Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[CH:28]=4)=[CH:20][N:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1>CN(C=O)C.C(Cl)Cl>[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:18]3[N:19]=[CH:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([C:1](=[O:3])[CH3:2])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:22][N:23]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1
Reactant: CC(=O)Cl
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Acetyl chloride (222 μl; 3.1 mmol; 2.0 eq.) was added to a solution of 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidine hydrochloride (example 1, 655 mg; 1.55 mmol; 1.0 eq.) and TEA (503 μl; 3.88 mmol; 2.5 eq.) in dry DMF (12 mL) and the reaction mixture was stirred at RT and under nitrogen for 2 h. The reaction mixture was diluted with DCM and washed with water. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient 100:0 to 80:20) afforded the title compound as a white solid (370 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58-8.50 (m, 2H), 8.26 (s, 1H), 8.21 (dt, J=8.0, 1.5 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.71 (dt, J=8.0, 1.5 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 4.58-4.43 (m, 2H), 4.01-3.83 (m, 4H), 3.29-3.17 (m, 1H), 2.74 (dd, J=14.1, 9.2 Hz, 1H), 2.19-2.02 (m, 5H), 1.98-1.69 (m, 2H). HPLC (Condition A): Rt 2.90 min (purity 98.0%). MS (ESI+): 428.36.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].Cl>C(Cl)Cl.O1CCOCC1>[Cl:17][C:16]1[C:11]([CH2:10][CH2:9][C:8]2[CH:36]=[CH:37][CH:38]=[CH:39][C:7]=2[C:4]2([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[CH:23]=2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNC4)c3)ncc2Cl)CC1
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 3-(4-(4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate A21 (0.164 g, 0.297 mmol) in DCM (5 mL) was added 4 M HCl solution in 1,4-dioxane (0.223 mL). The mixture was stirred for 5 hours before additional 4 M HCl in dioxane (3 eq.) was added and the mixture stirred for another 16 hours. Another portion of 4 M HCl in 1,4-dioxane (2 mL) was added and the mixture was stirred for 16 hours. The solvent was removed and the residue was diluted with 1 M HCl aq. (˜5 mL) and washed with EtOAc (2×10 mL). The aqueous layer was basified with 1 M NaOH and extracted with EtOAc (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give a crude white paste that was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the title compound as a red oil. Further purification by HPLC (Gradient: 20-100%, Acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) gave the title compound 20 as a clear gum (0.012 g, 9% yield). 1H NMR (300 MHz, MeOD) δ 1.14 (d, J=3.30 Hz, 2H), 1.64 (d, J=3.30 Hz, 2H), 2.32-2.44 (m, 1H), 2.46-2.65 (m, 1H), 3.12-3.26 (m, 4H), 3.43-3.54 (m, 1H), 3.60-3.80 (m, 3H), 5.21-5.32 (m, 1H), 7.23-7.45 (m, 4H), 7.64 (s, 1H), 8.08 (m, 1H), 8.29 (m, 1H). LCMS-C: rt 4.29 min; m/z 452 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13])=[N+:2]=[N-:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)CCC>[CH3:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]1[CH:21]=[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[N:2]1
Reactant: COCCOCCOCCN=[N+]=[N-]
Reactant: C#Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: COCCOCCOCCn1cc(-c2ccccc2)nn1

Procedure:
1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane (15.0 g, 79 mmol) was mixed with phenylacetylene (8.10 g, 79 mmol) in a 1:3 solution of water:butanol. The mixture was rotovap and the product extracted in ethanolamine and washed multiple times with water and brine, producing 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-phenyl-1H-1,2,3-triazole.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diisopropylethylamine (7.8 ml, 45 mmol) was added in one portion to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (7.6 g, 41 mmol) in DCM (100 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (10.0 g, 45 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (14.9 g, 89% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 7.97 (2H, d), 3.34 (4H, obscured), 2.96-2.92 (4H, m), 1.33 (9H, s). Tr=1.91 min m/z (ES+) ([(M−100)+H]+) 272.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1N1CCCCC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.05 g, 21.3 mmol) in DMSO (20 mL) was added piperidine (4.2 mL, 42.6 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil 5-bromo-3-nitro-2-(piperidin-1-yl)pyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (1H, d, J=2.3 Hz), 8.22 (1H, d, J=2.2 Hz), 3.39 (4H, d, J=5.7 Hz), 1.75 (6H, m).
Reaction SMILES: [CH2:1]([C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:18]N1C(=O)CCC1=O>C(C#N)(C)=O>[I:18][C:17]1[C:10]2[C:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:14][CH:13]=[N:12][C:11]=2[NH:15][CH:16]=1
Reactant: c1ccc(CCc2ncnc3[nH]ccc23)cc1
Reactant: O=C1CCC(=O)N1I
Agent: CC(=O)C#N
Product: Ic1c[nH]c2ncnc(CCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 4-phenethyl-7H-pyrrolo[2,3-d]pyrimidine (3.15 g, 14.1 mmol) in AcCN was added N-iodosuccinimide and the mixture was stirred at r.t. for 12 hr. The precipitate was collected and recrystallized from MeOH to give the title compound (4.06 g, 83%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:52]([CH3:54])[CH3:53])[C:10]([O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[S:36][C:35]4[C:30](=[N:31][CH:32]=[CH:33][C:34]=4[O:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][CH:48]5[CH2:50][CH2:49]5)=[O:46])=[CH:40][C:39]=4[F:51])[CH:29]=3)=[CH:26][CH:27]=2)[CH2:17][CH2:16]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:52]([CH3:54])[CH3:53])[C:10]([O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[S:36][C:35]4[C:30](=[N:31][CH:32]=[CH:33][C:34]=4[O:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][CH:48]5[CH2:49][CH2:50]5)=[O:46])=[CH:40][C:39]=4[F:51])[CH:29]=3)=[CH:26][CH:27]=2)[CH2:17][CH2:16]1)=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)OCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Yield: 33.3 %

Procedure:
A solution of 78 (115 mg. 0.15 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at RT for 3 h. The TFA was removed by co-evaporation with DCM, diluted with a minimum of water, and the pH was adjusted to around 9 with a saturated aqueous solution of sodium bicarbonate (and few drops of 1N NaOH at the end). The aqueous solution was extracted with DCM containing traces of methanol. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 10 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 20/80 over 20 CV), to afford the title compound 79 (36 mg, 0.05 mmol, 36% yield) as a white sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.4, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=10.4 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 6.58 (bd, J=2.2 Hz, 1H), 4.26-4.18 (m, 1H), 4.11-4.03 (m, 1H), 3.54 (s, 2H), 3.10 (d, J=5.3 Hz, 1H), 2.59-2.30 (m, 11H), 1.88-1.78 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H), NH2 is missing. MS (m/z): 662.7 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][C:31](OC)=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.[BH4-].[Li+].Cl>C1COCC1.CO.ClCCl>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31][OH:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a cold (0° C.) solution of racemic methyl 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate (4.00 g, 7.36 mmol) in THF (160 mL) and MeOH (10 mL) was added lithium borohydride (29.44 mL of 2 M solution, 58.87 mmol) dropwise over 30 minutes. The reaction mixture was slowly warmed to room temperature and then re-cooled to 0° C. A 1N HCl solution (294 mL, 294 mmol) was added dropwise. The mixture was stirred for 15 minutes and then diluted with dichloromethane. The phases were separated and the aqueous phase was extracted again with dichloromethane. The combined organic phases were washed with aqueous saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford 3.79 g of the desired product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][C:8]=1[Cl:19].CN(C)[CH:22]=[O:23].C(OCC)(=O)C>O1CCCC1>[Cl:19][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH:22]=[O:23])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(Cl)c(Br)c2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C=O)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of n-butyllithium (1.6 M in tetrahydrofuran, 0.46 mL, 0.73 mmol, 1.0 eq) is added at −78° C. to a stirred solution of 4-bromo-3-chloro-6-methoxy-quinoline (200 mg, 0.73 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 2 hours stirring at −78° C., N,N-dimethylformamide (0.3 mL) is added and the reaction mixture is stirred at 60° C. for two hours. Then solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-chloro-6-methoxy-quinoline-4-carbaldehyde as a light yellow solid (78 mg, 48% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([O:46][CH3:47])=[C:28]([CH:34]([NH:36][C:37]3[N:45]=[CH:44][N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)[CH3:35])[CH:29]=[C:30]([Cl:33])[C:31]=2[CH3:32])[CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:1]([N:22]1[CH2:25][CH:24]([C:26]2[C:27]([O:46][CH3:47])=[C:28]([CH:34]([NH:36][C:37]3[N:45]=[CH:44][N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)[CH3:35])[CH:29]=[C:30]([Cl:33])[C:31]=2[CH3:32])[CH2:23]1)(=[O:3])[CH3:2].[C:17]([OH:19])([C:16]([F:21])([F:20])[F:15])=[O:18]
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (2.0 μL, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H24ClN6O2 (M+H)+: m/z=415.2. found: 415.1
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH:36]=[C:35]2[C:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH:46]=1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:44]4[CH2:43][CH:42]=[C:41]([C:35]5[C:34]6[C:38](=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=6)[NH:37][CH:36]=5)[CH2:46][CH2:45]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1 H-indole (0.606 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.161 g (49%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf =0.38 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: O[N:2]1[C:6]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@@H:48]([CH3:52])[C:49](O)=[O:50])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:28][CH:27]=1>O1CCCC1.C(N(CC)CC)C>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@H:48]([C:49](=[O:50])[NH:2][CH3:6])[CH3:52])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:61][CH:60]=1
Reactant: C[C@H](NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](C)NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 20 °C
Yield: 111.9 %

Procedure:
60 mg of 1-hydroxybenzotriazole, 200 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.700 cm3 of a 2M solution of methylamine in tetrahydrofuran, 0.370 cm3 of triethylamine and 8 cm3 of tetrahydrofuran are added successively to a solution of 0.5 g of (S)-2-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoyl-amino]propionic acid in 15 cm3 of tetrahydrofuran, stirred at a temperature in the region of 20° C. under an inert atmosphere. The reaction medium is stirred at a temperature in the region of 20° C. for 18 hours. After concentration to dryness under reduced pressure, the residue is dissolved in a mixture consisting of 30/15 cm3 of dichloromethane/water. After separation by settling out, the aqueous phase is extracted twice with 15 cm3 of dichloromethane. The organic phases are combined, washed with 15 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and then concentrated to dryness, to give 0.415 g of a crude product which is purified by flash chromatography on a Merck 25 g silica cartridge (particle size: 15-40 μm; eluent: 100 ethyl acetate). After concentration of the fractions under reduced pressure, 0.293 g of a product is obtained which is triturated in a minimum amount of pentane. After filtration, concentration to dryness under reduced pressure and drying, 0.247 g of a solid cream is obtained. 147 mg of this solid cream are injected onto a column 6 cm in diameter containing 700 g of Chiralpak IA 20 μM chiral stationary phase. The elution is carried out at 80 cm3 per minute with a mobile phase composed of 95% acetonitrile and 5% dichloromethane. The dextrorotatory enantiomer is eluted in the second position. After concentration of the mobile phase, 105 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N—((S)-1-methyl-carbamoylethyl)benzamide are obtained in the form of an amorphous white powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]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.CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32 mmol), 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol), (prepared as described for the starting material in Example 60), triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (1 ml) and DMF (0.5 ml) cooled at 4° C. was added a solution of diethyl azodicarboxylate (101 μl, 0.64 mmol) in methylene chloride (0.4 ml). The mixture was stirred for 12 hours at 4° C. and overnight at ambient temperature. The mixture was poured onto a column of silica (IST Isolute®10 g of silica) and was eluted with methylene chloride (15 ml) followed by 5% methanol in methylene chloride (45 ml) followed by 5% methanol (saturated with ammonia) in methylene chloride (30 ml) followed by 10% methanol (saturated with ammonia) in methylene chloride (45 ml) followed by 15% methanol (saturated with ammonia) in methylene chloride (30 ml). The fractions containing the expected product were evaporated to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline (63 mg, 44%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]=[C:26]([C:28]3[C:29]([N:46](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:36][CH:35]=4)[N:33]=3)[O:25][N:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH:43]([S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:28]([C:26]3[O:25][N:24]=[C:23]([C:20]4[CH:19]=[CH:18][C:17]([NH:16][CH2:1][CH:3]5[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]5)=[CH:22][CH:21]=4)[CH:27]=3)[C:29]([NH2:46])=[N:30][CH:31]=2)=[CH:39][CH:38]=1)(=[O:41])=[O:42])([CH3:45])[CH3:44]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(N)cc4)no3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(NCC5CCCCN5)cc4)no3)n2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 2-formylpiperidine-l-carboxylate (18.45 mg, 0.08652 mmol) and tert-butyl N-[3-[3-(4-aminophenyl)isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (50 mg, 0.07865 mmol) in CH2Cl2 (5.0 mL) at 0° C. was added acetic acid (5.196 mg, 4.920 μL, 0.08652 mmol) and sodium triacetoxyborohydride (28.34 mg, 0.1337 mmol) and the resulting solution stirred at 0-10° C. for 2 h. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (5 mL) and dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and the combined organic extracts were then dried over MgSO 4 and concentrated in vacuo. The residue was taken up in CH2Cl2 (3.0 mL) and TFA (44.83 mg, 30.29 μL, 0.3932 mmol) was added and the resulting solution stirred at rt overnight. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 100 Å column, 5 M, 19 mm×150 mm, (solvent A: 0.05% TFA in water; solvent B: 0.05% TFA in CH3CN) over 16 minutes at 20 mL/min] The product fractions were collected and lyopholised to leave the title compound as a yellow solid (30.5 mg, 58% yield); 1H NMR (400 MHz, DMSO) δ 1.19 (d, 6H), 1.40-1.59 (m, 3H), 1.79 (m, 2H), 1.96 (m, 1H), 2.88 (m, 1H), 3.24 masked signal, 3.47 (m, 1H), 6.37 (t, 1H), 6.79 (m, 2H), 7.16 (br s, 2H), 7.64 (s, 1H), 7.78 (m, 2H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.38 (m, 2H), 8.52 (br s, 1H) and 8.94 (s, 1H) ppm; MS (ES+) 533.3 (M+H), (ES−) 531.2 (M−H)