Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][CH2:27][CH:26]([O:25][CH3:24])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COC(C)CCN
Product: COC(C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxybutan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (d, J=6.32 Hz, 3 H) 1.52-1.70 (m, 2 H) 3.17 (s, 3 H) 3.26-3.36 (m, 3 H) 7.72 (d, J=8.59 Hz, 2 H) 8.07 (d, J=6.57 Hz, 2 H) 8.27-8.50 (m, 2H) 8.61 (t, J=5.43 Hz, 2 H) 8.76-8.96 (m, 1 H) 13.46 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Reaction SMILES: [CH2:1]1[O:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([NH2:15])[CH2:12][CH2:13][NH2:14]>CO>[CH2:11]([NH:15][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][NH:14][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NCCCN
Reactant: CCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCC(O)CNCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-nonene oxide (120 g.) and 1,3-propanediamine (31.2 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,3-propylene)-bis[2-hydroxynonylamine] (I: R = CH3 (CH2)6, R' = H, X = (CH2)3, Z = H) (13.2 g., m.p. 107.0°-109.0° C.).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)=[O:7])([CH3:4])[CH3:3].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[C:25]1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH3:1][C:2]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:25]2[N:24]([CH3:23])[C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH:14]=1)=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A flask is charged with 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-bromo-pyridine (1.12 g, 3.0 mmol), N-methyl-6-chloroindole-2-boronic acid (754 mg, 3.6 mmol), finely crushed potassium phosphate (1.27 g, 6.0 mmol) and DMF (20 mL). After degassing for 15 min, Pd(PPh3)4 (173 mg, 0.15 mmol) is added. The flask is flushed with nitrogen and the mixture is heated to 90° C. and stirred for 5 h. The mixture is then cooled to room temperature and poured into water (100 mL). The mixture is extracted with EtOAc three times and the combined organic phase is washed with water (10 mL) twice. The organic phase is then dried over Na2SO4 and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:9) to give 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine. MS (ESI) m/z 458.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:13][CH:12]=1
Reactant: CO
Reactant: Nc1ccc(OCC(=O)O)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N)cc1
Yield: 58.5 %

Procedure:
To a mixture of (4-Aminophenoxy)acetic acid HCl 14 (250 g, 1.228 mol), in methanol (5 L) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 10 hours. Methanol (3.5 liters) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 15 was filtered, dried and recrystallised from a mixture of chloroform:hexane (1:5) to give pure 15 (130 g, 58.5%) as a light brown powder. The melting point was found to be 65-66.8° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(OC(C)(C)C)=O)[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc4c(c3)OCO4)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(O)c2)cc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-(tert-butoxycarbonyloxy)phenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-hydroxyphenyl)benzoic acid 17 mg of a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([O:16]CC)=[O:15])([O-:3])=[O:2].[OH-].[Li+]>C(#N)C.O>[N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (4.30 g, 17.0 mmol) and lithium hydroxide (2.86 g, 68 mmol) in acetonitrile (20 mL) and water (20 mL) was stirred at room temperature for 6 h. The acetonitrile was then removed, and the resulting mixture was extracted with EtOAc (100 mL×2). The extracts were combined and dried, and the solvent removed. The crude product was used in the next step without further purification. ESI MS: m/z 226 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:9]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(O)c(C(=O)Nc2ccc(C)c(C(F)(F)F)c2)c1
Yield: 63.7 %

Procedure:
Using 5-methylsalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH2:2])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: N=C1CCCCC(Cc2ccccc2[N+](=O)[O-])N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(Cc2ccccc2N)N1
Yield: 155.9 %

Procedure:
The product of Example 270 (0.150 g, 0.59 mmol) was dissolved in ethanol and treated with 5% Palladium on Carbon under 5 psi of Hydrogen to give the title product (141 mg, 0.46 mmol).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 15), 401 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](F)=[O:5].C[Si](C)(C)[O-:23].[Na+:26]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O-:23])=[O:5].[Na+:26]
Reactant: CCCCCCCCC(C(=O)F)(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCC(C(=O)[O-])(C(F)(F)F)C(F)(F)F

Procedure:
The procedure of Example 1 was followed using 2,2-bis(trifluoromethyl)decanoyl fluoride (6.11 g, 19.7 mmol), sodium trimethylsilanolate (2.21 g, 19.7 mmol) and dry ether (20 mL). The product, sodium 2,2-bis(trifluoromethyl)decanoate, was isolated as a waxy solid (5.5 g, 85% yield) by concentrating the filtrate under vacuum: 1H NMR (CDCl3) δ 0.88 (m, CH3, 3H), 1.30 (m, CH2, 12H), 2.10 ppm (m, CH2, 2H); 19F NMR (D2O/acetone) δ -62.0 ppm (brs, CF3,6F). Anal. Calcd. for C12H17F6NaO2 : C, 43.64; H, 5.19; F, 34.52. Found: C, 44.34; H, 5.10; F, 35.58.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=1)=[CH:13][C:12]([O:18]C)=[CH:11][CH:10]=4.Cl>>[CH:20]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[C:3]([OH:2])[CH:21]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4
Reactant: COc1ccc2c(c1)SCc1c-2[nH]c2ccc(OC)cc12
Agent: Cl
Product: Oc1ccc2c(c1)SCc1c-2[nH]c2ccc(O)cc12

Procedure:
A mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (805 mg, 2.69 mmol) and Py.HCl (3.11 g, 26.9 mmol, 10 eq.) was heated to 210° C. for 30 minutes. The reaction mixture was then partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2: MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][NH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: N
Product: NCC1(c2ccc(F)cc2)CCCCC1
Yield: 99 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)-cyclohexane-carboxylic acid and ammonia using General Procedure G, followed by General Procedure E in 99% yield as a clear oil. LCMS Rt=6.76 min, m/z=208 (M+1). 1H NMR (CDCl3, δ): 7.24 (ddd, J=3.2, 5.4, 12.2 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 2.67 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79(bs, 2H). 13C NMR (CDCl3, δ, mult): 162.1(0), 159.7(0), 140.3(0), 128.7(1), 128.6(1), 115.1(1), 114.9(1), 54.8(2), 43.2(0), 33.8(2), 26.6(2), 22.1(2).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[OH-].[Na+].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=O.[Na+]>CCO>[S:4]1[C:3]2[C:2](=[N:1][C:12]([C:11]([OH:16])=[O:15])=[CH:14][CH:7]=2)[CH:6]=[CH:5]1
Reactant: Nc1ccsc1C=O
Reactant: CC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2sccc2n1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To a solution of 3-amino-2-formylthiophene (10 g, 78 mmol) in EtOH (50 mL) was added a mixture of aqueous NaOH (50 mL, 5%) and sodium pyruvate (17.16 g, 156 mmol). The mixture was heated to 60° C. for 2 hr. The mixture was cooled and washed with Et2O: EtOAc 1:1 and then acidified with 1N HCl to pH 3 at 0° C. The mixture was filtered and the solid was air dried to give 10 g (71%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:15][CH:16]([F:28])[O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[F:28][CH:16]([F:15])[O:17][C:18]1[CH:19]=[C:20]([S:24]([NH:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: CN1CCN(c2cc(N)ccn2)CC1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Solvent: c1ccncc1
Product: CN1CCN(c2cc(NS(=O)(=O)c3cccc(OC(F)F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of 200 mg of 2-(4-methyl-piperazin-1-yl)-4-amino-pyridin (1.04 mmol) in 5 ml of pyridine 272 mg of (1.12 mmol) of 3-difluoromethoxybenzene sulfonylchloride (1.66 mmol) were added and the reaction mixture was stirred for 15 h at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. This mixture was washed with aqueous NaHCO3. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography with ethyl dichloromethane/methanol (0-15%) as eluent, yielding 231 mg of the purified product.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[O:9]=[C:10]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH2:11]1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[O:9]=[C:10]1[CH2:13][CH:12]([C:14]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:15])[CH2:11]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)ON2C(=O)CCC2=O)C1
Temperature: 16 °C
Reaction time: 2 h

Procedure:
Into a 5 L reactor equipped with a nitrogen flow and an overhead stirrer was added N-hydroxysuccinimide (250.0 g, 2.172 mol) and 3-oxo-cyclobutanecarboxylic acid (248 g, 2.17 mol). Ethyl acetate (3.4 L) was added and the reaction was cooled to 16° C. A solution of 25% DCC in EtOAc (2.17 mol) was added slowly via an addition funnel to the reaction mixture over 7 minutes then the mixture was then heated at 45° C. After 2 h, the mixture was filtered and the filtrate was washed once with EtOAc (1 L×1) and evaporated to dryness in vacuo to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 2.83 (bs, 4H), 3.30-3.39 (m, 2H), 3.52-3.60 (m, 2H) and 3.67-3.73 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 58% yield; NMR: 1.96 (m, 2H), 2.13 (s, 3H), 3.29 (m, 4H), 3.5 (m, 4H), 3.59 (m, 4H), 3.69 (m, 4H), 3.92 (s, 3H), 4.18 (m, 2H), 7.08 (m, 1H), 7.13 (s, 1H), 7.22 (s, 1H), 7.28 (m, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 7.81 (s, 1H), 8.27 (m, 2H), 9.39 (s, 1H), 10.29 (s, 1H); m/s: M+H+ 614.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH:15][CH3:16])=[O:14].CO.Cl.[O:26]([NH2:28])[CH3:27]>O>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:28][O:26][CH3:27])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1cc(C)ccc1C
Yield: 95.3 %

Procedure:
To 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-N-methyl-2-oxoacetamide (0.27 g, 0.9 mmol), added were methanol (2.0 ml) and methoxylamine hydrochloride (0.15 g, 1.8 mmol), and the reaction mixture was heated under reflux for 4 hours. After completion of the reaction, water (100 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl] -2-methoxyimino-N-methylacetamide (0.28 g; yield, 98.9%) as a mixture of E-form and Z-form.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate (0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.43 g, 1.5 mmol, from Example 108, Step 1) and DIPEA (0.53 mL, 3.0 mmol) in ethanol (6 mL) was heated at 100° C. overnight. The mixture was concentrated and purified on silica gel column (eluting with 0 to 100% EtOAc in hexanes) to give tert-butyl 3-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate. LCMS calculated for C28H38 ClN6O4 (M+H)+: m/z=557.3. found: 557.3. The Boc intermediate isolated was treated with trifluoroacetic acid (0.8 mL, 10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour. The mixture was stripped to dryness to give the desired product as TFA salt. 4 mg of the salt was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=[CH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH2:26][C:27](=[O:31])[NH:28]4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[N:3]=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:30]=[C:29]4[C:25]([CH2:26][C:27](=[O:31])[NH:28]4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCC(=Cc4ccc5c(c4)NC(=O)C5)CC3)cccc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)C5)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
6-{1-[2-(Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-1,3-dihydroindol-2-one (150 mg; 0.36 mmol) was dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml). Ammonium formate (229 mg; 3.6 mmol) was added, followed by 10% palladium on carbon (150 mg), and the resulting mixture stirred vigorously at ambient temperature for 2 h. The reaction mixture was filtered through Kieselguhr and the filtrate evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with 10% aq. ammoniacal methanol in dichloromethane (5:95), gave the title compound (150 mg; 100%) as a white foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P([N:73]=[N+:74]=[N-:75])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:73]([CH2:24][C:22]1[CH:21]=[CH:20][C:19]2[N:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH:10]=3)[CH:16]=[N:17][C:18]=2[CH:23]=1)=[N+:74]=[N-:75]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(COCc2nccs2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc2c(c1)ncn2-c1cccc(COCc2nccs2)c1
Reaction time: 2 h

Procedure:
To a mixture of 10g (0.1 g; 0.28 mmol) and PPh3 (0.11 g; 0.43 mmol) in THF (3 ml) was added DIAD (0.09 g; 0.43 mmol) at 0° C. After 5 min. diphenylphosphorylazide (0.12 g; 0.43 mmol) was added and the mixture was allowed to reach room temperature. Stirring was continued for 2 hours. The solvent was removed by evaporation and the residue was eluted through silica gel with a mixture of dichloromethane and methanol (50:1 v/v) to afford 25g. LC-ESI-HRMS of [M+H]+ shows 377.1188 Da. Calc. 377.118455 Da, dev. 0.9 ppm In analogy herewith the following compounds were prepared 5-Azidomethyl-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole (25c) from 10c. LC-ESI-HRMS of [M+H]+ shows 375.1671 Da. Calc. 375.168182 Da, dev. −2.9 ppm 5-Azidomethyl-1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole (25e) from 10e. LC-ESI-HRMS of [M+H]+ shows 374.1732 Da. Calc. 374.172925 Da, dev. 0.7 ppm
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([NH:31][C:32](=[O:34])[CH3:33])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:32]([NH:31][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=1)[C:6]([OH:35])=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O

Procedure:
A solution of (S)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid tert-butyl ester (100 mg) in TFA/methylene chloride (1:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure to give the title compound.