Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([I:22])[CH:24]=1
Reactant: NC(c1ccccn1)c1ccccn1
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(c1ccccn1)c1ccccn1)c1cccc(I)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
1.5 g of C,C-dipyridin-2-yl-methylamine are suspended in 50 ml of methylene chloride and 1.15 ml of triethylamine and treated dropwise at 0° with a solution of 3-iodo-benzoyl chloride. After 1 hr. at 0° the reddish suspension is concentrated, the residue is poured into water and extracted three times with methylene chloride. Chromatography on silica gel with methylene chloride/methanol 9:1 yields 1.31 g of brownish N-(di-pyridin-2-yl-methyl)-3-iodo-benzamide. Yield: 39%. Mass spectrum: peaks inter alia at m/e: 415 (M+, 8%), 320 (44%), 231 (36%), 184 (100%).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)CC(C)(N=C=S)N=NC(C)(C)C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 26.1 grams (0.3 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol in a 500 ml erlenmeyer flask, cooled to 5° C., was added 61.2 grams (0.3 moles) of 2-t-butylazo- 2-chloro-4-methylpentane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional two hours at 30° C., poured into 300 ml water and the product extracted with 200 ml pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 55.7 grams (80% crude yield) of a yellow liquid. The product had a strong broad band at 1980- 2080 cm-1 in its infrared spectrum which is indicative of the isothiocyano band.
Reaction SMILES: [CH3:1][C@@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=O.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21].C1COCC1>CO>[CH2:8]([O:7][C:6]([NH:5][C@H:2]([CH3:1])[CH2:3][NH:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: C[C@H](C=O)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNC[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A 1000 mL round bottom flask was charged with benzyl (1R)-1-methyl-2-oxoethylcarbamate (59.4 mmol) and 347 mL of anhydrous methanol. The resulting mixture was cooled to 0° C. and glycine methyl ester hydrochloride (29.3 g, 237.6 mmol) was added. After 10 minutes, 1.0 M NaCNBH4 in THF (95 mL, 95.0 mmol) was added and the reaction was allowed to warm to 22° C. overnight. The reaction mixture was then concentrated, redissolved in diethyl ether (200 mL) and placed in a separatory funnel. The organic phase was washed with saturated NaHCO3 (200 mL) and separated. The basic aqueous layer was washed twice with diethyl ether (2×200 mL), and the combined organic layers were washed with brine (2×200 mL), dried with Na2SO4 and concentrated. Silica gel chromatography using 2:1 hexanes/ethyl acetate with gradual polarization to 1:1 hexanes/ethyl acetate provided the desired product as a clear oil in 75% yield (12.5 g, 44.6 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29]Br.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][Br:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CC(C)(CCBr)CCBr
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCC(C)(C)CCBr
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 24 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 480 ml. of dimethylformamide is treated under argon at -10° C. with 0.16 mol. of sodium hydride (7.0 g. of a 55% dispersion in mineral oil) and then stirred in an ice-bath for 15 minutes. To this, 62 g. of 1,5-dibromo-3,3-dimethylpentane are added in one batch at -5° C., the mixture is then stirred for 1 hour at room temperature and subsequently heated for 18 hours at 60° C. After cooling, the mixture is poured into 4 liters of ice-water, 200 g. of sodium chloride are added, and the separated product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride as the eluant, care being taken that the eluate is shielded from daylight. The homogeneous fractions are combined, evaporated, and the solid residue recrystallized from ethanol, and there is obtained 2-(5-bromo-3,3-dimethylpentyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 87°-88° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[OH:8][CH2:7][C@H:5]([NH:6][S:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (3.0 g, 19.3 mmol) in CH2Cl2 (80 mL) was added with TEA (1.1 mol eq, 2.9 mL) and the mixture was stirred at r.t. for 10 minutes. Then 2-thiophen-sulphonyl chloride (1 mol eq, 3.52 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 5H as white solid (4.9 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 3.61 (s, 2H), 3.82 (t, 2H, J=6.3), 4.14 (m, 1H), 4.62 (t, 1H), 5.25 (t, 1H), 7.21 (m, 1H), 7.75 (dd, 1H, J=2.1), 7.96 (dd, 1H, J=1.9), 8.23 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:16][OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CO)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 187, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11]N(C)C)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][C:16]([NH2:18])=[O:17].Cl.[Cl-].[NH4+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:11]=[N:15][C:16](=[O:17])[NH:18][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Reactant: NC(N)=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=c1ncc(-c2ccc(Cl)cc2)c[nH]1
Yield: 29.7 %

Procedure:
A mixture of 2-(4-chlorophenyl)dimethylaminopropenal (Example 145a) (5.13 g), urea (2.4 g), concentrated HCl (10 ml), water (4 ml) and ethanol (150 ml) was refluxed for 4 hours. After cooling to room temperature concentrated ammonium chloride was added until the pH was 7. The resulting yellow solid was filtered off and dried yielding 1.5 g of 5-(4-chlorophenyl)-2-pyrimidinone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared from 2-bromo-1-fluoro-4-nitro-benzene and N,N-dimethyl-ethylenediamine
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCN=C=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCNC(=O)NC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with ethyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3091, observed 693.3078.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH2:13][O:14][C:10]1=[O:15]
Reactant: O=C1CCCO1
Reactant: O=Cc1ccccc1O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1OCCC1=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Salicylaldehyde (293 g) and γ-butyrolactone (413 g) were dissolved in toluene (2.4 L) and the solution was cooled to not more than 3° C. in an ice-salt bath. Thereto was added sodium methoxide (324 g) over 20 min. The temperature of the reaction mixture rose to 24° C. After stirring at room temperature for 3 hr, the mixture was stirred for 45 min under heating at 60–65° C. The reaction mixture was cooled again in an ice-bath and 10% sulfuric acid (2.51 ml) was added dropwise. The obtained white suspension was filtrated, washed with water and dried to give the title compound (324 g), melting point 162–164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([C:18]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: Cc1ccc(C#N)cc1
Product: CCOC(=O)c1nsc(-c2ccc(C)cc2)n1
Yield: 41.5 %

Procedure:
A solution of 7.48 g (0.0427 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 50.0 g (0.427 mol) of p-tolunitrile (redistilled) was held at 190° C for 72 hours. The reaction mixture, which contained the product in 16% yield, was concentrated under vacuum to 90° C (0.5 torr) to give 4.4 g of black residue. Elution chromatography of this material on 200 g of silica gel (Woelm, for dry column chromatography) with benzene gave 1.7 g of product. Crystallization of this material from hexane (charcoal) gave 0.72 g (7%) of solid, mp 65°-66.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2cccc(Cl)c2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2cccc(Cl)c2C1=O

Procedure:
1.30 g (5.25 mmol) of 7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one are stirred at 90° for 30 minutes in 10 ml of dimethylformamide with 800 mg (6 mmol) of N-chlorosuccinimide. Subsequently, the mixture is poured into water and extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained 3,7-dichloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 211°-212°.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 75 %

Procedure:
Following a procedure similar to that described in Preparation 5(c), but using 2-(diphenylmethoxy)ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 75%.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a cold (−20° C.) solution of Rac-(1S,3R)-3-Hydroxy-cyclopentanecarboxylic acid tert-butyl ester (0.905 g) in dichloromethane (12 mL) was added methanesulfonylchloride (0.664 g) and triethylamine (0.636 g). The reaction mixture was stirred 10 min at −20° C. then poured into ice-water. Organic layer was washed with brine and dried over sodium sulfate then concentrated in vacuo to afford the title compound (1.15 g, 89%) as light yellow oil, used without further purification in the next step. MS (EI): 282 (M+NH4)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[SH:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[OH-].[K+]>CC(O)C>[NH:8]1[CH:9]=[C:5]([CH2:4][CH2:3][S:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[N:6]=[CH:7]1
Reactant: ClCCc1c[nH]cn1
Reactant: Sc1ncc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1c[nH]c(SCCc2c[nH]cn2)n1

Procedure:
183 mg (1.1 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride, 110 mg (1 mmol) of 2-mercapto-1H-imidazole and 200 mg (3.26 mmol) of solid potassium hydroxide are brought to reflux in 10ml of 2-propanol for 4 h. The mixture is then evaporated and the semi-solid residue is chromatographed through silica gel, using a chloroform/methanol (5/1) mixture. The resulting product is treated with oxalic acid in ethanol to provide the title compound in the form of an oxalate salt, M.p.: 224°-226° C.
Reaction SMILES: C1(C2C=C(F)C=C[C:5]=2[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH:20]2[CH2:22][CH2:21]2)=O)CC1.C[Mg]Br.C1C[O:29]CC1>CCOCC>[CH:20]1([C:14]([C:13]2[CH:11]=[CH:5][C:16]([F:19])=[CH:17][CH:18]=2)([OH:29])[CH3:15])[CH2:21][CH2:22]1
Reactant: O=C(c1ccc(F)cc1C1CC1)c1ccc(F)cc1C1CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)C1CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of cyclopropyl-4-fluorophenyl ketone (523 mg, 3.19 mmol) in THF (10 mL) at 0° C. under N2 was added 3 M methyl magnesium bromide (1.7 mL, 5.1 mmol) in Et2O. After 90 minutes at 0° C., the reaction was quenched by addition of brine (10 mL) and diluted with Et2O (100 mL). The organic solution was washed with saturated NaHCO3 (100 mL) and brine (100 mL). Column purification (hexanes:EtOAc 9:1) yielded 1-cyclopropyl-1-(4-fluorophenyl)ethanol (512 mg, 89%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2)(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
To a solution ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (1 g, 3.19 mmol) and TEA (0.64 g, 6.38 mmol, 2 eq) in DCM (20 mL) was added Tf2O (1.8 g, 6.38 mmol, 2 eq) dropwise at 0° C. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water at 0° C., washed with sat.NaHCO3 (10 mL) and brine (5 mL*3). The organic layer was dried over Na2SO4 and concentrated to afford ethyl 1-((6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a brown solid (350 mg, yield: 90%). ESI-MS: 446.1 (M+H)+. 1HNMR (400 MHz, CDCl3) δ: 7.88 (d, J=9.2 Hz, 1H), 7.84-7.82 (m, 2H), 7.79 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 4.13 (q, J=7.6 Hz, 2H), 3.66 (s, 2H), 2.89-2.86 (m, 2H), 2.32-2.28 (m, 1H), 2.11-2.07 (m, 2H), 1.88-1.78 (m, 4H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].C(Cl)(Cl)Cl.[CH3:18][NH2:19]>O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[NH:19][CH3:18])=[O:4]
Reactant: CN
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccsc1C(=O)OC

Procedure:
43.5 G. (0.18 mol) of the obtained 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in 450 ml. of absolute chloroform and dry methylamine is led through the solution at 10° C. until a moistened pH paper shows an alkaline reaction with the solution. The mixture is then allowed to react at room temperature for a further 2 hours, the solution always remaining alkaline. The solution is then shaken out with 500 ml. of water and 500 ml. of a 5% sodium bicarbonate solution [the aqueous phases are back-extracted in each case once with chloroform]. The combined organic phases are dried over sodium sulfate and then evaporated. The crystalline residue is digested with ether for purification. There is obtained 3-methylsulfamoylthiophene-2-carboxylic acid methyl ester of melting point 115°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH:10]([CH3:16])[C:11]([CH:13]1[CH2:15][CH2:14]1)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH3:16])=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[CH:7]=1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Nc1ncc(Br)cn1
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ncc(Br)cn12
Temperature: 100 °C
Reaction time: 24 h
Yield: 12.3 %

Procedure:
To a solution of 5-bromopyrimidin-2-amine (500 mg) in DMF (10 ml) was added 2-bromo-1-cyclopropylpropan-1-one (1.02 g) at room temperature, and the mixture was stirred at 100° C. for 24 h. The mixture was partitioned between EtOAc and 1 M NaOH, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (89 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([OH:16])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]1([CH:7]([O:16][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 6-2 (2.12 g, 10.0 mmol) in tetrahydrofuran (25 ml) under a nitrogen atmosphere was added ethyl 4-hydroxybenzoate (6-3) (1.66 g, 10.0 mmol) followed by triphenyl phosphine (3.15 g, 12.0 mmol). The mixture was cooled in an ice bath and diethyl azodicarboxylate (2.09 g, 12 mmol) was added. This mixture was stirred overnight at ambient temperature and the solvent was removed in vacuo. The residue was taken up in the water and the ether layer was separated, washed with sodium bicarbonate and water, dried, filtered and concentrated in vacuo to yield an oil. Chromatographic purification on silica gel gave 6-4 as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NC2CCCCC2)c2nccn12
Temperature: 90 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
(5,8-Dibromoimidazo[1,2-a]pyrazine, 200 mg, 0.72 mmol), cyclohexylamine (86 mg, 0.86 mmol) and di-isopropylethylamine (140 mg, 0.74 mmol) are suspended in iso-propanol (5 ml). The mixture is stirred at 90° C. for 18 h. The solvent is evaporated in vacuo and the residue dissolved in dichloromethane (5 mL). The organic layer is washed with saturated NaHCO3(aq) (10 ml), H2O (10 ml) and brine (10 mL). The organic layer is dried (MgSO4) and evaporated in vacuo. The oily residue is purified by column chromatography, eluting with 5:1 hexane:ethyl acetate to give a brown oil (147 mg, 69%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 3.83 min (99.8%), m/z (APCI) 295 (M+H)+.