Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20](O)[CH3:21])[C:18]=3[C:10]=2[CH:9]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:20]([CH3:21])[CH2:19][N:17]1[C:18]2[C:10]3[CH:9]=[C:8]([O:7][CH3:6])[CH:24]=[CH:23][C:11]=3[CH2:12][CH2:13][C:14]=2[CH:15]=[N:16]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(cnn1CC(C)O)CC2
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)-c1c(cnn1CC(C)N=[N+]=[N-])CC2
Yield: 60 %

Procedure:
0.89 ml (11.8 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.52 g (5.88 mmol) of (RS)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-propan-2-ol and 3.27 ml (23.5 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.76 g (11.8 mmol) of sodium azide and the reaction mixture was heated to 85° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1 g (60%) of (RS)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indazole was obtained as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32]Br)(=[O:23])[CH3:22].C(O)(=O)C>CN(C=O)C>[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:23])[CH3:22]
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1Cn1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-6-benzyloxypurine (1 mmol) in DMF (2 mL) was added sodium hydride (1.15 eq) and the mixture stirred at room temperature for 30 minutes. A solution of 1(R)-acetoxymethyl-2(S)-bromomethylcyclohex-4-ene (1.1 eq) in DMF (0.75 mL) and the reaction stirred at 60° C. for 16 hours. The reaction was neutralized with acetic acid and concentrated. The desired compound was purified by silica gel chromatography (chloroform:methanol 95:5) as a colorless foam. 1HNMR (500 mHz, CDCl3): 8.02 ppm (s, 1H); 7.65 (s, 1H); 7.49 (d, 2H); 7.38-7.26 (m, 3H); 5.65 (dd, 2H); 5.56 (s, 2H); 4.33 (dd, 1H); 4.12 (dd, 1H); 4.06-3.97 (m, 2H); 2.40 (bs, 1H); 2.23-1.75 (m, 6H); 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1.[2H]C1([2H])C([2H])([2H])C2C(=CC=C(F)C=2)[C@H](C(C)C)[C@]1([CH2:36][C:37]([OH:39])=[O:38])O>>[F:17][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C@:4]([CH2:36][C:37]([OH:39])=[O:38])([OH:16])[CH2:3]1
Reactant: [2H]C1([2H])c2cc(F)ccc2[C@H](C(C)C)[C@@](O)(CC(=O)O)C1([2H])[2H]
Reactant: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)O

Procedure:
Carboxylic acid 15c is prepared from 12b in a manner analogous to that of Example 1, step 2 for acid 15b.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[C:22]=2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]3[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:10]=[CH:11][CH:12]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[N:18]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:19](=[O:25])[N:20]([CH3:24])[C:21](=[O:23])[C:22]=23)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Sc2c3c(=O)n(C)c(=O)n(CC(C)C)c3cn2Cc2cccc3ccccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(O)c3)n(Cc3cccc4ccccc34)cc21
Reaction time: 6 h
Yield: 61.7 %

Procedure:
A solution of boron tribromide in dichloromethane (1M, 3 ml) was added to a solution of 5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (200 mg) (compound of Example 23) in dichloromethane (20 ml) at ambient temperature. After 6 hours, water (10 ml) was added carefully and the reaction mixture was partitioned between dichloromethane and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by chromatography on silica gel, eluting with isohexane/ethyl acetate (2:1 to 1:1) followed by recrystallisation from isohexane/ethyl acetate (3:1), gave the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:17][C:18]([NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22]([NH:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN)cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C

Procedure:
To a 0° C. solution of (3,4-dimethoxyphenyl)methanamine (2 g, 12 mmol) in DCM (20 mL) was added sequentially (R)-2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid (3.28 g, 13.2 mmol), PyBOP (6.85 g, 13.2 mmol) and DIPEA (4.18 mL, 23.92 mmol). The reaction mixture was stirred and allowed to warm up to ambient temperature over 2 h. The reaction was then quenched by the addition of water and the mixture was extracted twice with 100 mL DCM. The organic fraction was washed with 50 mL water, 50 mL brine, and the layers were separated. The organic fraction was dried over sodium sulfate, filtered, and evaporated. The residue was purified via silica gel chromatography, eluting with 30% ethyl acetate/petroleum ether. Yield 3.5 gms (R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate. LCMS (Method F) RT 2.3 min, m/z 399.2 (MH+); 1H NMR (400 MHz, chloroform-d) δ 1.41 (s, 9H), 1.91-1.98 (m, 1H), 2.07 (s, 3H), 2.10-2.14 (m, 1H), 2.47-2.61 (m, 2H), 3.65 (s, 6H), 4.25-4.27 (br s, 1H), 4.33-4.42 (m, 2H), 5.16 (br s, 1H), 6.47 (br s, 1H), 6.80 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>C(O)C>[CH3:11][N:9]1[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[CH3:17])[CH2:10]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: CC1CCCN1
Solvent: CCO
Product: CC1CCCN1CCC1CN(C)C(=O)c2cccnc2O1
Yield: 35.7 %

Procedure:
To a solution of 3.5 g (0.0145 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one in ethanol (15 ml) was added 2-methyl pyrrolidine (5.0 g, 0.063 mole). The solution was heated to reflux for 3 hours with stirring. The ethanol was removed by rotary evaporation (water aspirator, 80° C.). The residual oil was partitioned between dilute aqueous sodium hydroxide (50 ml) and chloroform (50 ml). The organic layer was saved and the aqueous layer extracted with chloroform (2×30 ml). All the chloroform layers were combined, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (water aspirator, 70° C.). The residual oil was then distilled at 200° C. and low vacuum (vacuum pump) giving 1.5 g (35.7%) of a clear oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a 0° solution of 2.54 g of 2-(2-aminoethyl)pyridine, 50 ml of methylene chloride and 6.42 ml of pyridine is added, dropwise, 7.0 g of product from Example 3 in 250 ml of methylene chloride. The reaction is stirred at 0° C. for 2 hours followed by 14 hours at room temperature. The reaction is diluted with chloroform, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75-100% ethyl acetate/hexane) to give 3.58 g of the desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:16][C@@H:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C@@H:6]1[NH:28][C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])(=[O:3])[CH3:2].C[O-].[Na+].N1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(Cl)([C:48]1[CH:53]=[CH:52]C=[CH:50][CH:49]=1)=O>CO.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:18]([OH:19])[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[C:26]2[CH:52]=[CH:53][CH:48]=[CH:49][CH:50]=2)[O:16][C@@H:7]([S:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[C@@H:6]1[NH:28][C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])(=[O:3])[C:2]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(C)cc2)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O)[C@H](OC(=O)c3ccccc3)[C@H]2NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 56 %

Procedure:
Compound 21 (2.0 g, 3.41 mmol) in MeOH (10 mL) was treated with a catalytic amount of 1M NaOMe for 5 h, then neutralized with IR-120 (H+), filtered and concentrated. To a solution of the crude product (610 mg, 1.324 mmol), pyridine (700 μL) and DMAP (50 mg) in CH2Cl2 (20 mL), was added BzCl (338 μL, 2.916 mmol). The mixture was refluxed for 5 h under Ar, then concentrated and coevaporated twice with toluene, diluted with CH2Cl2 (100 mL), washed with 10% aq. H2SO4, brine, and sat. aq NaHCO3, dried over Na2SO4, filtered and concentrated. Column chromatography (Hexane/AcOEt, 2:1 to 1:2) of the residue gave 27 (495 mg, 56%) as white white solid; [α]D22 +28.4° (c, 0.5, CHCl3); 1H-NMR (500 MHz, CDCl3), δ 5.50 (d, 1H, J=9.5 Hz, H-2), 5.41 (t, 1H, J=9.5 Hz, H-3), 4.844 (d, 1H, J=10.0 Hz, H-1), 4.74–4.64 (m, 3H), 4.55 (d, 1H, J=12.0 Hz, OCH2CCl3), 3.90 (q, 1H, J=10.0 Hz, H-2), 3.79 (m, 2H, H-5, H-4), 3.42 (d, 1H, J=5.0 Hz, OH), 2.27 (s, 3H, Me); HRMS (M+Cs) calcd for C30H20O8Cl3NSCs 799.9655. found 799.9680.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([CH3:15])=[C:13]=[S:14].CCN(CC)CC>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([CH3:15])[C:4]2=[O:5]
Reactant: CN=C=S
Reactant: Nc1c(Br)cccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=S)[nH]c2c(Br)cccc2c1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A solution of 2-amino-3-bromobenzoic acid (Maybridge, Trevillett, UK; 3.03 g, 14.02 mmol) and isothiocyanatomethane (Aldrich; 1.151 mL, 16.82 mmol) in EtOH (28 mL) was stirred at 75° C. for 3.5 d. Additional isothiocyanatomethane (2.302 mL, 33.64 mmol) and Et3N (2.74 mL, 19.63 mmol) were added, and the resulting mixture was stirred at 75° C. for 1 d. The mixture was concentrated in vacuo and the residue was triturated with Et2O (40 mL) to provide 8-bromo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2.90 g, 10.70 mmol, 76% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (1H, br. s.), 8.11 (1H, d, J=8.0 Hz), 7.85 (1H, dd, J=7.9, 1.3 Hz), 7.20 (1H, t, J=7.9 Hz), 3.83 (3H, s). m/z (ESI, +ve) 271.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5](C(=O)C)[CH:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.[C:20](#[N:22])[CH3:21]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][C:20]1[N:22]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[C:11]3[O:10][CH:9]=[CH:8][C:7]=3[CH:6]=2)[N:17]=[N:16][N:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cc(CO)c2occc2c1
Reactant: CC#N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Product: Cc1nnnn1-c1cc(CO)c2occc2c1

Procedure:
A solution of 1-(7-hydroxymethyl-benzofuran-5-yl)-ethanone (250 mg,) and sodium azide (0.68 g) in acetonitrile (40 ml) was treated with titanium tetrachloride (0.29 ml) and heated at reflux for 1.5 h. The reaction mixture was allowed to cool, treated with 2N hydrochloric acid (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases were dried, combined, filtered and the filtrate evaporated in vacuo to give a yellow oil. Purification by FCC eluted with hexane:ethyl acetate (1:3) gave the title compound as a clear gum (131 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[CH2:18](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:19]1[O:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:12])[F:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 23 using 1-{2-hydroxy-5-[(trifluoromethyl)sulfonyl]phenyl}ethanone (3.2 g, 11.9 mmol), (R)-glycidyltosylate (3.2 g, 14 mmol), K2CO3 (2.0 g, 14.3 mmol) and DMF (30 ml). Yield 2.2 g. MS m/z (rel. intensity, 70 eV) 324 (M+, 4), 277 (83), 255 (69), 253(67), 199 (bp).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1

Procedure:
tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate from Example 137 (0.33 g) in DCM (5 mL) was treated with 4N HCl in dioxane (0.9 mL) for 30 minutes at room temperature. The reaction mixture was concentrated to dryness to afford quantitative yield of 4-(2-chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].O>O1CCCC1.CCCCCC>[CH3:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
A solution (10 mL) of 2-bromo-3-methylpyridine (1.0 g) in tetrahydrofuran was cooled to −70° C., and a 1.6 mol/L solution (4.0 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 15 min, tributyltin chloride (2.2 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1) to give the title compound as a colorless oil (yield 1.75 g, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1CC(=O)NN=C1c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
1 l three-necked round-bottomed flask equipped with a condenser connected to a gas inlet, a glass rod air driven stirrer and a thermometer was charged with 63.8 g, (306 mmol) of (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid from Example H and 2-propanol (400 ml) at 40° C. The solution was placed under an atmosphere of nitrogen and heated to 65° C. Then hydrazine monohydrate (45 ml, 2.2 mol) was added dropwise over 10 min. The reaction mixture was heated to 80°-81° C. (reflux), stirred for 1 hour then slowly cooled to 3° C. over 1 hour with gentle stirring. The formed precipitate was collected by suction filtration, triturated in a 1 L beaker with deionized water (300 ml) at 23° C. for 2 hrs and collected by suction filtration. The solids were dried to constant weight in an air oven (90° C.) to provide 51.9 g (83.5%) of pure (±}-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone, m.p. 268°-273° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:50][CH2:51]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: CO
Product: COCCN1CCN(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.4 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 241, step B) (102 mg, 0.37 mmol) and p-toluenesulfonicacid (185 mg, 0.98 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (125 mg, 0.17 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.33 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=5.31 Hz, 1H), 8.07 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.70, 1.74 Hz, 1H), 7.66 (d, J=8.97 Hz, 1H), 7.45 (s, 1H), 7.33-7.45 (m, 2H), 7.25 (d, J=8.79 Hz, 1H), 7.15 (t, J=8.06 Hz, 2H), 6.89-6.95 (m, 1H), 6.74 (s, 1H), 6.53 (d, J=5.13 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.43 (t, J=5.77 Hz, 2H), 3.21 (s, 3H), 2.83 (t, J=4.40 Hz, 4H), 2.47-2.58 (m, 6H), 2.11 (s, 3H); MS (ESI): 735 [M+H]+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.I[CH:21]([CH3:23])[CH3:22]>O.CC(O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH2:7][N:8]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)C(=O)O
Reactant: CC(C)I
Solvent: CC(C)O
Solvent: O
Product: CC(C)N1C=C(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C=CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 78.3 %

Procedure:
Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0° C., and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2×15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182-185° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:12])[N:35]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C:14](=[O:16])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Reactant: NCc1ccc(F)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C(=O)C1

Procedure:
A solution of 27 (547 mg, 2.35 mmol) and carbonyl diimidazole (837 mg, 5.16 mmol) in 4.7 mL of dry THF under a N2 atmosphere was refluxed for 5 minutes. Once the reaction cooled down to room temperature 4-fluorobenzyl amine (0.295 mL, 2.58 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was then concentrated and re-dissolved in EtOAc. The organic layer was washed with an aqueous 0.5 N HCl solution and the solvent was removed in vacuo. The product was purified by column chromatography eluting with CH2Cl2 to provide clean product 28 as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 4.39 (s, 4H), 4.92 (s, 2H), 6.99 (t, 2H, J=9 Hz), 7.40 (dd, 2H, J=5, 9 Hz); 13C NMR (75 MHz, CDCl3) δ 28.1, 42.0, 47.1, 82.3, 115.2, 115.5, 131.1, 131.2, 132.0, 153.0, 162.7 (d, J=245 Hz), 168.0; 19F NMR (282.6 MHz, CDCl3) δ 62.5; EI MS (m/z) 340.5 [M+Na].