Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]5)[CH2:16]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: O=C1CN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CCN1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)piperazin-2-one from Example 127 (90 mg) was reacted with 2-ethylbenzimidazole and sodium-tert-butoxide (instead of cesium carbonate) via General Procedure C to afford 10.2 mg of 134 following reverse phase HPLC purification. MS (Q1) 528.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH2:13]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][N:14]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:19]2[CH2:20][CH2:21][C:16]3([CH2:15][N:14]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:13]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)cc1
Reaction time: 15 h

Procedure:
To a solution of p-methoxyphenylacetic acid (1.26 g, 7.61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.00 g, 7.61 mmol) in dichloromethane (25 mL) was added triethylamine (2.12 mL, 15.2 mmol) and HATU (3.47 g, 9.12 mmol). The reaction was stirred for 15 hours. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate and the aqueous phase was washed with dichloromethane (2×20 mL). The combined organic layers were washed with water and brine, and dried over anhydrous MgSO4. Filtration and solvent removal afforded a crude product which was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.), 100/0 to 50/50 heptanes/ethyl acetate gradient. The final product (I-1a) was obtained as clear oil which solidified upon standing at ambient temperature (2.75 g, 96%). MS (ES+) 375.4 (M+H)+. 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.50 (br t, 2H), 1.65 (br t, 2H), 3.32 (br t, 2H), 3.52 (br t, 2H), 3.57-3.64 (m, 6H), 3.77 (s, 3H), 6.83 (d, 2H), 7.12 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:16][CH3:17].B(OB=O)=O.[OH:23][C:24]1[C:25]([O:32][CH3:33])=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[OH:23][C:24]1[C:25]([O:32][CH3:33])=[C:26](/[CH:27]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:16][CH3:17])[CH:4]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(C=CC(=O)CC(C)=O)ccc1O
Reactant: COc1c(O)cccc1C=O
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: CCCCN
Solvent: O
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2cccc(O)c2OC)ccc1O
Reaction time: 1 h
Yield: 32.6 %

Procedure:
6-(4-Hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 3-hydroxy-2-methoxybenzaldehyde (16 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol) in 0.7 mL of ethyl acetate. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution of 1N HCl and brine, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (10.2 mg, 32%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1.[NH2:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:25][C:24]([CH3:27])([CH3:26])[C@H:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[N:6]=1)=[O:17])[C:20](=[O:21])[NH:22][CH3:23]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(Br)c(OCC2CCCO2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 a) and (2S)-2-amino-N,3,3-trimethyl-butanamide, (CAN 89226-12-0) as starting materials, MS (EI): m/e=428.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@H:5]([CH2:16][C@@H:17]([CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:21][CH:20]=2)[N:6]=C(OCC)[C@@H](C(C)C)N=1)[CH3:2].Cl.C([O-])(O)=[O:38].[Na+]>CC#N>[NH2:6][C@@H:5]([CH2:16][C@H:17]([CH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][N:25]2[CH2:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:21][CH:20]=1)[CH:33]([CH3:35])[CH3:34])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](N)C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a stirred solution of 6-((S)-2-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (300 mg, 0.62 mmol) in CH3CN (5 mL) was added 1 N aq HCl (5 mL) at rt. The mixture was stirred for 5 h, poured into ice-cold, satd aq NaHCO3 and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to give (2S,4S)-ethyl 2-amino-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methylhexanoate (220 mg, 95%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.S(=O)(=O)(O)O.[OH-].[NH4+]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2O)c(OCc2ccccc2)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2=O)c(OCc2ccccc2)c1
Temperature: 18 °C
Reaction time: 5 h

Procedure:
To a cooled solution of 24.8 g. (50 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol, 100 ml. of acetone, 6.0 g. (60 mmols.) of chromium trioxide, 15 ml. of water and 20 ml. of acetic acid is added dropwise 20 ml. of concentrated sulfuric acid at such a rate as to maintain the temperature at 5° C. The reaction mixture is stirred 5 hours longer (t<18° C.) and then neutralized with concentrated ammonium hydroxide. The reaction mixture is extracted with 500 ml. of ether, the ether extract washed once with saturated sodium chloride, dried over magnesium sulfate and evaporated. Purification is accomplished via rapid column chromatography on 100 g. of silica gel eluted with ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=O)=[C:8](F)[CH:7]=1.O.[OH-].[Li+].[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10]([OH:12])=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:26][C:8]=2[CH:7]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 4-((2,4-dichlorobenzyl)oxy)-2-fluorobenzoate (2.0 g) in DMF (dry) (40 mL) were added lithium hydroxide monohydrate (0.978 g) and ethyl 2-mercaptoacetate (1.92 mL) at room temperature. The mixture was stirred at room temperature for 2 d. The mixture was diluted with water and the precipitate was collected by filtration, and washed with IPE to give the title compound (2.30 g).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:23][CH:22]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(C(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (4.889 g, 12.72 mmol) was dissolved in hydrogen bromide (33% in AcOH, 30 mL, 428.24 mmol) and stirred at room temperature for 18 h. The compound was purified by preparative HPLC (2 equal injections) on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 05-40% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. The product containing fractions were freeze dried and again treated with hydrogen bromide as described above. The compound was purified by preparative HPLC (3 equal injections) on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 05-40% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. 5-((2R,4S)-2-(4-(Trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (3.34 g, 80%) was isolated as a colorless solid. 1H NMR (400 MHz, dmso) δ 1.04-1.15 (m, 1H), 1.35 (qd, 1H), 1.72-1.80 (m, 2H), 2.49-2.58 (m, 1H), 2.61-2.81 (m, 4H), 2.94-3.02 (m, 1H), 5.66 (s, 1H), 7.42 (d, 2H), 7.62 (d, 2H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1305.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][CH2:59][C@H:60]1[CH2:64][CH2:63][CH2:62][N:61]1[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].O.[C:73]([OH:79])([C:75]([F:78])([F:77])[F:76])=[O:74]>CN(C=O)C>[F:76][C:75]([F:78])([F:77])[C:73]([OH:79])=[O:74].[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:58][CH2:59][C@H:60]3[CH2:64][CH2:63][CH2:62][N:61]3[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])=[O:19])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@H]3CCCN3C(=O)OC(C)(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
75 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 equivalent), 90 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.24 mmol, 1.05 equivalents) and 88 mg of N,N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 equivalents) were initially charged in 1.4 ml of DMF and stirred at RT for 20 min. 50 mg (0.25 mmol, 1.1 equivalents) of tert-butyl (2R)-2-(aminomethyl)pyrrolidine-1-carboxylate were then added, and the mixture was stirred at RT overnight. The reaction solution was diluted with water/TFA and purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 108 mg (76% of theory; purity 100%) of the title compound.
Reaction SMILES: Cl.[CH:2]1([P:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([S:16]([O-:19])(=[O:18])=[O:17])[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Na+].[CH2:27](O)[CH3:28]>>[CH:20]1([P:8]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([S:16]([O:19][CH2:27][CH3:28])(=[O:18])=[O:17])[CH2:11]2)=[O:9])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCO
Reactant: O=P(C1CCCCC1)(C1CCCCC1)C1CCCC(S(=O)(=O)[O-])C1
Agent: Cl
Agent: [Na+]
Product: CCOS(=O)(=O)C1CCCC(P(=O)(C2CCCCC2)C2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
Hydrochloric acid (0.7 g; 38 wt. % solution) is added to DCHPOCHS-Na (1.5 g; 3.8 mmoL) in ethanol (20 mL), and the mixture is stirred for 30 minutes. Then, the ethanol is evaporated, and the residue is dried in vacuum. Dichloromethane (20 mL) and triethylorthoacetate (1.85 g; 11.4 mmoL) are added to the residue, and the resulting mixture is stirred under reflux for 10 hours. The mixture is then washed with saturated sodium bicarbonate (15 mL), then water, and then dried with sodium sulfate. The organic solvent and excess reagent are removed. The residue obtained therefrom is dried in vacuum for 1 hour to yield Ethyl 3-(dicyclohexylphosphinyl)-cyclohexane-1-sulfonate (DCHPOCHS-Et). Yield: 1.36 g (89%) 31P{1H} NMR(C6D6, ppm): 51.28 (major) and 49.24 (minor).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(OC1N=C2N(C3C=CC=CC=3C)C=NC2=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]=[CH:16][N:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:27])[C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cc1ccccc1-n1cnc2ccc(OCc3ccccc3)nc21
Product: Cc1ccccc1-n1cnc2nc(OCc3ccccc3)ccc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and o-tolylboronic acid, prepared in a similar manner as the one described in Example 1.25, Step A, 5-(benzyloxy)-3-o-tolyl-3H-imidazo[4,5-b]pyridine and 5-(benzyloxy)-1-o-tolyl-1H-imidazo[4,5-b]pyridine were obtained, which was then dissolved in DCM and diluted with excess sulfuric acid. The resulting solution was stirred for 30 minutes at room temperature then acidified with the addition of 1 M aqueous hydrochloric acid. The solvent was removed from the organic layer and the residue was purified via preparative HPLC to give the title compound. LCMS m/z=225.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:24])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][C:16]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(Nc2nc(Cl)nc3scnc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
To a stirred solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol) and 3,4,5-trimethoxybenzenamine (230 mg, 1.25 mmol) in 7 mL of DMSO was added DIEA (188 mg, 1.45 mmol) in one portion at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, and the solid obtained was filtered, washed with water (10 mL) to give a crude product. It was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 98.6%) as a yellow solid. LC-MS: 353.0 [M+H]+, 726.9 [2M+H]+, tR=1.56 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]CC3C=CC=CC=3)[C:13]([C:30]#[N:31])=[CH:12]2)=[C:7](OC)[C:6]=1[O:34][CH3:35])[CH3:2].[C:37](OCC)(=[O:39])C>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][C:6]=1[O:34][CH2:35][O:39][CH3:37])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[4-(2-benzyloxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxy-methoxy-benzoic acid ethyl ester (2.3 g) in a mixed solvent of ethyl acetate (20 mL) and methanol (20 mL) was added palladium-carbon powder under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure to give the title compound (1.4 g)
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][C:25]#[N:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+].C([O-])(O)=O.[Na+]>O.C(O)(C)C.[Zn+2].[Br-].[Br-]>[NH:27]1[C:25]([CH2:24][NH:23][CH2:22][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]4[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]4)[CH:13]=3)[CH:18]=2)=[N:26][N:29]=[N:28]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC#N)ccc3c2)CC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCc4nnn[nH]4)ccc3c2)CC1
Temperature: 0 °C

Procedure:
To a solution of 2-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)acetonitrile (240 mg, 0.69 mmol) in water and isopropanol (10 mL, 1:5) was added NaN3 (50 mg, 0.76 mmol, 1.1 eq) and ZnBr2 (153 mg, 0.69 mmol, 1.0 eq), then refluxed for 18 h. The reaction was cooled to 0° C. and saturated NaHCO3 was added. The mixture was extracted with DCM (20 mL×3) and the aqueous layer was destroyed by NaClO solution. The organic layer was concentrated and the residue was the title compound as a white solid (27 mg, yield: 11%). ESI-MS (M+H+): 394.3. HPLC: 91.15%, 1H NMR (400 MHz, CD3OD) δ: 7.82 (s, 1H), 7.79-7.72 (m, 2H), 7.42 (d, 1H), 7.16 (d, 2H), 4.47-4.31 (m, 5H), 2.26 (d, 2H), 1.89 (d, 2H), 1.45-1.41 (m, 2H), 1.24-1.09 (m, 3H), 0.88 (s, 9H)
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.Cl.[NH2:48][C@@H:49]([CH2:53][CH2:54][CH2:55][CH2:56][NH:57]C(OCC1C=CC=CC=1)=O)[C:50]([NH2:52])=[O:51].C(N1CCNCC1)C1C=CC=CC=1>>[NH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C@H:49]([NH:48][C:40]([CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:41])[C:50](=[O:51])[NH2:52]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCC(=O)N[C@@H](CCCCN)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([CH3:28])=[N:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cn1

Procedure:
The title compound, white solid (100 mg, 89%), MS (ISP) m/z=450.4 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 6-methyl-nicotinic acid.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1)C1C=CC=CC=1>CCO.[Pd]>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1
Reactant: O=C(O)CCCc1cn(Cc2ccccc2)nn1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCc1c[nH]nn1
Reaction time: 72 h

Procedure:
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)butanoic acid (step 3) (5.34 g, 21.77 mmol) was dissolved in EtOH (435 ml) and re-circulated through a 75 mm 10% Pd/C catalyst cartridge and hydrogenated using the H-Cube continuous flow hydrogenation at 60° C., 30 bar pressure for 72 hr. The reaction mixture was evaporated under reduced pressure to afford the title compound;
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][C:5]=2[CH:4]=1)[NH2:2].[CH3:22][C:23]([CH3:25])=O>>[C:23](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][C:5]=2[CH:4]=1)([CH3:25])[CH3:22]
Reactant: CCCCCCCC(=O)N1CCc2nnc(NN)cc2C1
Reactant: CC(C)=O
Product: CCCCCCCC(=O)N1CCc2nnc(NN=C(C)C)cc2C1
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g of crude semicrystalline 3-hydrazino-6-octanoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 50 cc of acetone is heated to the boil at reflux while stirring for 30 minutes. The title compound has a M.P. of 118°-121° (decomp., from light gasoline).