Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C1C[O:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[C:31]([N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1)(=[O:32])[CH3:30]
Reactant: C1CCOC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 20 mg, 0.046 mmol) in THF (460 μL, 0.046 mmol) was added triethylamine (19 μL, 0.14 mmol) and acetic anhydride (5.7 mg, 0.056 mmol). After stirring at ambient temperature for 30 minutes, the reaction mixture was diluted in water. The reaction mixture was directly purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to afford 2-(1-acetyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (15 mg, 0.038 mmol, 82% yield) as a fluffy white solid. MS (apci) m/z=402.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH2:30][NH2:31])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH2:30][C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:21][N:20]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ncc1OCCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (120 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (130 mg, 0.48 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine hydrochloride (130 mg, 0.48 mmol, Amine-58) in a similar manner to Intermediate-2.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:18]1[CH:19]=[C:14]([N:8]2[CH2:13][CH2:12][N:11]([C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[N:23]=[C:22]([C:21]([F:36])([F:20])[F:37])[O:26][N:25]=4)[CH:28]=3)=[O:31])[CH2:10][CH2:9]2)[CH:15]=[N:16][CH:17]=1
Reactant: c1ncc(N2CCNCC2)cn1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2cncnc2)CC1
Yield: 32 %

Procedure:
This compound was synthesized from 5-(piperazin-1-yl)pyrimidine TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 32%). 1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.52 (s, 2H), 8.29-8.26 (dt, J=6.7 Hz, 1.9 Hz, 1H), 8.23 (m, 1H), 7.76-7.71 (m, 2H), 3.99-3.83 (m, 2H), 3.69 (m, 2H), 3.49 (m, 2H), 3.44-3.36 (m, 2H). MS (ESI) m/z: Calculated for C18H15F3N6O2: 404.12. found: 405.2 (M+H)+
Reaction SMILES: Cl[P:2]1([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[N:7]=[P:6](Cl)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[N:5]=[P:4](Cl)([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[N:3]=1.ClP1(Cl)N=P(Cl)(Cl)N=P(Cl)(Cl)N=1.[C:46]1([OH:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1>[O:52]([P:2]1([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[N:7]=[P:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[N:5]=[P:4]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[N:3]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Nc1ccccc1OP1(Cl)=NP(Cl)(Oc2ccccc2N)=NP(Cl)(Oc2ccccc2N)=N1
Reactant: Oc1ccccc1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1OP1(Oc2ccccc2)=NP(Oc2ccccc2)(Oc2ccccc2N)=NP(Oc2ccccc2)(Oc2ccccc2N)=N1

Procedure:
The procedure of Example 6 was used, with a sample of trichloro-tris(aminophenoxy)cyclotriphosphazene, prepared as in Example 4, as the starting phosphazene reagent. The reagent amounts were: hexachlorocyclotriphosphazene, 0.05 mole; phenol, 0.21 mole; sodium hydride, 0.22 mole. The product was isolated as an amber oil, which contained traces of THF.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[NH2:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[CH:14]=1>>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[C:22]([O:23][CH3:24])=[CH:21][C:16]4[NH:17][C:18](=[O:20])[S:19][C:15]=4[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: Clc1ncnc2[nH]c(Br)cc12
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]c(Br)cc12

Procedure:
25 mg (108 μmol) 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 784150-41-0) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 11.8 mg (27%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:9]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=2)=[O:10])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCCN(c2ccncc2NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of 3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-bromopyrazine-2-carboxamide in CH2Cl2 at a concentration of 0.5 M at room temperature was added triethylamine (3 eq) followed by acetic anhydride (1.2 eq). The reaction was stirred at room temperature for 30 minutes, concentrated, purified by reverse phase HPLC and lyophilized to provide N-(4-(3-acetamidopiperidin-1-yl)pyridin-3-yl)-3-amino-6-bromopyrazine-2-carboxamide, as the TFA salt. LCMS (m/z): 434.1 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(F)cc1
Yield: 9.7 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.00 g, 2.92 mmol) in 20 mL of dichloromethane and 4-fluoroaniline (0,657 g, 5.91 mmol) in 5 mL of pyridine. The crude product was triturated with hot ethanol-ethyl acetate mixture, filtered, and recrystallized from ethanol-DMF to yield 0.14 g of the title compound, mp 242°-244° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:14](=[O:15])[N:13]2[C:9](=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:20]([N:8]1[C:9]2=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[N:13]2[C:14](=[O:15])[C:6]([C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:5])=[CH:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O
Product: O=C(c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O)N1CCOCC1

Procedure:
By substituting 1-benzyl-1,4-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylic acid ethyl ester in part a and morpholine in part b of Example 33, 1-benzyl-3-(4-morpholinylcarbonyl)pyrimido[1,2-a]benzimidazole-4 (1H)one is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[C:8]([Cl:14])=[N:9][C:10](Cl)=[N:11][CH:12]=1.C(N(CC)CC)C.[Cl-:22].[NH4+]>C1COCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:10]1[N:11]=[C:12]([Cl:22])[CH:7]=[C:8]([Cl:14])[N:9]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)nc(-c2ncc[nH]2)n1
Reaction time: 16 h

Procedure:
Imidazole (9.5 g, 140 mmol) was added in one portion to a solution of trichloropyrimidine (24.7 g, 135 mmol) and triethylamine (30 mL, 216 mmol) in THF (500 mL). After 16 hrs, the reaction mixture was poured into saturated, aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The reaction mixture was filtered and all volatiles were removed under reduced pressure. 2-Imidazolyl-4,6-dichloropyrimidine (the compound of formula (VIIIa)) (9.61 g, 33%) was isolated by flash chromatography (20% ethyl acetate in hexane) as an off-white solid. 1H NMR: (CDCl3) δ 7.13 (s,1), 7.25 (s,1), 7.76 (s,1), 8.50 (s, 1).
Reaction SMILES: Cl.[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:22]1[N:42]=[CH:41][CH:40]=[CH:39][C:23]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25]>>[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:41]4[CH:40]=[CH:39][C:23]([C:24]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[O:25])=[CH:22][N:42]=4)[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: Cl
Product: O=C(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 350 was prepared as a light yellow solid (HCl salt) from compound 4 and compound 351 using chemistry similar to that described in example 200. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.06 (1 H, br. s.), 9.70 (1 H, s), 9.47 (1 H, s), 9.39 (2 H, br. s.), 8.67-8.75 (2 H, m), 8.51 (1 H, d, J=1.7 Hz), 8.37 (1 H, d, J=8.6 Hz), 8.02 (1H, dd, J=8.7, 2.3 Hz), 5.43 (1 H, dq, J=8.9, 8.8 Hz), 3.77 (4 H, br. s.), 3.18 (4 H, br. s.), 2.42-2.48 (2 H, m), 2.02-2.20 (4 H, m), 1.70-1.83 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 443.2.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16]>C(O)C>[O:12]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]1[CH2:5][C:4]([NH:15][NH2:16])=[O:3]
Reactant: NN
Reactant: CCOC(=O)Cn1ccccc1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1ccccc1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
As described for example 112a, (2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Begley, William J. et. al. Journal of the Chemical Society, Perkin Transactions 1 (1981), (9), 2620-4) in ethanol was reacted with hydrazine hydrate (1.1 equivalents) at 60° C. for 36 h. The mixture was cooled to rt and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 78%). MS: m/e=168.2 [M+H]+.
Reaction SMILES: [Li+].[OH-:2].[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#N)=[CH:6][CH:5]=1.C[OH:16]>O>[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]([OH:16])=[O:2])=[CH:6][CH:5]=1
Reactant: CC(C)(C#N)c1ccc(Br)nc1
Reactant: [OH-]
Reactant: CO
Agent: [Li+]
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(Br)nc1
Temperature: 85 °C
Yield: 96 %

Procedure:
To a solution of LiOH (252 mg, 10.5 mmol) in MeOH (15 mL) and water (5 mL) was added 2-(6-bromopyridin-3-yl)-2-methylpropanenitrile (example 40c) (800 mg, 3.5 mmol) and the reaction mixture was heated at 85° C. for 48 hrs. The methanol was evaporated and aqueous NaOH (1N, 10 mL) was added and the solution was washed with EtOAc, acidified with aq. HCl (6N) to pH˜4-5 and extracted with EtOAc. The organic layer was suuccessively washed with water and brine, dried over MgSO4, filtered and evaporated to give 700 mg (96%) of 2-(6-Bromopyridin-3-yl)-2-methylpropanoic acid (MS+H, 243.8).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27]>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[O:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(F)ccc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5 g) in THF (200 mL) at room temperature was treated with K2CO3 (19 g), followed by 2,5-difluorophenol (3.7 g). After stirring at room temperature for 18 hrs, the solid was filtered off and rinsed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated aqueous NaHCO3 solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residual was triturated with hexanes and collected by suction to furnish the desired product 21, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].CN(C=O)C>C(#N)C.O>[NH:31]1[C:1]([C:3]2[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]3[C:16]4[CH:23]=[N:22][N:21]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)[C:17]=4[CH:18]=[N:19][CH:20]=3)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=2)=[N:2][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C#N)c1
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(-c2nnn[nH]2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A sealed tube was charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide (75 mg, 0.19 mmol), sodium azide (37 mg, 0.58 mmol) and DMF (1 mL) and warmed at 120° C. After 16 hours, the reaction was diluted with a 4:1 mixture of acetonitrile in water, filtered and purified by reverse-phase chromatography. The desired fractions from the column were concentrated and dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:16][CH3:17])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18](OC(OCC)OCC)C>>[N:12]1([C@H:13]([CH2:16][CH3:17])[CH2:14][OH:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:18]1
Reactant: CCOC(OCC)OCC
Reactant: CC[C@H](CO)Nc1c(N)cnc2ccccc12
Product: CC[C@H](CO)n1cnc2cnc3ccccc3c21
Temperature: 145 °C

Procedure:
(2R)-2-[(3-Aminoquinolin-4-yl)amino]butan-1-ol (416.0 g, 1 eq.) and triethylorthoformate (1.2 L, 4 eq.) were combined and slowly heated to 145° C. Ethanol was distilled off as it formed during the reaction. After 500 mL of ethanol had been distilled off, the reaction mixture was allowed to cool to 50° C. under a nitrogen atmosphere. Excess triethyLorthoformate was removed under reduced pressure to provide crude (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([NH:6][NH:7]1)[CH:4]([OH:9])[CH2:3][CH:2]2[OH:10].O>C(O)C.[Ni]>[CH2:8]1[C@H:5]([NH2:6])[C@@H:4]([OH:9])[CH2:3][C@@H:2]([OH:10])[C@@H:1]1[NH2:7]
Reactant: OC1CC(O)C2CC1NN2
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: N[C@@H]1C[C@H](N)[C@@H](O)C[C@H]1O
Reaction time: 15 h
Yield: 88.8 %

Procedure:
6,7-Diaza-bicyclo[3.2.1]octane-2,4-diol (0.20 g) was dissolved in 20 ml. of a mixture of water and ethanol (1:1 by volume) to which was then added 0.2 g of Ranney nickel. The admixture was shaken for 15 hours under an atmosphere of hydrogen at a pressure of 3.4 kg/cm2 for the hydrogenation. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, giving a crystalline residue. This solid was dispersed in ethanol, removed by filtraton and then dried to afford 0.18 g of 2,5-dideoxystreptamine. Yield 91%. mp. 198°C. This substance was taken up into water, and to the resulting aqueous solution was added a slight excess of 1N hydrochloric acid. The mixture was concentrated by evaporation of the solvent, giving colorless platelets. Recrystallization of this product from water-ethanol gave 2,5-dideoxystreptamine dihydrochloride as colorless platelets of mp. 290°-295°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl[C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.Cl>C(O)CCC.CN(C=O)C.O1CCOCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[NH:28][C:27]5[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=5[N:25]=4)=[CH:20][CH:21]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3ccccc3[nH]2)cc1
Yield: 20.2 %

Procedure:
A solution of ethyl 4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (50.0 mg, 0.17 mmol) and 2-chlorobenzimidazole (30.2 mg, 0.17 mmol) in n-butanol (5 mL) and DMF (1 mL) were heated (90° C.) overnight in the presence of a trace amount of 4 M hydrogen chloride in dioxane. After cooling, the solution was concentrated under reduced pressure and the residue was purified by HPLC to afford the desired product (14.2 mg, 19%). 1H-NMR (300 MHz, DMSO-d6) 8.09 (s, 1H), 8.05 (br s, 1H), 7.89 (s, 1H), 7.79-7.85 (m, 2H), 7.24-7.34 (m, 4H), 6.89-6.99 (m, 2H), 5.14 (br, s, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.09 (t, J=7.1 Hz, 3H); ES-MS m/z 414.3 (MH)+; HPLC RT (Method A) 2.57 min.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].S(Cl)([Cl:12])=O.[CH3:14][CH2:15]O>>[ClH:12].[CH2:14]([O:8][C:7](=[O:9])[C@H:2]([C@H:3]([CH2:5][CH3:6])[CH3:4])[NH2:1])[CH3:15]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Product: CCOC(=O)[C@@H](N)[C@@H](C)CC
Product: Cl

Procedure:
L-isoleucine ethyl ester hydrochloride salt was prepared by the procedure in Example 1(B) utilizing L-isoleucine (5.0 g, 38.1 mmol), thionyl chloride (8.3 mL, 11.44 mmol) and EtOH (33.54 mL, 57.15 mmol). The ethyl ester 14t was obtained as a colorless oil (2.5 g, 14.91 mmol, 39%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N(CC)CC)C.[OH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:27]([C:26]1[C:25](=[O:24])[NH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: O=C(Cl)c1cccnc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a stirred solution of 4.0 g (0.016 mol) of L-alanyl-L-proline ethyl ester hydrochloride and 8 ml triethylamine in 200 ml dioxane, maintained at room temperature, a suspension of 3.0 g (0.019 mol) 2-hydroxynicotinoyl chloride in 200 ml anhydrous dioxane is added dropwise over 1 hour. After stirring for a further 3 hours at room temperature, the solvent is distilled off under reduced pressure. The crude product thus obtained is dissolved in 500 ml of chloroform and the solution washed twice with 100 ml of 5% aqueous sodium carbonate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is removed on a rotary evaporator. The solid crystallizes from methylene chloride/isopropyl ether to give 3.4 g of the title compound as a white microcrystalline solid (yield: 64%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>CO.O>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([C@H](C)N[S@](=O)C(C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc([C@H](C)N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide (2.90 g, 10.2 mmol) was dissolved in methanol (48 mL). A mixture of 12.0 M HCl in water (4.25 mL) and water (4.25 mL) was added drop wise over 3 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/triethylamine 90:5:5) on a short column to give (S)-1-(6-isopropoxy-pyridin-3-yl)ethylamine IM24 (1.71 g, 93%) as a pale-yellow oil sufficiently pure for the next step. The overall yield from 1-(6-isopropoxy-pyridin-3-yl)-ethanone IM16 was 54%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:9][C:8]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16]/[N:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][CH:24]=2)=[CH:9][C:8]=1[O:29][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([C:39]([F:38])([F:49])[F:50])=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCON=Cc2ccc(C(C)(C)C)cc2)cc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(OCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1OC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 4-[2-(4-tert-butyl-benzylideneaminooxy)-ethoxy]-2-hydroxy-benzoic acid tert-butyl ester (0.298 g, 0.72 mmol) in methylene chloride (10 mL) was added triethylamine (0.200 mL, 1.43 mmol) and 4-trifluoromethyl benzoyl chloride (0.200 mL, 1.42 mmol). The reaction was stirred at room temperature overnight, poured into brine and the aqueous layer extracted with ethyl acetate. The combined organics dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (8/92) to afford 4-{2-[({(E)-[4-(tert-butyl)phenyl]methylidene}amino)oxy]ethoxy}-2-{[4-(trifluoromethyl)benzoyl]oxy}benzoic acid tert-butyl ester (0.405 g, 96%) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.33 (d, 2H), 8.12 (s, 1H), 7.97 (d, 1H), 7.78 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 6.92 (dd, 1H), 6.76 (d, 1H), 4.50 (t, 2H), 4.33 (t, 2H), 1.40 (s, 9H), 1.30 (s, 9H).