Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](OC)=[O:19])=[CH:12][CH:11]=1>Cl>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: Cl
Product: O=C(CCc1ccc(O)cc1)NCc1ccccc1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
Add benzylamine (32.0 mL, 293 mmol) to methyl 3-(4-hydroxyphenyl)propionate (7.01 g, 38.9 mmol) and heat to 150° C. for 18 h under nitrogen. Cool to room temperature and pour the reaction mixture into 5 N hydrochloric acid (200 mL) and extract with ethyl acetate (3× 150 mL). Wash the ethyl acetate extracts with 5 N hydrochloric acid (200 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.74 g (98%) of N-benzyl-3-(4-hydroxy-phenyl)-propionamide: mass spectrum (ion spray): m/z=256.2 (M+1); 1H NMR (DMSO-d6): 9.15 (s, 1H), 8.28 (t, 1H), 7.39-6.96 (m, 7H), 6.66-6.63 (m, 2H), 4.23 (d, 2H), 2.72 (t, 2H), 2.37 (t, 2H).
Reaction SMILES: O1CCCC1.[N:6]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][NH:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:30]1[N:35]=[CH:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:32](=[O:44])[N:31]=1>O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:33]2[CH:34]=[N:35][C:30]([N:9]3[CH2:10][CH2:11][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:8]3[C:12]([O:14][CH3:15])=[O:13])=[N:31][C:32]2=[O:44])=[CH:38][CH:39]=1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncn(Cc2ccc(Cl)cc2)c(=O)n1
Yield: 43.1 %

Procedure:
To tetrahydrofuran solution (2.3 mL) of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (43 mg, 0.17 mmol), sodium carbonate (37 mg, 0.35 mmol) and 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (45 mg, 0.17 mmol) synthesized in Reference Synthesis Example 11 were added and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, water was added thereto and extraction with chloroform from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure and ethyl acetate was added to the obtained residue. The obtained solid was collected by filtration and dried under reduced pressure to obtain the title compound (34 mg, yield 42%).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:22][NH2:23]>C(O)(C)C>[NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]([NH:22][NH2:23])=[O:5]
Reactant: NN
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-amino-4,6-di(trifluoromethyl)-nicotinate (2.55 g., 8.45 mmole), 85% hydrazine hydrate (5 ml.) and isopropanol (5 ml.) is stirred in an oil-bath at 110° C. for 3 hours. On cooling, the dark red solution deposits colorless crystals which are filtered off and washed with a little isopropanol. A second crop of solid is obtained by evaporation of the mother liquors giving a total yield of 1.45 g. (59.6%) of product, m.p. 240°- 243° C. (dec.). Upon recrystallization from isopropanol (25 ml.) there is obtained 1.05 g. (42.8%) of product, m.p. 244°-245° C. (dec.).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][C:8]3=O)=[CH:3][CH:2]=1.[CH3:15][Li].[BH4-].[Na+].[ClH:19]>CCOCC.CO>[ClH:19].[CH3:15][CH:8]1[NH:9][CH2:10][CH:11]2[C:7]1([C:4]1[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=1)[CH2:12]2
Reactant: [Li]C
Reactant: Cc1ccc(C23CC2CNC3=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C23CC2CNC3C)cc1

Procedure:
Using the method of M. Takeda, et al., Chem. Pharm. Bull., 24, 2312 (1976), 1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one is reacted with methyllithium followed by sodium borohydride. Excess reagents are decomposed with methanol, followed by 1 N hydrochloric acid, and then 1 N sodium hydroxide and then evaporation of the solution gives a residue which is dissolved in ether. This solution is dried over sodium sulfate and filtered, and to the filtrate is added dry hydrogen chloride. Filtration of this suspension gives 2-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([C:25]1[C:24]([CH3:31])=[N:1][C:2]2[C:3]([C:21]=1[NH2:22])=[C:4]([O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9])[CH:18]=[CH:19][CH:20]=2)=[O:27])[CH3:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide (Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H), 1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H), 4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d, J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 8.09 (brs, 2H). MS 414 (MH+).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1.[CH:27]([OH:31])(CC)[CH3:28]>>[CH:3]1[CH:2]=[CH:9][C:8]2[O:31][CH2:27][CH2:28][C:6](=[O:7])[C:5]=2[CH:4]=1
Reactant: CCC(C)O
Reactant: O=Cc1ccc(I)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCNCC1
Product: O=C1CCOc2ccccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of protected hydroxyarylketone (1.0 equiv), 4-iodobenzaldehyde (1.0 equiv), piperidine (0.35 equiv), and DBU (0.35 equiv) in s-butanol (1.0 M) was heated at reflux. Using a Dean-Stark trap, half of the solvent was removed over 30-40 min, and the reaction was kept at reflux without further concentration for additional 4-8 h. The reaction mixture was cooled to 90° C., i-propanol (0.7-1.0 fold of s-butanol v/v) was added, and the reaction was allowed to cool to room temperature. Any large pieces of material were broken down with a spatula, and the suspension was stirred overnight (Note #1 & 2). The precipitate was collected by filtration to give the corresponding chromanone.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:3]=1)(=[O:12])=[O:11]
Reactant: OCCc1cn[nH]c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1cnn(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(1H-pyrazol-4-yl)ethanol (50 mg, 0.45 mmol) in dichloromethane (3 mL) at 0° C. was added methanesulfonyl chloride (0.104 mL, 1.39 mmol) followed by N,N-diisopropylethylamine (0.312 mL, 1.78 mmol) dropwise. The ice bath was removed and the mixture warmed to ambient temperature and stirred for 1 h. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel Biotage 25S) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give the title compound as a colorless solid. LC/MS 269.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].[CH2:11]([O:13][C:14](=[O:24])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[CH2:16])[CH3:12]>C1COCC1>[CH2:11]([O:13][C:14](=[O:24])[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=1)[CH2:16][N:6]1[CH2:7][CH2:8][CH:4]([N:3]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:5]1)[CH3:12]
Reactant: CCN(CC)C1CCNC1
Reactant: C=C(C(=O)OCC)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CN1CCC(N(CC)CC)C1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl-pyrrolidin-3-yl-amine (0.685 g, 6 mmol) in THF (10 mL) was added 2-(4-bromo-phenyl)-acrylic acid ethyl ester (1.27 g, 5 mmol) dropwise in THF at 0 degrees Celsius. Then the mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), washed with water (20 mL×2), brine, dried over Na2SO4, filtered and evaporated. The obtained oil was used directly without further purification. MS: calc'd 397 (MH+), exp 397 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].CO>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])=[O:6]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-chloropropanesulfonyl chloride (commercially available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an ice-water bath was added t-butylamine (commercially available, for example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and the cartridge eluted with methanol (2 column volumes). The methanol fraction was concentrated in vacuo to give the title compound as a white waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19].[OH-].[Na+].O>CC(O)CC>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: O=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)O
Product: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Yield: 71 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.72 g, 8.18 mmol), 3-ethoxycarbonyl-phenyl-guanidine nitrite (2.21 g, 8.18 mmol), sodium hydroxide (0.327 g, 8.18 mmol) in 2-butanol (40 mL) is heated to reflux for 24 hours before cooling to room temperature with the addition of water (40 mL). The solid is collected by filtration, washed with water and 2-propanol, and dried to give N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (2.06 g); ESI-MS (m/z): 355.1 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][C@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[NH2:12][C@H:10]([CH3:11])[CH2:9][N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCCCN(C[C@@H](C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCN(C[C@@H](C)N)C(=O)OC(C)(C)C
Yield: 94.9 %

Procedure:
A suspension of 300 mg of (R)-benzyl 1-{tert-butoxycarbonyl(butyl)amino}propan-2-ylcarbamate and 30 mg of 10% palladium-carbon in 10 mL of methanol was vigorously stirred at room temperature for 16 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 180 mg of the title compound as a colorless oil (95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To an equimolar amount of chloro-2,4-dinitrobenzene acid is added sodium ethoxide in ethanol to yield 2,4-dinitrophenyl ethyl ether. Next, to a weighed aliquot of poly(glycidol) containing 0.2 mole polymer in 300 ml of ethanol is added 0.2 mole 2,4-dinitrophenyl ethyl ether, and the reactants heated to reflux and maintained at reflux reaction conditions for 1 to 2 hours. The dry benzene is added and distillation initiated and continued until nearly all ethanol and water are azeotropically removed, to form the product identified as (I) where n is greater than 10. ##SPC17##
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].O>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)N
Reactant: COc1nc(Cl)ncc1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(NC(C)C)ncc1Br
Temperature: 60 °C
Yield: 63.6 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (1.2 g, 5.37 mmol) in THF (20 mL) was treated with TEA (1.57 mL, 10.74 mmol) and isopropylamine (0.7 mL, 8.1 mmol) and heated at 60° C. for 5 h. The mixture was cooled to RT, treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford 5-bromo-N-isopropyl-4-methoxypyrimidin-2-amine (0.84 g, 634%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.17 (br s, 1H), 3.96-3.94 (m, 1H), 3.87 (s, 3H), 1.12 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 246.0 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH2:17][Br:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(Cc3ccccc3)sc2c1
Temperature: 25 °C
Yield: 25 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.51 mmol), NBS (0.5 g, 2.63 mmol), AIBN (40 mg, 0.25 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the combined organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.2 g, 69%). MS (ES+) m/z: 319 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[CH:25]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)cc1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C2CC2)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylate (Step 37.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.54 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 461 [M+H]+ (LC-MS 2); Rf=0.18 (EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1.O.[OH-].[Na+]>CS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:9][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cccc(Br)c1)c1nc2cc(F)ccc2[nH]1
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol (example 437E, 3.30 g) and 1-methylpiperidin-4-ol (2.37 g) in methanesulfonic acid (10 mL) is heated overnight in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/1) to afford 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole. 1H NMR: 9.92 (sl, 1H), 7.60 (s, 1H), 7.55-6.85 (m, 6H), 5.80 (s, 1H), 3.65-3.50 (m, 1H), 2.80-2.65 (m, 2H), 2.34 (s, 3H), 2.15-1.65 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6](B(O)O)[CH:7]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 80 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:24])[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:34])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Reactant: Cc1ccc(N=C=O)cc1
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C)cc3)c2)cc1)OCC
Temperature: 50 °C
Yield: 87.2 %

Procedure:
A mixture of 1 g (3 mmol) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate (prepared according to Example 41b) and 0.8 mL (6 mmol) of 4-methylphenyl isocyanate is placed in a sealed tube and heated at 50° C. for 15 hours. The reaction medium is cooled and the residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.2 g (85%) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-p-tolylureido)biphenyl-4-yl]acrylate are obtained in the form of a white paste.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(Cl)c(C(=O)O)c1

Procedure:
For the preparation of the starting material [MS: 456 (1, M+H)], 6-(1-t-butyoxyformamido)hexanoic acid and 5-amino-2-chlorobenzoic acid are coupled to give 5-[6-(1-t-butoxyformamido)hexanamido]-2-chlorobenzoic acid, MS: 385 (2, M+H), the latter is coupled with β-alanine methyl ester to give N-[5-[6-(1-t-butoxyformamido)hexanamido]-2-chlorobenzoyl-β-alanine methyl ester, MS: 470 (14, M+H), and this is then saponified in methanolic sodium hydroxide solution.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH:1]1([CH2:4][C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Stir cyclopropaneacetic acid (30 g, 300 mmol) in dichloromethane (1 L) and treat with 1,1′-carbonyldiimidazole (52.5 g, 324 mmol) slowly. Stir for 2 hrs at room temperature and treat with N,O-dimethylhydroxylamine hydrochloride (30 g, 308 mmol), neat, in one portion; stir overnight. Pour mixture into water and extract twice with dichloromethane. Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate, filter, and evaporate to provide the title compound (38 g, 89%). 1H NMR (CDCl3) δ 3.66 (s, 3H), 3.18 (s, 3H), 2.35 (d, J=8.0 Hz, 2H), 1.08 (m, 1H), 0.54 (m, 2H), 0.16 (m, 2H).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O-:24])=[O:23])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].[CH3:27]O>>[CH3:27][C:20]1[C:19]2[C:14](=[CH:15][C:16]([C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:10][CH:9]=2)[N:21]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3ccc(C(=O)[O-])cc3n2)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Nc2ccc(S(N)(=O)=O)cc2)nc2cc(C(=O)O)ccc12
Temperature: 80 °C

Procedure:
To 2-(4-sulfamoylphenyl amino)quinazolin-7-carboxylate was added 2N sodium hydroxide (4 eq) and methanol and the mixture was heated to 80° C. for 10 min. The saponification went to completion. The reaction mixture was concentrated and 1N HCl was added to precipitate methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid as the HCl salt in quantitative yield. ES/MS m/z 344 (MH+).