Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.C(O)(C(F)(F)F)=O.[NH:44]1[CH2:47][CH2:46][CH2:45]1.CN(C)C=O>C(OCC)(=O)C>[N:44]1([C:2]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([Cl:18])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)([C:21]4[CH:22]=[N:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=4)[OH:20])[CH:8]=3)[N:3]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a 5 mL sealed tube was added (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol (200 mg, 0.38 mmol, 1 equivalent, Example 109), azetidine (108 mg, 1.89 mmol, 5 equivalents) and dimethylformamide (2 mL). The reaction vessel was sealed and heated in a 100° C. oil bath. After two days, the vessel was cooled and contents transferred to a reparatory funnel with ethyl acetate dilution. The organic phase was extracted with saturated, aqueous ammonium chloride solution and deionized water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide racemic (2-azetidin-1-yl-4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl)pyridin-3-yl]methanol. MS (ESI): mass calcd. for C29H23ClF3N5O, 549.15. m/z found, 550.3 [M+H]+. 1H NMR (600 MHz, MeOD) δ 8.76 (d, J=2.0 Hz, 1H), 8.04-7.97 (m, 2H), 7.83 (d, J=8.2 Hz, 1H), 7.78-7.70 (m, 2H), 7.58 (dd, J=8.9, 2.2 Hz, 1H), 7.51-7.41 (m, 3H), 7.33 (d, J=7.8 Hz, 2H), 6.33 (s, 1H), 3.72-3.61 (m, 4H), 3.48 (s, 3H), 2.10-2.02 (m, 2H).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][N:31]1[C:36](=[O:37])[CH2:35][O:34][C:33]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:32]1=2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][C:36](=[O:37])[N:31]([CH3:30])[C:32]=3[CH:41]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)COc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Reaction time: 25 h
Yield: 52.7 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 276 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Example 10, step (ii), 154 mg) followed by sodium carbonate (0.533 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h and then allowed to cool. The solution was absorbed onto silica and purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound (155 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(N(CCN)CC(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N(CCNC(=O)c2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A solution of crude 4-[(2-aminoethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.018 mg, 0.058 mmol) in CH2Cl2 (3 mL) was treated with TEA (0.0064 g, 0.063 mmol) and benzoyl chloride (0.0089 mg, 0.063 mmol) and stirred at rt for 1 h. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexanes gradient) and the product crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.016 g, 66% yield): MS (ES) mlz 416 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: Cl
Product: COC(=O)c1ccc(O)c(C)c1
Yield: 84 %

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (5.13 g, 33.7 mmol) and aqueous 12 N HCl solution (1.0 mL) in MeOH (100 mL) was heated to reflux for 16 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was taken in EtOAc. The resulting solution was washed with aqueous saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated with Hexane:EtOAc (9:1) to give the title compound (4.70 g, 84% yield) as a beige solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(OCc3ccccc3)c(F)c2C(C)(C)C1=O
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (0.29 g, 0.76 mmol, prepared in Example 23A-D) and K2CO3 (0.21 g, 1.5 mmol) in 5 mL ACN stirred at room temperature, was treated with 1-(bromomethyl)benzene (0.26 g, 1.5 mmol), and the resulting mixture was stirred for 12 hours, M+Na=492. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.27 g of the title compound as a white solid. MS (m/z)=492 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([NH:21][CH2:22][CH2:23][CH3:24])[CH3:20]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][CH3:24])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CCCNCC
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CCC)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 87 mg of N-ethylpropylamine, followed by stirring at 60° C. for 7 hours. Then, 166 mg of potassium carbonate and 87 mg of N-ethylpropylamine were added, and the mixture was stirred at a bath temperature of 60° C. for 6 hours. The reaction mixture was then left for cooling to room temperature and subjected to phase separation three times between ethyl acetate and an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel thin layer chromatography to give 136 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-propylamino)pyrimidine (the present compound (104)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[C:9](O)=[O:10].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[C:9]([Cl:16])=[O:10]
Reactant: COc1c(C(=O)O)ccn(C)c1=O
Reactant: O=S(Cl)Cl
Product: COc1c(C(=O)Cl)ccn(C)c1=O

Procedure:
3-Methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (Intermediate 6) (0.44 g, 2.4 mmol) was stirred in thionyl chloride (2.00 mL, 27.4 mmol) at reflux for 2 h. The cooled mixture was concentrated and dried under vacuum. Intermediate 12A was used directly for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1.[OH-].[Li+].Cl>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: COC(=O)c1ccc(OC)c(NC(=O)Nc2cnccn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1NC(=O)Nc1cnccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a stirred solution of 4-methoxy-3-(3-pyrazin-2-yl-ureido)-benzoic acid methyl ester (1.0 g; 3.3 mmol) in methanol (25 mL) was added lithium hydroxide (5 mL of a 2M aqueous solution). The reaction was heated to 60° C. and stirred for 12 hours. The reaction was allowed to cool to room temperature and the pH was adjusted to 5.5 with hydrochloric acid (IN). A precipitate formed which was filtered and dried under reduced pressure to yield an off white solid (58% yield).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]OC(OC)N(C)C.Cl.CO>C(#N)C=C.CO>[ClH:1].[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: C=CC#N
Solvent: CO
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1

Procedure:
To a suspension of 10.0 g. (39.0 m. mol) of 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in acrylonitrile (CH3CN) (50 ml.) is added 9.3 g. (78.0 m mol) of dimethylformamide dimethylacetal (DMF-DMA) and the resulting solution, in a bomb, is heated to 100°-105° C. for one hour. After cooling the reaction mixture is placed in a round bottom flask and concentrated under reduced pressure. The residue is partitioned between H2O and CHCl3 and the layers separated. The aqueous layer is extracted with CHCl3 (1×50 ml). The combined CHCl3 extracts are washed with H2O (1×50 ml) dried (MgSO4) and concentrated under reduced pressure. A small amount of the residue is triturated in hexane to give a white solid, having melting point 224. NMR and IR show the product to be identical with that of Example 3. The remainder of the residue is dissolved in MeOH and acidified with HCl/MeOH. The MeOH is removed under vacuum and the residue crystallized from CH3CN to give 6.8 g. (65%) of 1-(2',60'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one hydrochloride, melting point 234°-8° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:15][O:16][CH3:17])[C:7](=[O:14])[C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.[CH3:29][N:30]([CH2:32][CH2:33]Cl)[CH3:31]>CN(C)C=O>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][O:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:15][O:16][CH3:17])[C:7](=[O:14])[C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(O)ccc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCn1c(=O)c2cccnc2c2cc(OCCN(C)C)ccc21
Reaction time: 0.5 h
Yield: 53 %

Procedure:
The compound (60 mg, 0.234 mmol) prepared in step 5 was dissolved in N,N-dimethylformamide (5 ml), added with potassium carbonate (161 mg, 1.17 mmol) and potassium iodide (8 mg, 0.047 mmol). After stirring for 30 minutes, N,N-dimethylaminoethyl chloride hydrochloride was added at room temperature and the resulting mixture was stirred for one more day at 70° C. The mixture was extracted chloroform, dried over anhydrous magnesium sulfate, concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (40 mg, yield: 53%, white solid).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH:18]=[CH:19]1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Product: O=c1ccn(-c2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-2(1H)pyrazinone hydrochloride (1.5 g, from hydrolysis of the corresponding acetamido derivative with hydrochloric acid) 4H-pyran-4-one (0.71 g) and water (15 ml) was heated under reflux for 21/2 hours under a nitrogen atmosphere. The resultant solution was neutralised to give a solid, 1.79 g, m.p. 345° C. (dec). Recrystallisation from aqueous ethanol gave the title compound. 0.93 g. m.p. 354-357° C. (dec).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.C(N)=O.CN(C=NC=[N+](C)C)C.[Cl-:23].OC1C2C(=CC=CC=2)N=CN=1>O1CCOCC1>[Cl:23][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: [Cl-]
Reactant: c1ccc2ncncc2c1
Agent: CN(C)C=NC=[N+](C)C
Agent: Oc1ncnc2ccccc12
Solvent: NC=O
Solvent: C1COCCO1
Product: Clc1ncnc2ccccc12

Procedure:
Quinazoline starting materials are commercially available or readily prepared using conventional procedures. For example, 4-hydroxy quinazolines can be prepared from commercially available anthranilic acids via condensation with excess formamide at reflux (M. Endicott et al. J. Am. Chem. Soc., 1946, 68, 1299). Alternatively hydroxy quinazolines can be prepared in dioxane at reflux using Gold's reagent (J. Gipton; Correia, K.; Hertel, G. Synthetic Communications, 1984, 14, 1013). Once in hand, the 4-hydroxy quinazoline is chlorinated under standard conditions to provide 4-chloroquinazoline starting materials.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C@@H:10]1[NH:15][C:14](=O)[CH2:13][O:12][CH2:11]1)([CH3:9])[CH3:8]>C1COCC1>[CH:7]([C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][NH:15]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@H]1COCC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COCCN1
Temperature: 0 °C
Yield: 82.6 %

Procedure:
To ice-cold THF (6 mL) was added lithium aluminum hydride (1.0 M solution in THF, 18.0 mL, 18.0 mmol). Once the addition was complete, a solution of (S)-5-isopropylmorpholin-3-one (1.3 g, 9.0 mmol) in THF (6 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 18 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (0.75 mL), then a 15% aqueous solution of NaOH (0.75 mL), and then H2O (0.75 mL). The resulting mixture was stirred at room temperature for 1 h and then filtered washing the solid with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-isopropylmorpholine (0.96 g, 83%) as a clear, colorless oil. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C=O)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93.9 %

Procedure:
A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.00 g, 10.7 mmol) in anhydrous DMF (12 ml) was added dropwise to a stirred slurry of sodium hydride (60% dispersion in oil, 0.465 g, 11.6 mmol) in DMF (25 ml) at -10° C. under nitrogen and the mixture stirred at this temperature for 0.67 h. 4-Methoxybenzyl chloride (1.52 ml, 11.2 mmol) was added dropwise and the mixture warmed to 0° C. over 1 h and then stirred at RT for 2 h. Water was added and the mixture poured into ether and washed with water (×3). The ethereal layer was dried (MgSO4), evaporated in uacuo and the crude product chromatographed on silica gel, eluting with ethyl acetate/hexane (30:70), to afford the title pyrrolidine (3.09 g, 94%),δ (250 MHz, CDCl3) 1.46 (9H, br s, OC(Me)3), 1.73-2.09 (2H, m, CH2), 3.40-3.46 (4H, m, 2 of CH2), 3.81 (3H, s, OMe), 4.12 (1H, m, CHOCH2Ar), 4.45 (2H, s, OCH2Ar), 6.85-6.91 (2H, m, Ar--H), 7.23-7.27 (2H, m, Ar--H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH:26]12[CH2:31][CH:30]1[CH2:29][NH:28][CH2:27]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[C:16]([C:26]34[CH2:31][CH:30]3[CH2:29][NH:28][CH2:27]4)=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: C1NCC2CC12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(C23CNCC2C3)c1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 20b; 1.6 g, 4.2 mmol), 3-aza-bicyclo[3.1.0]hexane (1.00 g, 5.3 mmol), DIPEA (3.0 mL, 17 mmol) and dioxane (40 mL) at reflux (overnight).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[N:10]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[F:15][C:11]1[N:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(F)n1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(F)n1
Yield: 82.1 %

Procedure:
To 100 ml trifluoroacetic acid was added 11.6 g (50 mmol) of N-(1,1-dimethylethyl)-6-fluoro-2-pyridinesulfonamide and the mixture was refluxed for two days. The volatiles were then removed in vacuo and the residue triturated with ether to afford 7.23 g of tan solid, m.p. 110° C. to 111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[C:12]1([C:18]2[N:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([C:21]3[O:20][N:19]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:22]=3)[CH2:24]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2noc(C3CCCNC3)n2)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(F)c1)N1CCCC(c2nc(-c3ccccc3)no2)C1
Yield: 53 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 3-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (already prepared before in the Example 7). Yield: 53% (yellow oil); Rf=0.25 (DCM/MeOH:98/2); LCMS (Tr): 4.77 min (Method C); MS (ES+) gave m/z: 352.3.
Reaction SMILES: [CH:1]1([C@@H:7]([N:9]2[CH2:14][CH2:13][C@@:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:15][CH2:16][CH2:17][OH:18])[O:11][C:10]2=[O:26])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][CH2:16][CH2:15][C@@:12]1([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:11][C:10](=[O:26])[N:9]([C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:8])[CH2:14][CH2:13]1)(=[O:37])=[O:36]
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of (R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-6-(3-hydroxy propyl)-1,3-oxazinan-2-one (200 mg, 0.55 mmol) in CH2Cl2 (10 mL) was added Et3N (290 mg, 2.87 mmol) and MsCl (196 mg, 1.72 mmol) at 0° C. The reaction solution was stirred at rt for 2 h. The reaction was quenched by H2O and extracted with CH2Cl2. The organic phase was concentrated to give the 3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophen-yl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (240 mg, 92%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[N:20]1([C:11]2[N:12]=[C:13]([NH2:14])[N:8]3[N:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:19]=[C:9]3[N:10]=2)[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCNC1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)cc2n1
Solvent: CC#N
Product: Nc1nc(N2CCCNCC2)nc2cc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
7-Furan-2-yl-2-methanesulfonyl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (18 mmol; see Example 12(a) above) was suspended in 50 mL of CH3CN along with 5 eq. of homopiperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-[1,4]Diazepan-1-yl-7-furan-2-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][N:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26]([SH:28])=[N:27][C:23]=2[CH:22]=1>C(O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:28][C:26]3[NH:25][C:24]4[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][C:23]=4[N:27]=3)[C:11]=2[F:12])[CH2:14][CH2:15]1
Reactant: Fc1c(N2CCOCC2)ccnc1CCl
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3F)nc2c1
Yield: 74.8 %

Procedure:
5N NaOH (3.39 ml) was added dropwise to a stirred solution of 2-chloromethyl-3-fluoro-4-morpholinopyridine hydrochloride (2.06 g) and 5-methoxy-(1H)-benzimidazole-2-thiol (1.39 g) in ethanol (35 ml). After 3 hours excess solvent was removed and the residue treated with water (80 ml) and extracted with dichloromethane. The extracts were washed with water, dried (K2CO3), excess solvent removed and the residue crystallised from ethyl acetate to yield 2-(4-morpholino-3-fluoro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (2.16 g) m.p. 121°-123°.