (20 mL). The reaction was stirred at room temperature overnight. The reaction mixture was acidified with 1 N HCl, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate to give the compound (76, 1.2 g, 84.5%) as white solid. MS (ESI) [M−H+]+=242.1.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[CH:17]=[CH:16][N:15]=1>>[NH:4]1[CH2:5][CH2:6][CH:2]([NH:24][C:19]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc2cnccc12
Product: c1cc(NC2CCNC2)c2ccncc2c1

Procedure:
Reaction of tert-butyl 3-oxopyrrolidine-1-carboxylate and isoquinolin-5-amine using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:14]#[N:15].[C-]#N.[Na+].C(OCC)(=O)C>O>[C:14]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:15]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1C#N
Temperature: 195 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[PH2]([O-])=O.[Na+]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 75.3 %

Procedure:
To a mixture of 2-chloro-5,11-dihydro-11-ethyl-8-[trans-2-(4-pyridyl)ethen-1-yl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (2.3 g, 5.9 mmol) and palladium black (0.25 g) in 30 mL of 1,4-dioxane was added a solution of sodium hypophosphite (0.82 g 7.7 mmol) in 15 mL of water. The reaction mixture was heated at 80°-90° C. for 3 hours. The reaction mixture was then filtered through Celite and extracted with ethyl acetate. The product was purified by chromatography over silica gel, eluting with methanol/dichloromethane, and recrystallized from ethyl acetate/hexanes to give 1.75 g of the title compound as colorless crystals, m.p. 158°-159° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C[O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=O.[OH-].[Na+]>O1CCCC1.O.CO>[OH:19][CH2:20][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: OCc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 74.2 %

Procedure:
A solution of diisobutylaluminium hydride in toluene (1.5M, 9.4 ml, 14.1mmol) was added to a solution of 3-(4-[4-methoxycarbonylphenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1.64 g, 4.68 mmol) in tetrahydrofuran (100 ml) and the resultant mixture stirred at room temperature for forty minutes. Methanol (3.3 ml) was added, followed by water (2.0ml) and 2M aqueous sodium hydroxide (2.0 ml). The precipitate formed was collected, the filtrate concentrated in vacuo and the solid residue was recrystallised from methanol to afford the title compound (1.12 g, 74%), m.p. 207°-209° C. (dec.); (Found: C, 69.48; H, 7.00; N, 16.61. C19H22N4O.0.3 MeOH requires C, 69.82; H, 7.04; N, 16.87%); δH (DMSO-d6) 2.52 (4H, m, 2×piperazinyl CH2), 3.08 (4H, m, 2×piperazinyl CH2), 3.68 (2H, CH2N), 4.36 (2H, d, J 5.6 Hz, CH2OH), 4.92 (1H, t, J 5.6 Hz, CH2OH), 6.85 (2H, d, J 8.7 Hz, ArH), 7.05 (1H, dd, J 7.9, 4.7 Hz, 5-H), 7.13 (2H, d, J 8.7 Hz, ArH), 7.37 (1H, d, J 2.2 Hz, 2-H), 8.05 (1H, br d, J 7.9 Hz, 4-H), 8.19 (1H, dd, J 4.7, 1.5 Hz, 6-H), and 11.47 (1H, br s, NH); m/z (CI+, NH3) 323 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C:12]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(CN)CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NC1(CNc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamate was synthesized by treating 5-bromo-2,4-dichloropyrimidine with tert-butyl N-[1-(aminomethyl)cyclopentyl]carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) 405 (M+H).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:19][C:15]2([CH2:18][O:17][CH2:16]2)[N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]1[CH2:19][C:15]2([CH2:16][O:17][CH2:18]2)[N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCc2ccccc2)CC12COC2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)CC12COC2
Yield: 96.3 %

Procedure:
A solution of tert-butyl 7-{[(benzyloxy)carbonyl]amino}-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (566 mg, 1.56 mmol) in 20 mL of MeOH was stirred with 10% Pd/C (100 mg) under hydrogen atmosphere at room temperature for 50 minutes. The resulting mixture was filtered and the filtration was concentrated in vacuo to afford tert-butyl 7-amino-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (343 mg, yield: 96.3%) as light viscous oil.