Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][O:29][S:47]([C:44]2[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:46][CH:45]=2)(=[O:48])=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C1CN2CCN1CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.8 %

Procedure:
To a stirred solution of 2-[3-(tritylamino)phenyl]ethanol (5.00 g, 13.2 mmol) and triethylenediamine (2.22 g, 19.8 mmol) in DCM (52.7 mL) under nitrogen at 0° C. was added portion-wise p-nitrobenzenesulfonyl chloride (3.50 g, 15.8 mmol) over a period of 5 min. The resulting mixture stirred at 0° C. for 40 min and then saturated aqueous sodium bicarbonate solution (˜50 mL) was added. The mixture was stirred at room temperature for 10 min and then the layers were separated. The aqueous layer was extracted with DCM (2×˜50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (7.44 g, 100% yield) as an orange-yellow foamy solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]=[CH2:4].C([Li])CCC.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=[CH:2][CH2:3][CH3:4])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a stream of argon, 2.9 g (7.5 mmol) of allyltriphenylphosphonium bromide was suspended in 10 ml of anhydrous tetrahydrofurane, and thereto 4.3 ml of butyllithium was added dropwise under cooling with ice. After stirring the mixture at room temperature for 30 minutes, thereto was added dropwise a solution of 1 g (5.3 mmol) of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was stirred at room temperature for 15 hours. The reaction solution was filtrated, and ethyl acetate and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 40 g of silica gel and eluted with ethyl acetate-hexane (1:1 to 1:3) to obtain 200 mg of 1-benzyl-4-propylidenepiperidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[N:7]=2)[CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(N)n2)C1

Procedure:
[1-(6-amino-5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was synthesized from 6-chloro-3-nitro-pyridine-2-yl-amine by using the procedure as described in step 1 in Example 160 with the only change being pyrrolidin-3-yl-carbamic acid tert-butyl ester was used as the amine. The intermediate A had following spectral properties.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2)=[O:4].[CH:16]12[N:23]([C:24]([O-:26])=[O:25])[CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2>>[O:15]=[C:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][C:3]([CH2:2][N:18]2[CH2:19][CH:20]3[N:23]([C:24]([O:26][C:7]([CH3:11])([CH3:8])[CH3:6])=[O:25])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[O:4])[NH:10]1
Reactant: O=C([O-])N1C2CCC1CNC2
Reactant: O=C(CCl)Nc1cccc2c1CC(=O)N2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CC(=O)Nc1cccc3c1CC(=O)N3)C2

Procedure:
The subtitle compound was prepared from the product of step (i) (0.24 g) and 1,1-dimethyl, 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.26 g) by the method of Example 19 step (i) Yield: 0.8 g
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 75.1 %

Procedure:
69 mg of 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde was weighed into a 20 mL reaction vial fitted with a stir bar and cap. Added 2 mL of CH2Cl2 and 2 mL MeOH and stirred to obtain a clear amber solution. Added 14 mg of sodium borohydride. Stirred at room temperature for 3 hr. Quenched with 5 mL of saturated aqueous NH4Cl. Separated phases and extracted the aqueous phase with 2×2 mL CH2Cl2. Washed the combined organic phases with 5 mL of saturated aqueous NaHCO3. Dried over Na2SO4 and removed the solvent on rotavap. Crystallized the residue from isopropyl acetate to obtain 52 mg of the title compound as a white solid. MS (ESI) 639 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=1[CH2:9][NH:10][C:11]([C:13]1[CH:26]=[CH:25][C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:27]([CH3:34])[CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:15]=2[CH:14]=1)=[O:12].C(=O)([O-])O.[Na+].C(=O)=O>C(Cl)Cl>[OH:6][C:7]1[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=1[CH2:9][NH:10][C:11]([C:13]1[CH:26]=[CH:25][C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:27]([CH3:34])[CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[C:15]=2[CH:14]=1)=[O:12]
Reactant: COc1ccccc1CNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3ccccc3O)cc21
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
A solution of boron tribromide (5.01 g) in methylene chloride (100 cc) is added dropwise and with stirring during 15 minutes to a solution, cooled to -50° C., of N-(2-methoxybenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (4.74 g) in methylene chloride (100 cc). Stirring is maintained at -50° C. for 45 minutes and then at 20° C. for 48 hours. Saturated aqueous sodium hydrogen carbonate solution (120 cc) is then added cautiously. After stirring until the evolution of carbon dioxide has ceased, the organic phase is separated, washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The yellow meringue-like residue is purified by chromatography on a column (height: 48 cm; diameter: 2.4 cm) of silica gel (0.06-0.2 mm), eluting with ethyl acetate (2 liters) and collecting 100-cc fractions. Fractions 4 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The yellow meringue-like residue (2.84 g) is purified by chromatography on a column (height: 33 cm; diameter: 2.4 cm) of silica gel (0.06-0.2 mm), eluting successively with a mixture (50:50 by volume) (250 cc) of cyclohexane and ethyl acetate, then with a mixture (25:75 by volume) (500 cc) of cyclohexane and ethyl acetate and then with ethyl acetate (500 cc) and collecting 60-cc fractions. Fractions 7 to 18 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-(2-hydroxybenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.9 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][NH2:41]>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][NH:41][CH3:40])[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Reactant: CN
Solvent: CCO
Product: CNCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 16 %

Procedure:
A solution of 120 mg (0.2 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 4 ml of 40% methylamine in ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material purified by flash column chromatography on silica gel eluting with dichloromethane/methanol/acetic acid/water (120:14:3:2). Product containing fractions were combined and evaporated to give 18 mg (16%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-[2-(methylamino)ethyl]phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a solid of melting point 120-122° C. [Mass spectrum (ESI) MH+ =519].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[Li][CH2:21]CCC.IC>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[C:14]([CH3:21])[S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)O)s1
Temperature: 25 °C

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarboxylic acid (6 g, 18.60 mmol) in anhydrous tetrahydrofuran (240 mL) at −78° C. and under nitrogen was added nBuLi (2.5 M in hexane, 30 mL, 74.4 mmol). The mixture was stirred at this temperature for 2 h before the addition of iodomethane (6.6 g, 74.4 mmol). The mixture was then poured into crushed ice and then allowed to warm to room temperature. After acidification with concentrated HCl to pH ˜1, the mixture was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried (MgSO4), the solids were filtered and the filtrate was concentrated to give N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid and the starting material in about a 2:1 ratio (8.5 g combined weight).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[C:21]([O:23]CC)=[O:22])[CH:16]=[CH:17][CH:18]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8]>[OH-].[Na+]>[CH3:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH:16]=[CH:17][CH:18]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8]
Reactant: CCCCN(C(=O)C(=O)OCC)c1cccc(NC(=O)C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCN(C(=O)C(=O)O)c1cccc(NC(=O)C(=O)O)c1

Procedure:
Diethyl 4-butyl-N,N'-(m-phenylene)dioxamate (1.0 gm., 2.74 mmoles) is stirred at room temperature in 1.0 N NaOH (10 ml.) until the solution is complete. The solution is adjusted to pH 3 and the resulting white solid collected (0.5 gm., mp. 232°).
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:17][CH3:18])[C:6]=2[CH2:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:7]1[C:6]2[CH2:5][NH:4][CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:18]
Reactant: CCn1c2c(c3ccccc31)CCN(C(C)=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCn1c2c(c3ccccc31)CCNC2

Procedure:
A portion of the crude 2-acetyl-9-ethyl-1,2,3,4-tetrahydro-β-carboline (1.7 was heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water (2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-ethyl-1,2,3,4-tetrahydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-ethyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 55.3 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Chloro-4-morpholin-4-yl-benzaldehyde (42.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 46.98 mg (45%) of the title compound. (300 MHz, DMSO-d6) 12.89 (s, 1H), 7.95 (s, 1H), 7.72 (m, 2H), 7.21 (s, 1H), 7.09 (m, 3H), 6.30 (s, 2H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 3.75 (s, 4H), 3.27 (s, 4H), 2.87 (s, 1H), 2.78 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz). MS=499 (M+H), HPLC: 2.47 min. (G Method).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[CH2:17][CH3:18]>O>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[N:2][OH:3])[CH2:17][CH3:18]
Reactant: NO
Reactant: CCC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Hydroxylamine hydrochloride (3.2 g, 46.3 mmol) and sodium acetate (3.8 g, 46.3 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Thiophen-2-yl)propan-1-one (5.9 g, 42.1 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (20 mL) was added and the product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 6.3 g of the title compound. MS: (+) m/z 156.32 (M+1).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][CH2:34][O:35][CH3:36])[C:29](O)=[O:30])=[CH:23][CH:22]=1)[CH3:17]>ClCCl>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][CH2:34][O:35][CH3:36])[C:29]([Cl:4])=[O:30])=[CH:23][CH:22]=1)[CH3:17]
Reactant: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (92 mg) was added to (±)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoic acid (100 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 16 hours and evaporated to dryness to give the title compound as a gum which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])C(C)C.BrC1C=C2C(CN(CC(OC)=O)C2=O)=CC=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:16][N:8]1[CH2:4][C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 333 was prepared analogous to compound of example 330 by reaction of the compound of example 332, compound of example 327 and Pd(dppf)Cl2: CH2Cl2. The compound of example 333 was used directly without isolation for the preparation of compound of example 334.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[C@@H:15]([CH2:29][CH2:30][S:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1>Br.C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][C@@H:15]([CH2:29][CH2:30][S:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CSCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSCC[C@@H]1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
1-(4-Amino-quinazolin-7-ylmethyl)-4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (100 mg, 0.215 mmol) is dissolved in 5 ml of 30% hydrogen bromide in acetic acid. The mixture is stirred for 1 hour, diluted with ethyle ether. The ether is decanted and the resulting solid is washed thoroughly with ethyle ether. The resulting crude product is purified by column chromatography eluting with a 4/2/1 mixture of CH2Cl2/MeOH/NH4OH (30% in H2O). with a gradient of 5% MeOH:CH2Cl2 to 10% MeOH:CH2Cl2. The resulting product is purified by another column chromatography eluting with a gradient of 20% MeOH:CH2Cl2 to 50% MeOH:CH2Cl2. The title bound (30 mg, 42% yield) is obtained as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]([CH2:32][CH3:33])[CH:4]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]=[C:15]([NH:17][C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:19])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:34])[CH:3]([CH2:32][CH3:33])[CH:4]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]=[C:15]([NH:17][C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:19])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate (15 mg, 0.031 mmol) and lithium hydroxide (6.6 mg, 0.157 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 50° C. for 4 h. The reaction was evaporated, water was added and neutralized to pH 7. The slurry obtained was evaporated and extracted with DCM-methanol mixture and evaporated. The crude acid was purified by PTLC using DCM-methanol mixture as eluent to afford 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoic acid. MS ESI: m/462.11 [M−1−].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:35])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc(C)cc2C)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1ccc(Cc2sc3ncccc3c2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1
Yield: 72.6 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(2,4-dimethylbenzyl)thieno[2,3-b]pyridine-3-sulfonamide (87 mg, 0.16 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from chloroform/hexane provided 52 mg (72%) of the title compound as a white crystalline solid, m.p. 123-125° C.
Reaction SMILES: [F:1][C:2]([F:24])([O:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=1[N+:21]([O-])=O)[C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4]>CO.[Pd]>[F:24][C:2]([F:1])([O:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:12]=1[NH2:21])[C:3]([N:5]([CH2:6][CH3:7])[CH2:8][CH3:9])=[O:4]
Reactant: CCN(CC)C(=O)C(F)(F)Oc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)C(F)(F)Oc1cc(F)c(N)cc1N
Yield: 86 %

Procedure:
A solution of 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-N,N-diethyl-acetamide (13.5 g, 38.4 mmol) and Pd/C (10% Pd, dry catalyst, 2.0 g, 1.9 mmol) in MeOH (395) was stirred under an atmosphere of hydrogen (pressure of 0.1 bar) at 50° C. for 2 h. After completion of the reaction the pressure was released, the catalyst was filtered off and the filtrate was evaporated to dryness. The product was purified by column chromatography (SiO2, cyclohexane/EtOAc mixtures). The product was obtained as an off-white solid (11.0 g, 88% pure by NMR, 33.2 mmol, 86% yield).