Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[Na].F[C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[N:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[N+:31]([O-:33])=[O:32].CO.C(Cl)Cl.CCOC(C)=O>C1COCC1.C(Cl)Cl.CCCCCC.CCOC(C)=O.CO>[CH3:30][C:26]1[CH:25]=[C:24]([NH:23][C:17]2[C:16]3[C:21](=[CH:22][C:13]([O:10][CH2:9][CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[C:14]([N+:31]([O-:33])=[O:32])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OCCCN1CCOCC1
Reactant: Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Agent: [Na]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(Nc2ncnc3cc(OCCCN4CCOCC4)c([N+](=O)[O-])cc23)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 3-morpholinopropan-1-ol (8.40 mmol, 1.22 g) in THF (40 mL) under N2 was added sodium metal (11.8 mmol, 0.27 g). The resulting suspension was stirred at 20° C. for 2 hours and then cannulated into a solution of 7-fluoro-4-[(3-methyl-phenyl)amino]-6-nitroquinazoline (0.70 g, 2.35 mmol) in THF (30 mL) under N2. The reaction procedure and workup above were followed to give after chromatography on silica gel eluting with MeOH/CH2Cl2/EtOAc (5:45:50) to MeOH/CH2C0.50/EtOAc (3:7:10) 4-[(3-methylphenyl)-amino]-7-[(3-morpholino)propyloxy]-6-nitroquinazoline (0.87 g, 88%) as a yellow powder, mp (CH2Cl2/hexane) 169-170° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20](Cl)[N:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:23]=1
Reactant: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cl)nc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.74 g (3.4 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 1.0 g (3.2 mmol) (2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was mixed with water and stirred for 30 min at RT. The precipitated solid was suction filtered, stirred with diisopropylether and isopropanol and suction filtered again. After drying the crude product was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([N:21]3[CH2:24][C:23](=O)[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36][CH3:37].C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([N:21]3[CH2:24][CH:23]([N:36]([CH3:37])[CH3:35])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1CN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C1CN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
To a stirred solution of the product from Example 185 (74 mg, 0.14 mmol.) in methanol (5 ml) was added dimethylamine hydrochloride (58 mg, 0.7 mmol.). The mixture was stirred 5 minutes, sodium cyanoborohydride (27 mg, 0.42 mmol.) and sodium acetate (34 mg, 0.4 mmol.) added, and the mixture stirred a further 18 hours at ambient temperature. Ethyl acetate (20 ml) was added and the mixture washed with 1N sodium hydroxide and brine, dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate to afford the desired product (21 mg). 1H NMR (CDCl3) δ 7.37 (2H, d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 7.09–7.04 (2H, m), 6.88–6.81 (1H, m), 4.49 (1H, d, J=6.4 Hz), 3.87–3.78 (4H, m), 3.59 (1H, m), 3.08 (1H, m), 2.6–2.5 (2H, m), 2.41–2.33 (2H, m), 2.17 (6H, s), 2.05–2.00 (2H, m) and 1.53–1.41 (2H, m). MS (ES+) 548 ([MH]+).
Reaction SMILES: [BH4-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][C:12](=[N:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].O>O1CCCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) is slowly added to a solution of 0.12 mole of 4-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (compound 5 g) in 100 ml of dry tetrahydrofurane. After complete addition, the mixture is stirred for another 30 min after which a 100 ml of water is added to destroy the excess of borohydride. Subsequently the tetrahydrofurane is evaporated and the resulting aqeous solution extracted with diethyl ether. After drying the solvent over magnesium sulfate, the ether is evaporated. M. p. 112-115° C.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:23])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)N4CCOCC4)c3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylic acid (Example 37) instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44), and with morpholine instead of dimethylamine hydrochloride. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 8.35 (s, 1H), 7.78 (s, 1H), 4.36-4.42 (m, 1H), 4.33-4.35 (m, 1H), 3.76-3.99 (bs, 8H), 3.39 (s, 3H), 1.71-1.93 (m, 10H), and 0.87 ppm (t, J=7.2 Hz, 3H); LCMS: 440.1 m/z (M+H)+; ret. Time: 3.850 min (Analytical Method A).
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].C(O)(=O)C.P(=O)(O)(O)O.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([O:36][CH3:37])=[O:35])[N:28]2[CH3:33]>C(#N)C>[C:3]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[Br:23])[N:28]([CH3:33])[C:27]=1[C:34]([O:36][CH3:37])=[O:35])(=[O:4])[CH3:2]
Reactant: COC(=O)c1cc2c(Br)cccc2n1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1c(C(C)=O)c2c(Br)cccc2n1C
Reaction time: 0.17 h

Procedure:
33 ml of trifluoroacetic anhydride are added to a solution of 13.2 ml of acetic acid, of 1.6 ml of phosphoric acid and of 170 ml of acetonitrile, stirring is carried out for 10 min at room temperature and a solution of 20.6 g (77 mmol) of methyl 4-bromo-1-methyl-1H-indole-2-carboxylate in 120 ml of acetonitrile is added. The mixture is stirred for 4 h at room temperature and is poured onto water and extracted with ether. The organic phase is dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is taken up in a mixture of cyclohexane and of dichloromethane. The precipitate is collected by filtration, washed with ether and dried under reduced pressure. 18.8 g (61 mmol) of product are obtained. The mother liquors are concentrated and the residue is purified by chromatography on a column of silica gel. 3.2 g (10 mmol) of additional product are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH:7]2O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Nc1ccc(Br)c2c1C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
7-Amino-4-bromo-3-hydroxyisoindolinone (3.11 g, 12.8 mmol) was dissolved in nitromethane (125 mL), and the solution was added with trifluoroacetic acid (9.90 mL, 128 mmol) and triethylsilane (4.10 mL, 25.6 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain 7-amino-4-bromoisoindolinone (2.16 g, yield 74%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][CH3:13])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:23](I)=[CH:22][N:21]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:18]2=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.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]>[Br:14][C:15]1[CH:16]=[C:17]2[C:23]([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][C:4]=3[O:12][CH3:13])=[CH:22][N:21]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[C:18]2=[N:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: COc1cc(F)c(C)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1cc(F)c(C)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Temperature: 90 °C

Procedure:
A solution of (4-fluoro-2-methoxy-5-methylphenyl)boronic acid (100 mg, 0.5434 mmol) 134 and 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine 78 (259.23 mg, 0.5434 mmol) in acetonitrile was added cesium carbonate (356.4 mg, 1.86 mmol). The reaction was degassed and purged with nitrogen for 10 min and Pd(dppf)Cl2 (22.17 mg, 0.0217 mmol) was added to the reaction. The reaction was degassed and purged with nitrogen for another 10 min. The reaction was heated to 90° C. under sealed condition for overnight. The reaction mixture was allowed to cool to room temperature, diluted with chloroform. The organic layer was filtered through celite plug and concentrated to get the crude compound 135. The crude was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted in 5% ethyl acetate in hexane as half white solid 5-bromo-3-(4-fluoro-2-methoxy-5-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine 135.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:20][CH3:21])[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH3:21][O:20][C:6]1[CH:7]=[C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
A 50 ml eggplant type flask equipped with a magnetic stirrer, a dropping funnel, a reflux condenser and a gas-introducing tube was charged with 250 mg of a 5% palladium/carbon dispersed in 25 ml of ethanol and 5.0 g (24 mmol) of 1-(4-allyloxy-3-methoxyphenyl)-4,4-dimethylpentane-1,3-dione. After completely replacing the atmosphere of the reaction system with hydrogen, stirring was continued for 2 hours at room temperature. A light yellow oily material was obtained by removing the palladium/carbon by filtration and subsequently distilling off the solvent. Thereafter, the thus obtained oily material was subjected to silica gel column chromatography using hexane/ethyl acetate (10/1-5/1 (v/v)) as a developer to obtain 4.0 g (80% in yield) of the compound of interest, 1-(3-methoxy-4-propoxyphenyl)-4,4-dimethylpentane-1,3-dione, as an achromatic solid substance. This compound is hereinafter referred to as Compound (1d).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([O:20][CH2:21][O:22][CH3:23])=[C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:8]=3[N:9]=2)[CH:17]=1
Reactant: NCc1ccccn1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) (567 mg, 1.5 mmol), 2-(aminomethyl)pyridine (1.08 g, 10 mmol), and Na2CO3 (excess) in CH3CN (30 mL) was stirred overnight at room temperature. After filtration of the reaction mixture, the filtrate was concentrated in vacuo. Water (20 mL) was added to the residue, which was extracted with CHCl3 (20 mL) three times. The combined organic layer was washed with brine and water, dried over MgSO4, and evaporated. The resulting oily material was purified by silica gel column chromatography (CHCl3-ethyl acetate) to afford the objective compound as a pale yellow oil (386 mg, 63%). 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.87 (s, 3H), 4.01 (s, 2H), 4.30 (s, 2H), 5.23 (s, 2H), 7.02 (dd, 1H, J=9.2, 1.2 Hz), 7.15 (dd, 1H, J=7.6, 4.4 Hz), 7.21 (d, 1H, J=9.2 Hz), 7.29-7.36 (m, 2H), 7.41 (d, 1H, J=7.6 Hz), 7.49 (d, 1H, J=7.6 Hz), 7.62-7.65 (m, 2H), 8.55 (d, 1H, J=4.4 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30])=[N+:25]=[N-:26]>C(Cl)Cl>[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])=[O:30])=[N+:25]=[N-:26]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCCCCCCCCCNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methyldodecanamine (5.0 g, 25.1 mmol) and DIEA (5.70 mL, 1.3 equiv, 32.6 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (4.05 g, 1 equiv, 25.1 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The content of the reaction was poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.08 g, quant). This material was purified on an ISCO flash chromatography system with a gradient from 10-40% ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (7.28 g, 89.3%). 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.26-1.35 (m, 6H), 1.47-1.48 (d, J=4, 6H), 1.50-1.59 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40, 3H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C18H36N4O (324.3); Found: 325 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:23])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+]>O>[CH:10]1([C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=3[Cl:23])[N:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2ccc(S(C)(=O)=O)cc2Cl)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2ncc(C(=O)O)c2C2CC2)c(Cl)c1

Procedure:
5-Cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester is hydrolyzed with a base such as sodium hydroxide in water to form 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid, analogous to an acid of formula IX′. The carboxylic acid pyrazole is then activated with coupling agent such as thionyl chloride to form the activated compound, analogous to a compound of formula X′. The activated compound is then coupled with guanidine to form the NHE-1 inhibitor, N-{5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carbonyl}-guanidine.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9]C)=O.[CH2:11]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: O=C1CCC(C(=O)N2CCC(Cc3ccccc3)CC2)N1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
Methyl pyroglutamate (4.3 g) and 7.9 g of 4-benzylpiperidine were dissolved in 20 ml of toluene and the mixture was heated to reflux with stirring for 24 hours. The reaction solution was treated with a silica gel column chromatography to give 7.2 g of the product which was recrystallized from diethyl ether to afford 6.5 g of desired product, m.p. 160°-161° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.ClCCl.[I-].[C:29]([O:33][C:34]([N:36]1[CH2:39][CH:38]([Zn+])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[NH4+].[Cl-]>CN(C)C(=O)C.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].[Cu]I>[C:29]([O:33][C:34]([N:36]1[CH2:39][CH:38]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)OC(C)(C)C)C4)ccc2-3)n(C(C)C)n1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (5.000 g, 0.01234 mol) was dissolved in N,N-dimethylacetamide (35 mL) and the solution was degassed for 5 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.5037 g, 0.0006168 mol) and copper(I) iodide (0.2349 g, 0.001234 mol) were added and the reaction was further purged with N2. (1-(Tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (0.01480 mol, 0.38M in DMA, 40 mL), was added and the reaction was heated to 80° C. overnight. Saturated NH4Cl and methylene chloride were added. The mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The crude was purified by flash chromatography (10-80% ethyl acetate in hexanes) to afford 3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester as a white solid (4.11 g). MS (ESI+) 482.2
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl>CO>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(N2CCC(C(OC)OC)CC2)cc1
Agent: Cl
Solvent: CO
Product: COC(OC)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
A solution of methyl 4-(4-(dimethoxymethyl)piperidinyl)benzoate(5.6 g, 18.2 mol) was in methanol (50 mL) 1N sodium hydroxide (27 mL) was heated at 80° C. for 5 hours. The reaction was neutralized with 1N HCl (27 ml) and concentrated in vacuo. Additional methanol was added to the residue which was filtered (0.5 micron filter) and evaporated to give 5.0 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1)=[O:4].[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][P:13]([O:16][CH3:17])([O:14][CH3:15])=[O:18])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COC(=O)c1ccc(CP(=O)(OC)OC)cc1

Procedure:
Methyl 4-(bromomethyl) benzoate (compound 47) (11.2 g, 49 mmol) was dissolved in 25 mL trimethyl phosphite and refluxed under N2 for 5 hrs. Excess trimethyl phosphite was removed by co-distillation with toluene to give crude 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester (compound 48).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1cc(CBr)cc(OC)c1
Product: COc1cc(Cn2c(Oc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 64.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (275 mg, yield: 64.8%).
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][C@@H:4]([C:33]([O:35]CC1C=CC=CC=1)=[O:34])[C:5]([CH2:23][N:24]1[C:28](=[O:29])[N:27]([CH3:30])[N:26]([CH3:31])[C:25]1=[O:32])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8]CC1C=CC=CC=1)=[O:7]>CO.[Pd]>[C:19]([O:18][C:16]([C:5]([CH2:23][N:24]1[C:25](=[O:32])[N:26]([CH3:31])[N:27]([CH3:30])[C:28]1=[O:29])([C:6]([OH:8])=[O:7])[C@H:4]([C:33]([OH:35])=[O:34])[CH2:3][CH:2]([CH3:43])[CH3:1])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2.464 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]-1,1,2(R)-pentanetricarboxylate were dissolved in 40 ml of methanol containing 0.25 g of 10% palladium-on-charcoal catalyst. The mixture was hydrogenated for 2 hours, the catalyst was removed by filtration and the solvent evaporated to give 1-(tert.butoxycarbonyl)-4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]-1,2(R)-pentanedicarboxyic acid in the form of a colorless gum. The gum was dissolved in 60 ml of toluene containing 0.43 ml of N-methylmorpholine and the mixture was heated under reflux for 1 hour. The solution was washed with 5% aqueous citric acid solution, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give 1.422 g of 2(R)-[1(R or S)-(tert.butoxycarbonyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)ethyl]-4-methylvaleric acid in the form of a waxy solid as an approximately 6:1 mixture of diastereoisomer 1 and diastereoisomer 2.