Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:14])/[C:10](=[CH:12]/[CH3:13])/[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:14])/[C:10](=[CH:12]/[CH3:13])/[CH3:11])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C/C=C(\C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C(\C)C(=O)c1ccc(OC)cc1
Yield: 28 %

Procedure:
Anisole (128 mg), tigloyl chloride (140 mg), and aluminium chloride (155 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (63 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:8][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1nc(C(F)(F)F)cc(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)nc(N)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-(trifluoromethyl)-4(3H)-pyrimidinone (250 mg, 1.4 mmol), triethylamine (196 μL, 1.4 mmol), N,N-dimethylaminopyridine (17 mg, 0.14 mmol), in CH2Cl2 (13 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (534 mg, 2.8 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with CH2Cl2, washed with H2O (2×20 mL) followed by brine, dried (Na2SO4), evaporated, and dried under vacuum. Desired compound (466 mg, 1.4 mmol; 99+% yield; ES MS [M+H]+=140.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][C:9]([CH3:14])([C:11]([O:13][CH3:15])=[O:12])[CH3:10])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Boc-α-methylalanine in DMF (0.4 M) was added K2CO3 (1 eq) and MeI (1.2 eq). The mixture was stirred at RT for 6 h and then diluted with EtOAc, washed with water and sat. aq. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.20 (1H, br. s), 3.58 (3H, s), 1.40-1.27 (15H, m). MS (ES) C10H19NO4 requires: 217. found: 240 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[CH2:22]([C:21]1[N:40]2[N:41]=[CH:42][N:43]=[C:39]2[N:38]([CH:35]2[CH2:34][CH2:33][C:32]3([O:28][CH2:29][CH2:30][O:31]3)[CH2:37][CH2:36]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[F:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.55 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (2.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 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 pale-yellow oil (2.88 g, 60%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Cl)c3cccccc-3c2-c2ccccc2)cc1
Yield: 45.6 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.20 g) in CCl4 (10.0 ml) was added N-chlorosuccinimide (0.08 g) and α,α'-azobis(isobuthyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/EtOAc, 20:1) to give the title compound (0.10 g) as green crystals; mp 140°-142° C.
Reaction SMILES: [C:1]([C:9]1[C:17]2[C:12](=[C:13]([N:18]3[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][CH2:19]3)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CCOC(C)=O.O>C(O)(C)C>[CH2:1]([C:9]1[C:17]2[C:12](=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1c[nH]c2c(N3CCN(C(=O)C(F)(F)F)CC3)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(Cc2c[nH]c3c(N4CCNCC4)cccc23)cc1
Temperature: 25 °C
Yield: 126.5 %

Procedure:
To a solution of 1-[4-(3-benzoyl-1H-indol-7-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (638 mg, 1.59 mmol) in isopropanol (30 ml) was added NaBH4 (0.12 g, 3.17 mmol). After heating at reflux for 3 days, the reaction mixture was allowed to cool to room temperature and poured into a mixture of EtOAc/H2O. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give crude 3-benzyl-7-piperazin-1-yl-1H-indole as an oil (586 mg) which was used without further purification.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]([CH2:6][O:7][CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=2[O:2]1.[CH3:18][O:19][SiH:20]([O:23][CH3:24])[O:21][CH3:22]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:18][O:19][Si:20]([O:23][CH3:24])([O:21][CH3:22])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:14][C:13]2=[CH:12][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: C=CCOCc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: CO[Si](CCCOCc1cc2c(cc1[N+](=O)[O-])OCO2)(OC)OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A 10-ml eggplant type flask was purged with nitrogen, and charged with 1.0 g (4.2 mmol) of allyl 3,4-methylenedioxy-6-nitrobenzyl ether, 0.616 g (5 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20: 1) as the eluent, 0.80 g (2.2 mmol) of the desired product was obtained in a 52% yield. Its Rf value (for the aforesaid eluent) was 0.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])=[O:3]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
To a stirred mixture containing 66 g of 5-acetyl-1,2 -dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile and 450 ml of chloroform was added dropwise over a period of about 40 minutes a solution containing 60.8 g of bromine in 50 ml of chloroform. The resulting mixture was stirred at room temperature for about 3 hours and then heated on a steam bath for 30 minutes during which time the red color of the reaction mixture disappeared. The reaction mixture was allowed to stir at room temperature for 1 hour and then filtered using a sintered glass funnel. The filtered product was washed with acetone and dried at 60° C. to yield 97.8 g of 5-(bromoacetyl)-1,2-dihyro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 212°-214° C. with decomposition. A 20 g portion of this product was dissolved in a boiling mixture of 400 ml of methanol and 200 ml of dimethylformamide, the hot solution treated with decolorizing charcoal and filtered and the filtrate concentrated on a rotary evaporator to remove the solvents. The residue was boiled with methanol and the white powdery solid was collected, washed with methanol and dried to yield 16.4 g of 5-(bromoacetyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 213°-215° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[C:8](=[O:18])[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[CH3:25])=[O:4]>C1COCC1.Cl.[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[C:8](=[O:18])[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[CH3:25])=[O:4]
Reactant: COC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(N)cccc12
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A suspension of 3-methyl-8-nitro-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester (320 mg, 0.95 mmol) and Zn (898 mg, 13.8 mmol) in THF (4.5 ml) and 2M aq. HCl (4.5 ml) was stirred for 10 min, filtered and partitioned between ethyl acetate (3×150 ml) and sat. aq. NaHCO3 (100 ml). The combined organic solution was dried (MgSO4) and evaporated to give 8-amino-3-methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester as a dark oil (200 mg, 0.645 mmol, 69% yield. LC-MS (m/z) 309.4 (MH+); tR=1.2. It was dissolved in conc. aq. HCl (0.4 ml) and H2O (3.25 ml). To the obtained solution NaNO2 (46.3 mg, 0.645 mmol, in 0.12 ml H2O) was added dropwise at 0° C. After 15 min it was neutralized (pH=6-7) with sat. aq. NaHCO3 to give diazonium salt solution. To a solution of KCN (202 mg, 3 mmol) in water (0.4 ml) solution of CuSO4×5H2O (197 mg, 0.774 mmol) in water (0.8 ml) was added dropwise at 0° C. After addition completion benzene (2 ml) was added and the mixture was warmed to +60° C. To this mixture diazonium salt solution was added dropwise during 15 min then kept at 70° C. for 85 min. It was allowed to cool to r.t., diluted with ethyl acetate (10 ml) and filtered via plug of cellite. The organic layer was washed with brine (10 ml), dried (MgSO4) and evaporated to give 97.9 mg of the title compound (48% yield). LC-MS (m/z) 319.2 (MH+); tR=1.15.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)C>[N+:13]([C:4]1[CH:3]=[C:2]([O:1][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred and refluxed mixture of 25 parts of ethyl 4-hydroxy-2-nitrobenzoate, 11 parts of potassium carbonate and 200 parts of 2-propanone were added dropwise 21 parts of (bromomethyl)benzene. Upon completion, stirring was continued overnight at reflux temperature. After cooling, the whole was filtered and the filtrate was evaporated, yielding 25 parts (69%) of ethyl 2-nitro-4-(phenylmethoxy)benzoate as a residue (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:13].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:13][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH:7]=[O:8]
Reactant: ClCCOCCOCCCl
Reactant: COc1cc(C=O)cc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OCCOCCOCCCl)c1OC
Temperature: 55 °C
Yield: 80 %

Procedure:
A solution of 500 mg (2.75 mmol) 4,5-dimethoxy-3-hydroxybenzaldehyde 1 and 860 μl (1.03 g, 5.50 mmol) 1,2-bis(2-chloroethoxy)ethane in 20 ml DMF was treated with 2.24 g (6.88 mmol) caesium carbonate and heated to 55° C. for 20 hrs. After cooling the mixture was poured into 100 ml of ice water and extracted with chloroform. The organic extracts were washed twice with 50 ml of water and with brine, dried over sodium sulfate and evaporated. The resulting yellow oil was flash-chromatographed (petroleum ether/ethyl acetate 2/1) to yield 3-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}-4,5-dimethoxybenzaldehyde (730 mg, 2.20 mmol, 80%), which was directly used for the next synthesis step.
Reaction SMILES: [C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].Cl>[Zn].O>[C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CCOC(=O)CC(=O)N(C)c1ccccc1N
Temperature: 5 °C
Reaction time: 8 h

Procedure:
11 g of N-carbethoxy acetyl N-methyl o-nitro aniline are admixed with 16.2 g of powdered zinc, and 100 g of cracked ice are added, whilst agitating; 62 c.c. of concentrated hydrochloric acid, diluted with 250 c.c. of iced water, are then added, and this is cooled to -5°-10° C for 10 to 15 minutes; the temperature is allowed to raise again to + 5° C within thirty minutes, this is filtered, the filtrate is alkalinized with ammonium hydroxide and extracted with chloroform; the chloroformic phases are washed with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is dissolved in 30 c.c. of xylene and the solution is kept overnight at -10° C; the formed precipitate is washed with ether and recrystallized in xylene, to obtain N-carbethoxy acetyl N-methyl o-phenylene diamine, melting at 63°-64° C. Analysis: C12H16N2O3 = 256.26; Calculated: C % 61.00; H % 6.83; N % 11.86; Found: 61.19; 6.98; 12.00.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.FC(F)(F)C(O)=O.[OH:32][CH2:33][C@H:34]1[NH:38][CH2:37][C@H:36]([OH:39])[CH2:35]1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([N:38]4[C@H:34]([CH2:33][OH:32])[CH2:35][C@@H:36]([OH:39])[CH2:37]4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: OC[C@@H]1C[C@@H](O)CN1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N3C[C@H](O)C[C@H]3CO)c21
Temperature: 120 °C
Yield: 75.7 %

Procedure:
220 mg (0.57 mmol) 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide, 159.23 mg (0.69 mmol) (3R,5S)-5-hydroxymethyl-pyrrolidin-3-ol trifluoroacetate (prepared from commercial Boc-trans-4-hydroxy-L-prolinol) and 197.52 μl (1.15 mmol) diisopropylethylamine are placed in 4 ml dioxane, and heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is combined with water and dichloromethane and extracted. The organic phase is separated off using a phase separation cartridge and evaporated to dryness. 200.3 mg of the product (75%) are obtained as a racemic mixture. Analytical HPLC-MS (method A): RT=2.26 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)CCOc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cn(S(=O)(=O)c2ccc(Br)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 16.5 mmoles) was stirred with dimethyl formamide (ca 8 mL) in a ice-cooled, three necked round bottom flask. A solution of [2-(1H-indol-3-yloxy)ethyl]dimethylamine (15 mmole), in dimethyl formamide (ca 5 mL) was then added dropwise to this cooled suspention of sodium hydride. After the addtion was complete, the reaction mixture was allowed to attain the room temperature (25° C.). After about one hour of stirring at 25° C., a solution of 4-Bromobenzenesulfonyl chloride (18 mmole) was added dropwise to this solution. The reaction was further stirred at 25° C. for next 3-4 hours. After the completion of reaction (TLC), reaction mixture was poured on the ice cooled water and extracted by Ethyl acetate (3×20 mL). The combined organic extract was washed with water and brine, dried over sodium sulphate and the volatiles were evaporated under vacuume to get the product as a thick dark oil. The residue was purified by column chromatography, on silica gel; using hexane (100%) to triethylamine:ethyl acetate (2:98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (I) can be further purified by preparation of their acid addition salts. Melting range (° C.): Isolated as oil; Mass (m/z): 423, 425 (M+H)+; IR spectra (cm−1): 1150 (SO2); 1H-NMR (ppm): 2.40 (s, 6H); 2.83-2.88 (t, 2H, J=5.4 Hz); 4.11-4.16 (t, 2H, J=5.4 Hz); 6.87 (s, 1H); 7.19-7.38 (m, 3H); 7.50-7.67 (m, 4H); 7.95-7.99 (d, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:34])[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:34])([CH3:1])[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[CH:11]=1
Reactant: C[Mg]Br
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (ca. 15 μL, 0.04 mmol) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-2-{fluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (10 mg, 0.02 mmol) in tetrahydrofuran (3 mL). After warming slowly to ambient temperature, the reaction was quenched with a few drops of water and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{2-fluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][C:10]1=[O:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:11]1[CH:12]([CH:15]([CH3:16])[CH3:17])[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C1NC(=O)N(c2cc(F)ccc2Cl)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)N(c2cc(F)ccc2Cl)C(=O)N1Cc1ccccc1
Yield: 76.4 %

Procedure:
This compound was synthesized in analogy to example 155 (step A to E). In step A, 2-methyl-propionaldehyde was starting material in place of cycloheptanone and ammonium acetate in place of cyclopropylamino acetate. In step B, 2-chloro-5-fluoro-phenyl amine was used in place of 4-Amino-benzoic acid ethyl ester. The pure 3-(2-chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione that resulted from this procedure was then benzylated by stirring of 300 mg (1.11 mmol) of 3-(2-Chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione with 141 ml (1.16 mmol) of benzyl bromide and 51 mg (1.16 ml) of sodium hydride (55% in oil) in 5 ml DMF for 3 h at RT. The reaction mixture was then taken up in ethyl acetate and was washed with 1N HCl and water. The crude product was purified by silica gel chromatography with Ethyl acetate/Heptane 1:3 to give 306 mg of pure 1-benzyl-3-(2-chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione that was reduced with the same procedure described in step D and E to give pure 3-benzyl-1-(2-chloro-5-fluoro-phenyl)-4-isopropyl-imidazolidin-2-one as a colorless viscous oil MS (ESI): 347.3 (MH+).