Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1C.[N+](C1C=CC=CC=1)([O-])=O.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH2:24].Br>CCCCCC>[CH3:22][C:23]([NH:12][C:10]([NH:9][C:1]1[CH:2]=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1)=[O:11])([CH3:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(NC(N)=O)c(C)c1
Agent: Br
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
12.4 parts of 2,4 -xylylurea was suspended in 50 parts of nitrobenzene, and 30 parts of α-methylstyrene was added. The mixture was stirred while introducing anhydrous hydrobromic acid portionwise. When the amount of the mixture increased by 10 parts, the introduction of the hydrobromic acid was stopped. The reaction was then performed at 40° C. for 5 hours. The resulting reaction mixture was allowed to stand overnight. Then, 30 parts of n-hexane was added, and the mixture was further allowed to stand overnight. The precipitated crystals were recrystallized from 60% methanol to afford 13.4 parts of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea having a melting point of 203° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34]>>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: NCCOCCO
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NCCOCCO)nc21

Procedure:
1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.350 g (0.887 mmol) 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.267 mL (2.66 mmol) 2-(2-amino-ethoxy)-ethanol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.331 g (86%) of 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 143° C.–146° C.; MS (APCI) m+1/z 436.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:17])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(3,5-difluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.24 mmol) in methylene chloride (5 ml), 2-aminoethanol (0.016 ml, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (0.029 ml, 0.26 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.26 mmol) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (36 mg, 0.07 mmol, 31%) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3].CCC(N=[C:23]=[O:24])C.N12CCN(CC1)CC2.C(Cl)(Cl)=O.[N-]=C=O>C1(C)C(C)=CC=CC=1>[N:1]([S:2]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3])=[C:23]=[O:24]
Reactant: CCC(C)N=C=O
Reactant: COC(=O)c1sc2ccccc2c1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1sc2ccccc2c1S(=O)(=O)N=C=O

Procedure:
Methyl 3-aminosulfonylbenzothiophene-2-carboxylate (10 grams), 75 ml of xylene, 3.5 g. of 3-butyl isocyanate and 0.2 g. of 1,4-diazabicyclo[2,2,2]octane in admixture were heated to reflux under a dry ice cooled reflux condenser for 10 minutes. Phosgene gas was passed into the system until the reflux temperature dropped to 120°. The addition was discontinued until the temperature rose to 130° and then additional phosgene was added to cause the temperature to drop to 120°. The cycle was repeated until the reflux temperature remained at 120° for one half hour with no further addition of phosgene. The mixture was then cooled, filtered and the filtrate was concentrated to remove the xylene and recovered butyl isocyanate. The residue thus obtained showed absorption peaks by infrared at 2200 and 1700 cm-1 consistent for the isocyanate and carboxylate groups. This product was used for the synthesis of the herbicides of this invention without further purification. The isocyanate derivatives of Tables I-Ic can be prepared from the appropriately substituted sulfonamides by the method set forth in Examples 1 and 2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=2)[N:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.[OH-].[NH4+:26].C1COCC1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH2:26])=[O:18])[N:15]=2)[N:9]=[C:8]([C:21]([F:23])([F:22])[F:24])[CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 29 (345 mg, 0.966 mmol) in methanol (1.5 mL) at room temperature was added ammonium hydroxide (1.5 mL, 38.5 mmol). The resulting solution was allowed to stir for 1 h at 50° C. THF (1 mL) was then added and the mixture was stirred for 16 h at 50° C. Solvent was evaporated, and the crude product 30 was isolated. LRMS (ESI): calc. 328.0; found 329.0 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.O>[Cl:13][C:11]1[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[CH3:20])[N:8]=[C:7]([CH2:6][C:5]2[CH:30]=[CH:31][C:2]([NH:1][CH2:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)CC(=O)NC1CCCC1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NCC3CCCCC3)cc2)nc1N(C)CC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of methyl {2-(4-aminobenzyl)-4-chloro-6-[[2-(cyclopentylamino)-2-oxo-ethyl](methyl)amino]pyrimidin-5-yl}acetate (0.150 g, 0.336 mmol), cyclohexanecarbaldehyde (0.042 g, 0.370 mmol), acetic acid (0.019 mL, 0.336 mmol) and sodium triacetoxyborohydride (0.107 g, 0.505 mmol) in 1,2-dichloroethane (3 mL) was stirred overnight at room temperature. Water was then added and the mixture was neutralized with 1N NaOH followed by extraction with dichloromethane. The combined organic extracts was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed by preparative TLC to give methyl {4-chloro-2-{4-[(cyclo-hexylmethyl)amino]benzyl}-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)amino]pyrimidin-5-yl}acetate (0.092 g, 51% yield) as an amorphous solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22](=[O:31])(=[O:30])[CH2:21][CH2:20]2)[CH:9]=1)=[O:6])=[N+]=[N-]>CO.[Pd]>[O:31]=[S:22]1(=[O:30])[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH2:25][N:19]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][NH2:1])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CN=[N+]=[N-])c2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CN)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide (110 mg, 0.25 mmol) in methanol was added 10% palladium on carbon (507 mg). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford 30 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1 H), 8.12 (s, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 8.00 (d, J=7.6 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H), 7.67-7.12 (m, 2 H), 7.57 (t, J=8.0 Hz, 1 H), 5.31 (s, 2 H), 4.66 (brs, 2 H), 4.25 (s, 2 H), 3.78 (s, 2 H), 2.52 (s, 3 H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].CCN(C(C)C)C(C)C.ClC(OC(Cl)C)=O>ClCCl>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15]
Reactant: C[C@@H](c1ccccn1)c1c(CCN(C)C)sc2ccccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCCc1sc2ccccc2c1[C@@H](C)c1ccccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-{2-[3-((R)-1-pyridin-2-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 12-2) (0.305 mg, 0.98 mmol) in dichloromethane (3 mL), DIEA (1 mL, 5.8 mmol) and 1-chloroethyl chloroformate (0.32 mL, 2.95 mmol) were added. The mixture was stirred for 1 hour at 40° C. The solvent was removed in vacuo and 1N HCl was added to the residue. The mixture was stirred at 40° C. for an additional hour and cooled to ambient temperature. After neutralization with NH4OH the product was extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 300 mg of crude product, which was purified by mass triggered HPLC to give methyl-{2-[3-((R)-1-pyridin-2-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 21-1). (MH+=297, tR=1.675, Method 4)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ncccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (46 mg, 1.142 mmol, 60% dispersion in mineral oil) in DMF (1.1 mL) was added methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) and 2-chloropyrimidine (131 mg, 1.142 mmol). The resulting suspension was stirred at RT for 1 h. The reaction mixture was diluted with DMF, filtered, and purified by HPLC to afford the title compound as a white-pink solid.
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[O:27]=[C:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-octanesulfonyl chloride and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=5.4 Hz, 3 H), 1.15–1.40 (m, 10 H), 1.60–1.75 (m, 2 H), 2.40 (t, J=4.5 Hz, 4 H), 2.94 (t, J=5.7 Hz, 2 H), 3.54 (t, J=4.5 Hz, 4 H), 6.99 (d, J=6.9 Hz, 2 H), 7.09 (d, J=6.9 Hz, 2 H), 9.31 (s, 1 H); MS (ES) m/z: 367.0 (MH+); HRMS Calcd. for C19H30N2O2S(M+): 366.1977. Found: 366.1969. Anal. Calcd. for C19H30N2O2S: C, 62.26; H, 8.25; N, 7.64. Found: C, 62.40; H, 7.98; N, 7.59.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(OC([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=O)(C)(C)C>>[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NCC(F)(F)F
Product: NCc1ccc(C(=O)NCC(F)(F)F)cc1
Yield: 94 %

Procedure:
Use the General Procedure 6-1, using 2,2,2-trifluoroethylamine (197 mg, 2 mmol) and 4-(tert-butoxycabonylamino-methyl)-benzoic acid, to give the title compound as a clear oil (440 mg, 94%). MS (ES+) m/z: 233 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([OH:36])[CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:36][C:32]1[CH:31]=[C:30]([CH3:29])[CH:35]=[CH:34][N:33]=1)[CH3:28]
Reactant: Cc1ccnc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)ccn2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4-methylpyridin-2-ol (0.19 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 25%).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:4]2[C:5]([F:12])=[C:6]([F:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[C:3]=2[F:14])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(F)c2F)CC1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Pentafluoronitrobenzene (10 g, 46.9 mmol) is cooled to 0° C. and treated dropwise with 1-methylpiperazine (5.2 ml, 47 mmol) in triethylamine (14 ml, 94 mmol). After 30 minutes at 0° C., the reaction mixture is allowed to reach room temperature. After one hour, the orange suspension is diluted with water (100 ml) and extracted with ether (3×100 ml). The combined organic layers are washed with saturated aqueous sodium chloride solution (100 ml), dried with magnesium sulfate and evaporated. Recrystallization from n-hexane-ether (1:1) yields 10 g of 1-methyl-4-(2,3,5,6-tetrafluoro-4-nitrophenyl)piperazine as red-brown crystals (73%): mp: 77°-78° C.; NMR(CDCl3):2.35(s,3H),2.54 (m,4H),3.44(m,4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:3]=1.CO.O.C1C=C(C([O-])=[O:34])C(C(O[O-])=O)=CC=1.[Mg+2].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:34])[C:13]2[NH:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: -10 °C
Reaction time: 0.58 h
Yield: 91.3 %

Procedure:
To a solution of 3.44 g of pyrmetazole (10.5 mmol) in 30 mL of 9:1 v/v methanol/water at -10° C. was added dropwise a solution of 3.10 g of MMPP in 30 mL of 9:1 v/v methanol/water over a 10 minute period. The reaction mixture was stirred at -10° C. for 35 minutes then poured into a mixture of 100 mL of saturated aqueous sodium bicarbonate and 40 mL of methylene chloride. The layers were separated and the aqueous layer was extracted 3 times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was slurried in EtOAc and the slurry stirred for 10 minutes. The solid was collected and then dried to provide 3.31 g of omeprazole (92% yield). LC analysis showed that the product was 99.5% pure.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][N:2]([CH3:1])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Reaction time: 6 h
Yield: 11.8 %

Procedure:
A solution of 4-dimethylamino-4-phenyl-1-[3-(2-triethylsilanyl-1H-indol-3-yl)propyl]cyclohexanol (852 mg, 1.8 mmol) in absolute tetrahydrofuran (50 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (1.66 g, 5.3 mmol), stirred 6 h with reflux, then stirred over the weekend at 50° C. and then concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography (38 g, 20×2.5 cm) with ethyl acetate/methanol (9:1). 80 mg of the title compound were obtained that were stirred overnight with cyclohexane (20 mL). 406 mg of the target compound were also obtained, which contained still larger amounts of impurity. This mixture was purified once again by flash chromatography (38 g, 20×2.5 cm), in which case cyclohexane/ethyl acetate (4:1) was firstly used as mobile solvent. All fractions that contained the target compound were treated with cyclohexane as above.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]C(N1CCCCC1)CCBr>>[N:1]1([CH:7]([CH3:21])[CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCBr)N1CCCCC1
Reactant: Nc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Product: CC(CCn1nc(N)c2cc(Cl)ccc21)N1CCCCC1

Procedure:
The same procedures for preparing 1-(3-piperidinopropyl)-3-amino-5-chloroindazole as described in Example 100 were repeated except that 1-(1-methyl-3-bromopropyl)piperidine was employed instead of the 3-bromopropylpiperidine. As a result, 1-(3-piperidinobutyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Yield: 35.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (2.2 g, 11 mmol), 4-methylstyrene oxide (5.8 g, 44 mmol) and NaH (1.3 g, 32.5 mmol) were heated in DMF (70 mL) at 120° C. for 16 h (overnight). The contents were quenched by methanol and evaporated to dryness. The resulting crude product was purified by silica gel chromatography (230-400 mesh) using ethyl acetate-hexane gradient to obtain 1.3 g of racemic-2(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol. The free base was converted into its hydrochloride salt by treatment of ethanolic HCl.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]=1.BrBr.C(N(CC)CC)C>C(OCC)(=O)C>[Cl-:1].[ClH:1].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][CH:7]3[NH:2][CH2:3][CH2:4][CH:5]=[C:6]3[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(CCCN)=CCO2
Agent: BrBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C1=CCCNC1CO2
Product: [Cl-]

Procedure:
To a suspension of 20 g of 4-(3-aminopropyl)-6-methoxy-2H-[1]-benzopyran hydrochloride in 200 ml of ethyl acetate is added 12.5 g of bromine at room temperature. After 15 minutes at room temperature 24 g of triethylamine is added and the reaction mixture is refluxed for 2 hours. After washing with water and drying the solvent is removed in vacuo. The residue chloride to afford 9-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 285°-286°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with isonipecotic acid. A yellow solid 127 was obtained (0.014 g, 28%). 1H-NMR (CDCl3, 400 MHz) δ 1.89–1.98 (m, 2H), 2.08–2.15 (m, 2H), 2.68–2.76 (m, 1H), 3.40–3.48 (m, 2H), 4.13–4.20 (m, 2H), 4.28–4.34 (m, 4H), 6.91–6.98 (m, 3H), 7.04 (dd, J=1.9 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.20 (d, J=6.2 Hz, 1H); MS (APCI) m/z 517 (M+H)+.