Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1C(F)(F)F
Yield: 96.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclobutylamine (0.33 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g, 96%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][N:8](C2CCCCO2)[C:7](=[O:17])[CH:6]=1.Cl.O>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][NH:8][C:7](=[O:17])[CH:6]=1
Reactant: O=c1cc(Oc2c(F)cccc2F)cnn1C1CCCCO1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1cc(Oc2c(F)cccc2F)cn[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of 5-(2,6-difluoro-phenoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (92.3 mg, 0.30 mmol) in methanol (0.6 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (0.25 L, 1.2M). The reaction was heated at 110° C. for 1 h and then stood at 25° C. overnight. At this point, the reaction was charged with water (10 mL). The solids were crushed, filtered, rinsed, and dried in vacuo to afford 5-(2,6-difluoro-phenoxy)-2H-pyridazin-3-one (45.7 mg, 68%) as an off-white solid; 1H-NMR (400 MHz, DMSO-d6) δ ppm 5.91 (s, 1H), 7.25-7.43 (m, 2H), 7.43-7.57 (m, 1H), 8.11 (d, J=2.6 Hz, 1H), 13.10 (brs, 1H).
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][F:2])[CH2:5]2)[N:11]=1
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Reactant: Fc1cccc2c1CCN2
Agent: [Na]
Product: O=C(Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1)N1CCc2c(F)cccc21

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 670 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 345 mg of 4-fluoro-2,3-dihydro-1H-indole. 161 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoromethylmorpholin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7](COCC[Si](C)(C)C)[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:33])[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[CH3:25][N:26]([CH3:33])[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][O:30][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CN(C)CC(C)(C)CO
Product: CN(C)CC(C)(C)COc1ccnc2[nH]c3cnc(C#N)cc3c12

Procedure:
The title compound was prepared following a similar procedure to the previous example with 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile, using 3-(dimethylamino)-2,2-dimethylpropan-1-ol. 1H NMR (400 MHz, d6-DMSO) δ 12.78 (s, 1H), 8.99 (d, J=0.8, 1H), 8.55 (d, J=5.7, 1H), 8.39 (d, J=0.8, 1H), 7.06 (d, J=5.8, 1H), 4.12 (s, 2H), 2.41 (s, 2H), 2.24 (s, 6H), 1.10 (s, 6H). LCMS (Method E): RT=3.58 min, M+H+=324.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][N:11]1[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: COC(=O)c1ccnc(O)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 17.5 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (306 mg, 2 mmol) in N,N-dimethylformamide (30 mL) was added (1-bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was heated to 110° C. and stirred at the same temperature for 12 hours. The solvent was evaporated in vacuum and the residue was purified by preparative-HPLC to give methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (90 mg, 17%) The product was used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:4]1[CH3:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.5 %

Procedure:
To a suspension of sodium hydride (73 mg, w/w=60%, 1.8 mmol) tert-butyl 2-methyl-1H-indole-3-carboxylate (350 mg, 1.5 mmol) in tetrahydrofuran (30 mL) was added benzoyl chloride (250 mg, 1.8 mmol). The reaction solution was stirred at room temperature for 12 hours. The mixture was concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give tert-butyl 1-benzoyl-2-methyl-1H-indole-3-carboxylate (440 mg, 88%).
Reaction SMILES: [N:1]1[N:2]2[CH2:16][CH2:15][CH2:14][C:3]2=[CH:4][C:5]=1[NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:1]1[N:2]2[CH2:16][CH2:15][CH2:14][C:3]2=[CH:4][C:5]=1[NH2:6]
Reactant: CC(C)(C)OC(=O)Nc1cc2n(n1)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2n(n1)CCC2
Reaction time: 5 h

Procedure:
To a solution of 162b (45 mg, 0.20 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The solution was stirred for 5 h. It was then concentrated under reduced pressure to afford 162c which was used in the next step without further purification. MS-ESI: [M+H]+ 124.3
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>C1COCC1>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: Clc1nc2ccccc2o1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2nc3ccccc3o2)cc1)Cc1nc2ccccc2[nH]1
Yield: 50.4 %

Procedure:
Using the General N-Alkylation Procedure: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (128 mg, 0.32 mmol) and triethylamine (100 ul, 0.72 mmol) in THF (5 mL) was added 2-chlorobenzoxazole (50 uL, 0.44 mmol) and the mixture was stirred at reflux for 16 h. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 125:1:1) afforded the desired amine (83 mg, 37%) as a yellow foam.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:53])[N:39]([CH:54]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][N:57]=2)[CH3:55])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:53])[N:39]([CH:54]([C:56]2[CH:61]=[CH:60][C:59]([C:1]#[N:2])=[CH:58][N:57]=2)[CH3:55])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O

Procedure:
Example 18 is prepared as described for Example 15, substituting preparation 15b with preparation 18b. ESI mass spectrum: [M+H]+=437; Retention time HPLC: 0.76 min (002_CA03).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:14]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (16.82 g) in anhydrous benzene (140 ml), methyl isocyanate (8.90 g) and triethylamine (0.5 ml) are added. The resulting mixture is stirred at room temperature for about 8 hours, allowed to stand overnight and refluxed for 1 hour. After ice cooling, the reaction mixture is filtered to give a precipitate which is recrystallized from ethyl acetate to give 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (21.61 g) as colorless needles melting at 187.0° to 187.5° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[I:28]I.Cl>C1COCC1>[F:16][C:17]1[C:25]([I:28])=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(I)c(F)c(C(=O)O)c1
Temperature: -60 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (42 g, 298 mmol, 2.5 eq) in THF at −60° C. under N2 was added n-BuLi (2.2 M, 141 mL, 309.3 mmol, 2.6 eq) dropwise over a period of 30 min. The reaction mixture was stirred at −60° C. for 2 h, then a solution of 2-fluoro-5-methoxy-benzoic acid (15 g, 119 mmol, 1.0 eq) in THF (300 mL) was added dropwise with stirring. The reaction was stirred for a further 2 h at −60° C., then iodine (45 g, 179 mmol, 1.5 eq) was added in portions. The reaction was warmed to room temperature slowly and the resulting mixture acidified by addition of 1M HCl and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (5.6 g, 16%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)(=O)=O.[N:26]1([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:26]1([C:31]2[CH:36]=[CH:35][C:34]([O:5][CH2:6][CH2:7][C:8]3[CH:25]=[CH:24][C:11]([O:12][CH2:13][C:14]4[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=4[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: COC(=O)c1ccccc1COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 75 °C
Yield: 113.7 %

Procedure:
Methyl 2-[(4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)methyl]benzoate (0.2 g, 0.55 mmol) and 4-(1H-imidazol-1-yl)phenol (0.11 g, 0.66 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (0.09 g, 0.66 mmol) was added. The mixture was stirred over night at 75° C. Remove the acetonitrile by evaporation, dilute with EtOAc (10 ml) and wash the organic phase with Brine three times, dry (MgSO4) and evaporate. This gave 0.268 g of methyl 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}phenoxy)methyl]benzoate (yield 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:23][CH2:24]1)[CH3:2]
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64 %

Procedure:
To 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (0.19 g, 0.89 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.20 g, 1.1 mmol), and K2CO3 (0.43 g, 3.1 mmol) was added DMSO (12 mL). The reaction was heated to 100° C. for two days. Reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step B (0.22 g, 0.57 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 6.57 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.20 (d, J=11.6 Hz, 2H), 3.00-3.13 (m, 2H), 2.92 (s, 3H), 2.67 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.77-1.97 (m, 4H), 1.36-1.68 (m, 6H), 1.24 (t, 3H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11](=O)[C:10]2[N:9]([CH3:13])[N:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=2[CH2:5][C:4]1([CH3:20])[CH3:19].[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:36]([NH2:38])=[NH:37])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>CN(C)C=O.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:36]2[N:38]=[CH:2][C:3]3[C:4]([CH3:20])([CH3:19])[CH2:5][C:6]4[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][N:9]([CH3:13])[C:10]=4[C:11]=3[N:37]=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)c1cnc(Nc3ccc(N4CCN(C)CC4)c(Cl)c3)nc1-2
Yield: 32.7 %

Procedure:
A solution of ethyl 6-(hydroxymethylene)-1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (400 mg, 1.44 mmol) and N-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (424 mg, 1.58 mmol) in anhydrous dimethylformamide (5 mL) was heated at 10° C. for 3 hours. After cooling, the reaction mixture was poured into brine (50 mL) and extracted with ethyl acetate (50 mL×2). The extracts were collected, dried on Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography on silica gel eluted with dichloromethane/methanol 9:1 to give the pure title compound (240 mg, 33% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1coc(N2CC(O)C2)n1)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
To a solution of 3-hydroxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (370 mg, 1.48 mmol) (obtained as described in Reference Example 72(2)) in methylene chloride (19 ml) were added methanesulfonyl chloride (344 μl, 4.44 mmol) and triethylamine (622 μl, 4.44 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (93:7) as the eluant to afford 3-methanesulfonyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (404 mg, yield 100%) as pale yellow crystals.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][CH:12]1[CH2:16][CH2:15][CH:14]([CH3:17])[C:13]1=[O:18]>>[CH3:11][C:12]12[C:13](=[O:18])[C:14]([CH3:17])([CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: CC1CCC(C)C1=O
Reactant: Cc1ccccc1C(Br)Br
Product: CC12CCC(C)(Cc3ccccc3C1)C2=O

Procedure:
A process for the preparation of the compounds of the present invention which are substituted by alkyl substituents, e.g., methyl substituents in the 8 and/or 11 positions, begins with the treatment of an α,α-dihaloxylene with an alkylated or dialkylated derivative of the appropriate cycloalkanone-enamine. Thus, for example, α,α-dibromoxylene is treated with the pyrrolidine enamine of 2,5-dimethylcyclopentanone to produce the corresponding 6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene-11-one, followed by thallation as described hereinabove, to introduce the corresponding 2'-hydroxy compound and subsequent conversion to the oxime, followed by catalytic reduction to the desired d,1-11-endo-amino-6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cccnc2c1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2cccnc2c1Br
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 8-bromo-7-hydroxyquinoline (65 g, 0.29 mol), potassium carbonate (120 g, 0.87 mol), and methyl iodide (82 g, 0.58 mol) in acetone (500 mL) was heated to reflux for 4 hrs. The mixture was then cooled to rt and filtered. The filtrate was concentrated, dissolved in ethyl acetate (1 L), washed with water (2×300 mL) and saline (200 mL), dried over Na2SO4 and concentrated. The residue was recrystallized in ethyl acetate and hexane (1:1) to give 8-bromo-7-methoxyquinoline (40 g).
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>C(O)(C)C>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 10 °C
Yield: 31.4 %

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred for dissolution. 30 g of esomeprazole was taken into a separate round bottom flask and dissolved in 150 ml of isopropanol and this solution was added to the above sodium hydroxide solution. The combined mixture was stirred for 1.5 hours, and distilled completely at 55° C. The residue was dissolved in 30 ml of isopropanol with stirring and the solution was cooled to 10° C. The mixture was stirred at 10° C. for 1 hour and filtered. The compound was dried at 34° C. for 5 hours to yield 10 g of the title compound.
Reaction SMILES: COC([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=O.[C:32]([O:36][C:37]([O:39]C([O-])=O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC(C)(C)C
Yield: 93.4 %

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropanol Ve2 is prepared by the same manner as described in (41) by using tert-butyldicarbonate instead of methyl chloroformate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([CH2:15][NH2:16])[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18]OC(OC)N(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:17])[CH2:10][O:11][CH2:12][CH:13]3[CH2:15][N:16]=[CH:18][N:14]23)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COCC(CN)N2)cc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COc1ccc(C2(C)COCC3CN=CN32)cc1
Temperature: 25 °C

Procedure:
A solution of 31 mmol of C—[5-(4-methoxyphenyl)-5-methylmorpholin-3-yl]methylamine and 31 mmol of N,N-dimethylformamide dimethyl acetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The crude title compound is obtained as a yellow oil from the residue and is employed without further purification in the next stage. Rf=0.17 (dichloromethane-methanol-25% aqueous ammonia solution 200:20:1), Rt=2.61 (gradient I)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1>[Pd].CO.C1COCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cn2)nc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cn2)nc(N)n1
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a suspension of 11 (790 mg, 2.16 mmol) in 1:1 MeOH/THF (100 ml) was added 10% Pd/C (100 mg) and hydrogenated at 45 Hg mm. for 20 h. The reaction mixture was filtered and evaporated to dryness and recrystallized from DCM/Pert.ether to give 12 (695 mg, 96%); mp (DCM/pet.ether)>300° C.; 1H NMR [(CD3)2SO] δ 9.78 (s, 1H, NH), 9.45 (s, 1H, NH), 8.63 (dd, J=2.4, 0.3 Hz, 1H, H-2′), 8.09 (d, J=9.0 Hz, 1H, H-5′), 7.98 (dd, J=9.0, 2.6 Hz, 1 H, H-4′), 7.72 (d, J=8.7 Hz, 2H, H-2, 6), 6.61 (d, J=8.7 Hz, 2H, H-3, 5), 6.43 (s, 1 H, H-5″), 6.13 (s, 2H, NH2), 5.73 (s, 2H, NH2), 2.12 (s, 3H, CH3); HRMS (FAB+) calc. for C17H18N7O (M+1) m/z 336.1573, found 336.1578; Anal. calc. for C17H17N7O.0.25H2O: C, 60.1; H, 5.2; N, 28.9; C, 60.2; N, 5.3; N, 29.0%.