Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1.C[O-].[Li+].[N:23]#[C:24]Br>ClCCl>[CH3:19][N:3]([O:2][CH3:1])[C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:24]([NH2:23])[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7]=2[CH:6]=1)=[O:18]
Reactant: CON(C)C(=O)c1ccc(N)c(NC2CCCC2)c1
Reactant: N#CBr
Agent: C[O-]
Agent: [Li+]
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc(N)n(C3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Combine N-[methoxy]-N-[methyl]3-cyclopentylamino-4-aminobenzamide (1.79 g, 6.82 mmol) and lithium methoxide (0.27 g, 7.16 mmol) in anhydrous dichloromethane (25 mL) and stir for 20 minutes. Add a solution of cyanogen bromide (0.83 g, 7.84 mmol) anhydrous dichloromethane (8 mL) and stir overnight at room temperature under nitrogen. Concentrate under reduced pressure and partition the residue between ethyl acetate and water. Wash the organic layer sequentially saturated aqueous sodium bicarbonate (2×20 mL), saturated aqueous sodium chloride (2×20 mL), and water (2×20 mL). Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound as a dark solid (1.62 g, 82%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:25]=1
Reactant: COC(=O)CBr
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
Methyl bromoacetate (2.1 g) was added to a stirred mixture of N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)propylamine (3.87 g) and anhydrous potassium carbonate (5.73 g) in dry acetone (180 ml). The mixture was stirred and boiled under reflux for 7 hours, then left to stand at ambient temperature for 18 hours then hot filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica using ethyl acetate/triethylamine, 9 to 1 as the mobile phase. The product was obtained as an oil which was dissolved in ether, and extracted into 5M hydrochloric acid. The acid extracts were basified with 5M sodium hydroxide solution and the product extracted into ether to give methyl N-[2-(4-chlorophenoxy)ethyl]-N-[3-(imidazol-1-yl)propyl]glycinate as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(CN)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(C)(C)CO)cn1
Yield: 59 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of methylamine, to the title compound (235 mg, 59%) which was obtained as a white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:5](=[O:6])[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH2:16][CH3:17])=[C:3]1[NH:18][C@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([C:4]2[C:5](=[O:6])[C:2](=[O:1])[C:3]=2[NH:18][C@H:19]([CH3:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[C:25](=[O:27])[CH3:26])=[C:9]([CH2:16][CH3:17])[CH:10]=1)#[N:13]
Reactant: CCc1cc(C#N)ccc1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(C#N)ccc1N(C(C)=O)c1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Reaction time: 24 h

Procedure:
(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile (0.36 g, 1.11 mmol), acetic anhydride (0.31 mL, 3.29 mmol) and pyridine (3.4 mL) were mixed and allowed to stand at room temperature for 24 hours. The reaction mixture was filtered to remove undissolved solid material and the filtercake was rinsed with ethyl acetate. The combined filtrate was concentrated and the resulting solid was purified by recrystallization (EtOAc/CH2Cl2) and trituration (EtOAc) to afford the title compound as 0.29 g (71%) of a white solid: mp 229°-231° C.; [α]D25 -224.43° (DMSO, c 0.0092); 1H NMR (CDCl3): δ 7.72 (s, 1H), 7.64 (m, 1H), 7.54-7.40 (m, 1H), 7.38 (m, 1H), 4.37 (m, 1H), 2.72-2.53 (m, 2H), 1.92 (s, 3H), 1.32-1.23 (m, 6H), 0.99 (d, 9H). IR (KBr): 3450, 3340, 2970, 2240, 1800, 1725, 1680, 1610 cm-1 ; MS (m/z) 367 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[NH2:6].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[NH:6][C:26](=[O:27])[CH2:25][S:24][CH2:23][C:22]([O:21][CH3:20])=[O:29]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)CSCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CSCC(=O)Nc1cc(Cl)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
21.24 g (0.114 mol) of 4-chloroanthranilic acid methyl ester and 19.1 ml (0.137 mol) of triethylamine are placed in 180 ml of methylene chloride at 0°. A solution of 20.9 g (0.114 mol) of 2-(chloroformylmethylthio)-acetic acid methyl ester (T. Terasawa and T. Okada, J. Org. Chem., 42, 1163 (1977)) in 20 ml of methylene chloride is added dropwise thereto and the mixture is then stirred for 15 minutes at 0° and for 3 hours at room temperature. The reaction mixture is extracted with water and brine and the aqueous phases are washed with methylene chloride. The organic phases are combined, dried with sodium sulfate, filtered and concentrated. Chromatography of the crude product on silica gel with hexane/ethyl acetate (4:1) yields, in the form of yellowish crystals, 4-chloro-N-(methoxycarbonylmethylthio)acetylanthranilic acid methyl ester which is still impure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][Br:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(Cl)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr

Procedure:
To 13.0 g (84.92 mmol) 3-chloro-2-methylanisole in 80 ml CCl4 at reflux were added 0.4 g dibenzoyl peroxide and then, subsequently and portion-wise, a mixture of 15.2 g N-bromosuccinimide and 0.4 g dibenzoyl peroxide. After completion of reaction the mixture was evaporation-concentrated, the residue was dissolved in dichloromethane, was sequentially washed with water and saturated NaCl solution, was dried over MgSO4, was filtered and again evaporation-concentrated. 20.8 yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>C1COCC1>[OH:11][CH2:10][C@@H:9]1[CH2:13][CH:14]=[CH:15][CH2:16][C@@H:8]1[CH2:7][OH:12]
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C

Procedure:
To a 0° C. suspension of lithium aluminum hydride (4 eq) in dry THF (250 mL) was added portionwise phtalic anhydride over 20 minutes. The mixture was brought to room temperature then warmed to reflux for 6 hours then cooled to 0° C. The reaction was quenched with saturated sodium sulfate solution, filtered and concentrated. The residue was taken into ethyl acetate washed with water, brine, dried and concentrated to yield the desired compound as a viscous oil. 1HNMR (500 mHz, CDCl3): 5.62 ppm (s, 2H); 3.76-3.70 (m, 2H); 3.72-3.55 (m, 4H), 2.20-1.98 (m, 6H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18])(=[O:7])[CH3:6]>S(=O)(=O)(O)O>[C:5]([NH:8][C:9]1[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18])(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 60% nitric acid in sulfuric acid (410 mL) was added 4-acetamido-3-methylbenzoic acid (43 g, 0.22 mol) in small portions over 40 min while cooling with an ice bath. After addition of all amide was complete, the reaction mixture was stirred for 1 h at 0° C. and then very slowly poured over 1500 mL of ice. The yellow solid was collected by filtration and washed with ice cold water to give the title compound (38 g, 72% yield). 1H-NMR (CD3OD, 300 MHz) δ 8.29 (s, 1H), 8.18 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H). Mass spec.: 237 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH:20]=[O:21])=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].B>O1CCCC1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20][OH:21])=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2C=O)c(F)cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CO)c(F)cc1Cl
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 0.5 g of 2-chloro-4-fluoro-5-[4-formyl-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester in 50 ml of anhydrous tetrahydrofuran was added 4 mL of 1M borane in THF solution. The reaction was stirred overnight and then poured onto water, extracted into diethyl ether, dried over anhydrous magnesium sulfate and concd in vacuo to give 0.5 g of 2-chloro-4-fluoro-5-[4-(hydroxymethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester as a clear oil: 1HNMR (CDCl3) δ 8.10 (d, 1H J=7.7,), 7.36 (d, 1H, J=9.6), 5.29 (m, 1H), 4.62 (s, 2H), 4.10 (s, 3H), 1.42 (d, 6H, J=6.6); 19FNMR (CDCl3) ppm: -58.82, -109.09.
Reaction SMILES: [ClH:1].Cl.[F:3][CH:4]([F:32])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1.CN(C)C=O.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Br.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:1].[ClH:1].[F:32][CH:4]([F:3])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1
Reactant: CN(C)CCBr
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCNC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (75 mg) and N,N-dimethylformamide (1.5 mL) were added 2-(dimethylamino)ethyl bromide (26 mg) and potassium carbonate (85 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100, and subsequently chloroform:methanol=100:0-80:20). Desired fractions are combined and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (0.5 mL) and a 4 M solution (80 μL) of hydrogen chloride in 1,4-dioxane was added thereto. Diisopropyl ether (10 mL) was further added thereto. The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{(3S)-1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-6-morpholin-4-ylpyrimidin-2-amine dihydrochloride (10 mg) as a white powder.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:16][C:17]1[CH:21]=[C:20]([CH:22]2[CH2:24][CH2:23]2)[NH:19][N:18]=1>>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:1]3[N:2]=[C:6]([OH:7])[C:5]4[C:4]([CH:3]=3)=[CH:12][C:11]([O:13][CH3:14])=[C:10]([F:15])[CH:9]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1F
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(O)c2cc1F

Procedure:
Similar procedure as described in example 9B was used, starting from 2-Cyanomethyl-5-fluoro-4-methoxy-benzoic acid (1.75 g), 3-amino-5-cyclopropylpyrazol, to give 3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-7-fluoro-6-methoxy-isoquinolin-1-ol. LC-MS: m/e 315 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:23]2[CH:19]([O:20][CH:21]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22]2)[CH:18]([CH2:32]O)[O:17]1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:56][O:57][C:58]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:59]>C(#N)C.C(OCC)(=O)C>[CH3:56][O:57][C:58](=[O:59])[CH:60]=[CH:32][CH:18]1[CH:19]2[CH:23]([O:22][CH:21]([CH:24]=[CH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:20]2)[CH:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[O:17]1
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CO)C2OC(C=Cc3ccccc3)OC21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(C=CC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Reaction time: 2 h
Yield: 52 %

Procedure:
1-Ethyl-3-[9-(6-hydroxymethyl-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-urea (5.0 g, 11 mmol) was suspended in dry acetonitrile (50 mL) and Dess-Martin periodinate (6.7 g, 16 mmol) was added. The suspension was stirred 2 h, after which time proton NMR of an aliquot showed complete conversion to the aldehyde. (Methoxycarbonylmethylene)triphenylphosphorane (3.9 g, 12 mmol) was added and stirring was continued overnight. The reaction mixture was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate/thiosulfate solution (100 mL), dried with sodium sulfate and filtered. The filtrate was evaporated and the solid was dissolved in hot isopropyl alcohol (50 mL). It was allowed to cool, then heptane was added and it was stirred overnight. The resulting precipitate was washed with heptane and dried under vacuum, affording the desired product (2.9 g, 71%). 1H-NMR (300 MHz, d6DMSO) 1.15 (t, 3H, J=7 Hz), 3.21 (q, 2H, J=7 Hz), 3.59 (s, 3H), 4.98 (m, 1H), 5.28 (ψt, 1H, J=6 Hz), 5.51 (dd, 1H, J=6 Hz, <2 Hz), 5.70 (d, 1H, J=16 Hz), 5.90 (d, 1H, J=6 Hz), 6.30 (dd, 1H, J=6 Hz, 16 Hz), 6.45 (d, 1H, J=2 Hz), 6.95 (d, 1H, J=15 Hz), 7.35 (m, 3H), 7.45 (d, 2H, J=7 Hz), 8.50 (s, 1H), 8.60 (s, 1H), 9.30 (t, 1H, J=6 Hz), 9.60 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:15]1[N:7]([CH:6]([CH3:8])[C:5]([O:4][CH2:2][CH3:3])=[O:9])[C:11]([CH3:13])=[CH:10][CH:14]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)[C@H](C)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)n1c(C)ccc1C
Yield: 59 %

Procedure:
Alanine ethyl ester hydrochloride (30.8g; 0.2 mole) was dissolved in 100 ml of acetic acid. Acetonylacetone (22.8 g; 0.2 mole) and then 16.4 g (0.2 mole) of sodium acetate were added to the solution, and the mixture heated under reflux for 5 hours. The acetic acid was distilled off under reduced pressure, and ethyl acetate added to the residue. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 29.2 g of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (4/1) as an eluent to afford ethyl 2-(2,5-dimethylpyrrol-1-yl)propionate (23.0 g, 0.118 mole, 59.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl(O)(=O)(=O)=O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[CH:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(N)C(CCCCC(=O)N2CCCCC2)SC1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C1=C(NC(C)=O)C(CCCCC(=O)N2CCCCC2)SC1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 7.4 g (.0226 mole) of 3-amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide in 50 ml of acetic anhydride was added dropwise 1 ml of perchloric acid. The reaction was stirred for 1.5 hrs. and then was worked up. Acetic anhydride was removed under vacuum. The residue was partitioned between 50 ml of 10% by weight aqueous sodium bicarbonate solution and 150 ml of methylene chloride. The basic, aqueous phase was extracted three times with 30 ml portions of methylene chloride. The methylene chloride phase was dried over sodium sulfate, filtered, and evaporated to yield 8.2 g (0.022 mole, 100%) of 3-acetamido-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)ccc1F
Temperature: 120 °C
Yield: 96.9 %

Procedure:
A mixture of 4-Fluoro-3-methoxy-benzaldehyde (6.16 g, 40 mmol), and malonic acid (6.24 g, 60 mmol) in pyridine (30 ml) and piperidine (1 ml) was heated at 120° C. for 2 hrs. The mixture was cooled to room temperature and neutralized with concentrated HCl to PH<3, the white solid was collected and dried to give 7.6 g of product (97% yield). LC-MS: m/e 195 (M−1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 114.4 %

Procedure:
A mixture of (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (1.0 g) and 10% Pd/C (150 mg) in MeOH (30 ml) was shaken under a hydrogen atmosphere at ambient temperature for 10 hours, then filtered through a plug of Celite and reduced in vacuo to give (3,4-diamino-phenyl)-morpholin-4-yl-methanone (900 mg). (1H NMR (300 MHz, DMSO-d6) δ 6.6 (s, 1H), 6.5 (s, 2H), 4.8 (s, 1.5H), 4.6 (s, 1.5H), 4.1 (s, 1H), 3.6 (m, 4H), 3.4 (m, 4H)).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: CCO
Product: NNc1nc(N)c2ccccc2n1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
A mixture of 2-chloroquinazolin-4-amine (Example 38) (100 mg, 0.56 mmol) and hydrazine (0.09 mL, 2.79 mmol) in ethanol (5 mL) was heated in a sealed tube at 80° C. overnight. After the reaction mixture was cooled down, the resulting precipitate was collected by filtration, rinsed with ethanol and dried in the air to give the title compound (84 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 4.2 (bs, 2H), 4.6 (bs, 2H), 7.0 (t, J=7.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.61 (s, 1H), 7.87 (d, J=7.6 Hz, 1H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][NH:6]C(=C1C(=O)CC(C)(C)CC1=O)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CC(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NCCC[C@H](N)C(=O)O

Procedure:
Fmoc-Orn(Dde)-OH (386 mg, 0.744 mmol, 4 equiv.), HOBt (114 mg, 0.744 mmol, 4 equiv.) and HBTU (282 mg, 0.744 mmol, 4 equiv.) were dissolved in 2.3 ml DMF. This mixture was let stand at room temperature for 10 min before 0.4 M N-methylmorpholine (in DMF) (3.7 ml, 1.488 mmol, 8 equiv.) was added to it. The resin was treated with this new mixture with gentle rocking for ˜3 h. After the solution was filtered away, the resin was washed three times with DMF (5 ml each time).
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:15]=2)[N:13]=1)[NH:3][CH2:4][CH2:5][O:6][CH3:7].Cl.O1CCOCC1>CO>[NH2:1][C:2](=[N:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH:15]=2)[N:13]=1)[NH:3][CH2:4][CH2:5][O:6][CH3:7]
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CNC(=O)OC(C)(C)C)c2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CN)c2)cs1
Yield: 63.8 %

Procedure:
A solution of 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-t-butoxycarbonylaminoacetylaminomethylphenyl)thiazole (1.6 g) and 4N-hydrogen chloride/dioxane (10 ml) in methanol (10 ml) was stirred at room temperature for 2.5 hours. The resulting precipitate was collected by filtration and then dissolved in water (50 ml). The mixture was alkalized to pH 10 with a 30% aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-aminoacetylaminomethylphenyl)thiazole (0.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: COc1ccccc1
Product: COc1ccc(S(=O)(=O)c2ccc(Br)cc2F)cc1

Procedure:
The subtitle compound was prepared by the method of example 9 step (i) using 4-bromo-2-fluorobenzenesulfonyl chloride and anisole.