Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: Nc1nc(-c2cccnc2)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3cccnc3)cs2)cc1

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (2.3 mg) with purity >90%. MS (pos) m/z 360.2.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[C:13]1([CH2:19][O-:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>>[C:13]1([CH2:19][O:20][C:2]2[C:3]3[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc2c(Cl)nccn2c1C
Reactant: [O-]Cc1ccccc1
Agent: [Na+]
Product: Cc1nc2c(OCc3ccccc3)nccn2c1C

Procedure:
For example, treating 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine with sodium phenylmethoxide yields an 8-phenylmethoxy-2,3-dimethylimidazo[1,2-a]pyrazine as shown in rection Scheme V. ##STR17##
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C(ONC(=O)CCCOC1C=CC=C(C2C=CC(F)=CC=2)C=1)C1C=CC=CC=1.N>>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:28])=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)#[N:27]
Reactant: N#Cc1ccc(-c2ccc(CCCC(=O)NOCc3ccccc3)cc2)cc1
Agent: N
Agent: O=C(CCCOc1cccc(-c2ccc(F)cc2)c1)NOCc1ccccc1
Product: N#Cc1ccc(-c2ccc(CCCC(=O)NO)cc2)cc1

Procedure:
The desired compound was prepared according to the method of Example 15, step 4, except substituting N-benzyloxy-4-[4-(4-cyanophenyl)phenyl]butyramide, prepared as in step 1, for N-benzyloxy-4-[3-(4-fluorophenyl)phenoxyl]butyramide. 1H NMR (DMSO-d6) δ 1.82 (m, 2H), 1.99 (t, 2H, J=8 Hz), 2.62 (t, 2H, J=7 Hz), 7.33 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 7.89 (m, 4H), 8.68 (s, 1H), 10.38 (s, 1H). MS (DCI/NH3) 298 (M+NH4+, 80), 280 (M+H+, 75), 236 (100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[CH3:14])[CH:5]=[C:4]([CH3:15])[N:3]=1.CN(C)CCN(C)C1N=C(C2SC(N[C:33](=[O:35])[CH3:34])=NC=2C)C=C(C)N=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:33](=[O:35])[CH3:34])=[N:10][C:9]=2[CH3:14])[CH:5]=[C:4]([CH3:15])[N:3]=1
Reactant: Cc1cc(-c2sc(N)nc2C)nc(C)n1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1
Product: CC(=O)Nc1nc(C)c(-c2cc(C)nc(C)n2)s1

Procedure:
This is prepared by acylating 5-(2,6-dimethyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (intermediate AF) using the procedure described for N-(5-{2-[(2-dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4-yl}-4-methyl-thiazol-2-yl)-acetamide (Example 39, step 2).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[CH2:32][CH2:31]1
Reactant: c1cc2c(cn1)CCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cnccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 45 mg (0.38 mmol) 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine, 0.15 mL (0.87 mmol) DIPEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. Then the reaction mixture was mixed with water, the precipitate formed was suction filtered and dissolved in DMF/NMP. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised. A second purification was carried out by preparative HPLC-MS.
Reaction SMILES: [CH:1]1([C:7]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])O.[Na+]>ClCCCl>[Br:21][CH2:20][C:17]1[O:16][C:15]([C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(O)(c2ccccc2)C2CCCCC2)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: OC(c1ccccc1)(c1ncc(CBr)o1)C1CCCCC1
Temperature: 80 °C

Procedure:
A solution of cyclohexyl-(5-methyl-oxazol-2-yl)-phenyl-methanol (Intermediate 3) (3.0 g, 11.1 mmol) in 1,2-dichloroethane (22 mL) was treated with N-bromo-succinimide (2.16 g, 12.2 mmol) followed by 2,2′-azobis(2-methylpropionitrile) (0.18 g, 2.1 mmol). The mixture was heated to 80° C. for 2.5 h and then allowed to cool to RT. Satd. sodium hydrogen carbonate solution (aq.) was added and the phases were separated. The organic layer was washed with brine and the combined aqueous layers were extracted with DCM. The combined organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product as a brown oil. Purification was achieved via column chromatography eluting with 33-100% DCM/cyclohexane, followed by 25% EtOAc/DCM.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid methyl ester (56 mg, 0.17 mmol) in THF (0.6 mL) was added a solution of lithium hydroxide monohydrate (15 mg, 0.34 mmol) in water (0.6 mL) followed by methanol (0.2 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was then evaporated and acidified with HCl (1 N) and the mixture cooled to 0° C. for 30 min. A solid formed which was filtered off, washed with water and dried to afford the title compound (41 mg, 76%) which was obtained as a white solid. MS: m/e=310.3 [M−H]−.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:14][C:13]([NH2:15])=[N:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]([O:32]CC)=O)=[CH:24][CH:23]=1>C(O)C>[N:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:15]=[C:13]3[NH:14][CH:9]([C:6]4[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=4)[CH2:10][CH2:11][N:12]3[C:30](=[O:32])[CH:29]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCC(c2ccncc2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccncc1)N2
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
A suspension containing 1.0 g (4.01 mmoles) of 6-(4-pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride in 30 ml of ethanol was treated with 1.94 g (14.05 mmoles) of potassium carbonate and allowed to stir for 5 min. 1.0 g (4.01 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate were added and the resulting mixture was heated at reflux temperature for 18 h. The cooled solution was evaporated to remove solvent and the residue was dissolved in water and extracted with dichloromethane. The organic extracts were washed with a saturated solution of aqueous sodium chloride, dried and the solvent evaporated under reduced pressure. The crude product thus obtained was purified using silica gel chromatography eluting with a gradient of dichloromethane/methanol/concentrated aqueous ammonia solution in the proportions 95/5/0.5 to 80/20/2. 0.26 g (21%) of pure product was obtained. Mp: 268-270° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5](=[O:14])[CH2:6][CH2:7][NH:8][S:9]2(=[O:13])=[O:12])=[CH:3]1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:8]3[CH2:7][CH2:6][C:5](=[O:14])[C:4]4=[CH:3][N:2]([CH3:1])[CH:11]=[C:10]4[S:9]3(=[O:13])=[O:12])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Cn1cc2c(c1)S(=O)(=O)NCCC2=O
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Yield: 57.7 %

Procedure:
A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg (1.2 mmol) of 1-(3-chloropropyl)-4-(4-fluoro-phenyl)piperazine and 304 mg (2.2 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate), whereby 276 mg of the title compound were obtained (yield: 58%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.[CH3:13][O-:14].[Na+].CO.[Cl-].[NH4+]>>[CH3:13][O:14][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2c(=O)nc[nH]c2c1

Procedure:
A microwave vial was charged with 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (110 mg, 0.606 mmol), a 0.5 M solution of sodium methoxide in methanol (3.65 mL, 1.817 mmol) and sodium methoxide (327 mg, 6.06 mmol). The vial was capped and irradiated in a microwave reactor at 145° C. for 30 minutes. The reaction was neutralized with saturated aqueous ammonium chloride (3 mL), concentrated, and diluted with cold water. The resulting precipitate was collected by vacuum filtration and dried in vacuo to provide the title compound (107 mg, 0.604 mmol) as pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.49 (d, J=2.74 Hz, 1H) 8.11 (s, 1H) 8.47 (d, J=2.74 Hz, 1H). LC/MS (ESI+) m/z=178 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:15]=1[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)[C:15]=3[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC(C)(C)c3ncc(Br)cc32)c1C
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.44 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (126 mg, 0.44 mmol) and hydrochloric acid in 1,4-dioxane (0.11 mL, 0.44 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline was obtained as a yellow film. Mass Spectrum (ESI) m/e=477 [(M+1) (79Br)] and 479 [(M+1) (81Br)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[CH3:21][C:22]1[N:23]([CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][N:26]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH3:21])[CH2:29][CH2:30]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: Cc1nccn1CC1CCNCC1
Agent: Cl
Product: Cc1nccn1CC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 27 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-(2-methyl-imidazol-1-ylmethyl)-piperidine, dihydrochloride salt using standard reductive amination conditions. The resulting crude solid was purified on silica using a gradient of 0%-40% methanol in ethyl acetate as the eluent to give 2-chloro-6-[4-(2-methyl-imidazol-1-ylmethyl)-piperidin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pure white solid (27% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 328 as an off white solid (62% yield). NMR (CDCl3, 400 MHz), 1.32-1.46 (2H, m), 1.65 (2H, d, J=11.6), 1.69-1.75 (1H, m), 2.08 (2H, t, J=11.2), 2.39 (3H, s), 3.01 (2H, d, J=11.2), 3.75 (2H, d, J=7.2), 3.82 (2H, s), 3.89-3.91 (4H, m), 4.03-4.06 (4H, m), 5.22 (2H, br s), 6.80 (1H, s), 6.93 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=506
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)C=CC=CC=1.N[CH2:29]CCNC1C(C)=CC=CN=1.CI.O>CS(C)=O>[NH2:17][CH2:16][CH2:15][CH2:14][N:7]([C:8]1[C:13]([CH3:29])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:1]
Reactant: Cc1cccnc1NCCCN
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: Cc1cccnc1N(C)CCCN
Reaction time: 1 h
Yield: 801.1 %

Procedure:
A mixture of 3-methyl-2-bromopyridine (15 g), 1,3-diaminopropane (37.3 g) and pyridine (10 ml) was heated under reflux for 3 hr. After stripping, the residue was treated with 2N sodium hydroxide and the product extracted into chloroform. The extract was dried, stripped and the residue distilled at reduced pressure to give 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) bp 100° C., 0.09 mm Hg. (ii) Sodium hydride (1.11 g) was dissolved in DMSO (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) in DMSO (10 ml) added at room temperature. Methyl iodide (6.56g) in DMSO (20 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hr, water (100 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid. The pH of the acid extract was raised to 9.5 and extracted with chloroform. The pH was raised further to 14 and again extracted with chloroform. After stripping the final extract, the residue was taken back up in water and the product extracted out again with ether. After drying (K2CO3), stripping the ether extract gave 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (4.46 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (1.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.46 g) were heated together under reflux in pyridine (10 ml) for 20 hr. The mixture was stripped and the residue triturated with water (pH adjusted to 7 with 6N hydrochloric acid) until a solid (2.1 g) was obtained. This was chromatographed (silica gel, 1-3% methanol/chloroform) and crystallised from acetone/water to give 2-[3-[N-methyl-N-(3-methylpyrid-2-yl)amino]-propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.48 g (22%) mp 83°-85° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of the compound (300 mg, 0.54 mmol) synthesized in Example 52-2), 2-bromo-5-methylpyrazine (234 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol), and potassium carbonate (149 mg, 1.08 mmol) in water (2 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (70 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=60:40 to 100:0) to obtain the title compound (139 mg, 49%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[AlH3].N(CC)(C)C>C1COCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1])=[CH:8][C:9]=1[O:16][CH3:17])[CH3:15]
Reactant: CCOc1ccc(CC(=O)NCCN)cc1OC
Agent: CCN(C)C
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(CCNCCN)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Treat a solution of N-(2-amino-ethyl)-2-(4-ethoxy-3-methoxy-phenyl)acetamide (0.7 g, 2.77 mmol) in THF (10 mL) with AlH3.NMe2Et (55 mL, 27.74 mmol) and heat to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (0.5 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuoo and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a white oil.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH:10]([OH:12])[CH3:11].[CH:20]12[CH2:29][CH:23]([CH:24]([C:26](Cl)=[O:27])[CH2:25]1)[CH:22]=[CH:21]2>C1COCC1>[CH:20]12[CH2:29][CH:23]([CH:24]([C:26]([O:12][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])([C:14]([F:15])([F:16])[F:17])[C:7]([F:18])([F:19])[F:6])=[O:27])[CH2:25]1)[CH:22]=[CH:21]2
Reactant: O=C(Cl)C1CC2C=CC1C2
Reactant: CC(O)CC(O)(C(F)(F)F)C(F)(F)F
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CC(O)(C(F)(F)F)C(F)(F)F)OC(=O)C1CC2C=CC1C2
Reaction time: 8 h
Yield: 87.3 %

Procedure:
N-butyllithium (1600 ml) (2.56 mol, 1.6M solution in hexanes) was added to a 3-L, three-necked round bottomed flask equipped with an overhead stirrer, a digital thermometer, a 500-mL capacity constant-pressure dropping funnel and a nitrogen inlet. The dropping funnel was charged with a solution of 1,1,1-trifluoro-2-trifluoromethyl-2,4-pentanediol (289 g, 1.28 mol) in anhydrous THF (250 ml). The flask was cooled in ice and the THF solution was slowly added over about 2 hours, while maintaining a temperature below 100 C. Once the addition was complete, the dropping funnel was recharged with a solution of norbornene-5-carbonylchloride (201 g, 1.28 mol) in anhydrous THF (250 ml), which was then slowly added over about 1.5 hours, while maintaining a temperature below 10° C. The solution was allowed to reach room temperature with stirring overnight. The resulting suspension was transferred to a 4-L separatory funnel and washed once with water (1 L). The organic layer was separated and the aqueous wash was adjusted to pH 6 (litmus) with concentrated HCI and extracted twice with ether (1 L). The combined organic solutions were washed once with water and once with brine and dried over anhydrous magnesium sulfate. The suspension was filtered, the solvent removed on a rotary evaporator and the resulting oil distilled twice at 1200 C. and 0.5 mm Hg to yield 387 g of the title compound as an oil.
Reaction SMILES: C(Cl)CCl.ClC1C=CC(C(NC2C=CC(OC)=CC=2)C(F)(F)F)=C(C=1)C[NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[C:35]([OH:45])(=O)[C@@H:36]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[OH:37].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH:38]1([C@@H:36]([OH:37])[C:35]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:19])=[O:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)(F)F)cc1
Reactant: O=C(O)[C@H](O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Reaction time: 16 h
Yield: 116.4 %

Procedure:
EDC (44.0 mg, 0.23 mmol) was added to a stirred mixture of N-(5-chloro -2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-L-prolinamide (68 mg, 0.15 mmol), (R)-(−)-hexahydromandelic acid (24.2 mg, 0.15 mmol) and HOAT (10.4 mg, 0.076 mmol), in DMF (2 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (eluting with EtOAc/CHCl3, 1:2) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl)}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (44.4 mg) as a glass: MS: 582.4 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([NH2:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:29][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:22])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC3CC3)c(C3CC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (13 mg, 23%) as colorless oil; MS (ESI, m/z): 383.6 (M+H+)