Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1.[H-].[Na+].[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[F:32])[C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1
Reactant: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(Cc1ccccc1F)c1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47 mg (0.12 mmol) of the compound from example 15A were initially charged in 3 ml of THF, and the mixture was cooled to 0° C. Subsequently, 5 mg (0.12 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 14 μl (0.12 mmol) of 2-fluorobenzyl bromide were added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). The crude product obtained in this manner was purified by means of preparative thin-layer chromatography (mobile phase: dichloromethane-methanol 20:1). This gave 8 mg of the target compound (13% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1

Procedure:
Then, trans-4-(p-chlorophenyl)cyclohexane carboxylic acid (160 g, 0.67 mole) was stirred together with 100 ml of thionyl chloride and 500 ml of carbon tetrachloride at a reflux temperature for one day and a night. Then the solvent was distilled off by an evaporator. The residue was distilled under reduced pressure, whereby trans-4-(p-chlorophenyl)cyclohexane carboxylic acid chloride was obtained as a yellow liquid. The amount was 152 g, the yield was 88%, and the boiling point was 144° C./0.3 mmHg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[C:18]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])[CH:17]=[N:16]2>>[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[C:18]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[C:7]([C:4]1[C:5]([C:20]3[CH:15]=[CH:14][C:13]([F:12])=[CH:22][CH:21]=3)=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:9])[CH:17]=[N:16]2
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Reactant: Cn1ccc(C(=O)O)n1
Agent: Cl
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)c1nn(C)cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 4-4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (46 mg, 0.21 mmol) and N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol) according to the procedure described for Example 1, as a yellow solid (65 mg, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]Br.OC1C=CC(C)=CC=1C1C2N=NNC=2C=CC=1OC(CC(C)(C)C)(C)C>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:39])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccc(OC(C)(C)CC(C)(C)C)cc3n2)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc(O)c(-c2c(OC(C)(C)CC(C)(C)C)ccc3[nH]nnc23)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)Oc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 8.236 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2 (2′hydroxy 5′methyphenyl)-5-tert-octyloxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was 7.8 g (81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][C@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH:9]([O:8][C:4]1[CH:3]=[C:2](/[CH:16]=[CH:15]/[CH2:14][C@@H:13]([OH:17])[CH3:12])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: C=CC[C@H](C)O
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Temperature: 135 °C
Yield: 60.7 %

Procedure:
A mixture of 5-bromo-3-isopropoxypyridine (12.56 g, 58.13 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35 mL, 252 mmol) and acetonitrile (35 mL) was heated in a sealed glass tube at 130-140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (50 mL) was added and the mixture was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 7.80 g (60.7%) of a pale-yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([CH3:13])=[CH:9][C:10]([N+:19]([O-:21])=[O:20])=[C:11]1[CH3:12])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NCCn1c(C)cc([N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
18.0 g (0.1 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole are introduced into 54 ml of concentrated sulphuric acid at -10° C., during which the temperature rises to 9° C. After the mixture has been subsequently stirred for 5 minutes, 10.9 g (0.11 mol) of potassium nitrate are introduced at about 5° C. After further stirring for 30 minutes, the mixture is poured onto 300 g of ice and extracted with methylene chloride, the extract is concentrated and the residue is chromatographed over a short silica gel column.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[C:6]1([S:12][CH:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([S:12][C:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1=CSCC1Sc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cscc1Sc1ccccc1
Yield: 90 %

Procedure:
3.6 parts by volume of sulfuryl chloride in 25 parts by volume of methylene chloride are added, at 0° C., to a solution of 8.76 parts of 3-phenylthio-4-dihydrothiophene-nitrile in 100 parts by volume of methylene chloride. During the reaction, nitrogen is passed into the mixture. The end product is isolated from the reaction mixture by the method described in Example 5c. 7.8 parts (90% of theory) of 3-phenylthio-4-thiophene-nitrile of melting point 32°-34° C. are obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1.N1C=CC=CC=1>O>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
75 μl of methanesulfonyl chloride was added to a mixture comprising 100 mg of 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline and 3 ml of pyridine. The obtained mixture was stirred at room temperature for 1.5 hours. 20 ml of water was added in portions to the reaction mixture to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 109 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[CH:16]([Li])=[CH2:17]>>[CH3:8][C:2]([C:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:1])[CH2:3][CH2:4][C:5](=[O:7])[CH:16]=[CH2:17]
Reactant: [Li]C=C
Reactant: CC1=CC=C(C(C)(C)CCC(=O)O)CC1
Product: C=CC(=O)CCC(C)(C)C1=CC=C(C)CC1

Procedure:
reacting the 4-methyl-4(4-methyl-1,3-cyclohexadien-1-yl)pentanoic acid with vinyl lithium to form the intermediate 6-methyl-6(4-methyl-1,3-cyclohexadien-1-yl)hepten-3-one which is converted via an internal Diels-Alder reaction to form the 1,7,7-trimethyltricyclo[6.2.2.03,8 ]dodec-9-en-4-one.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:14][CH2:13][CH2:11][OH:12]
Reactant: NCCO
Reactant: Fc1cccc(F)c1CBr
Solvent: CCO
Product: OCCNCc1c(F)cccc1F
Temperature: 75 °C
Yield: 97.5 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (3.7 g, 17.8 mmol) and ethanolamine (6.46 mL, 107 mmol) in ethanol (18 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (75 mL) and the aqueous layer extracted with dichloromethane (50 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellow solid (3.25 g). (m/z): [M+H]+ calcd for C9H11F2NO, 188.08. found, 188.1. 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H), 7.10-7.05 (m, 2H), 4.47 (t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J=5.5 Hz, 2H), 2.25 (t, J=5.7 Hz, 2H), 1.82 (br s, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].OC1C=CC=CN=1.[C:13]([O:17][C:18](=[O:48])[NH:19][C@H:20]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:24][C:23]1([CH3:38])[CH3:37])([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18](=[O:48])[NH:19][C@@H:20]([CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:24][C:23]1([CH3:38])[CH3:37])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:44]([CH3:45])[CH3:46])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCCCN
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CN1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
0.89 ml of n-butylamine (9.5 mmol) and 28 mg of 2-hydroxypyridine (0.48 mmol) were added to 250 mg of {(S)-2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (62f) (0.48 mmol), and the mixture was stirred at 70° C. for one hour. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 254 mg of the title compound (yield: 89%).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:24]1[C:32]([NH2:33])=[C:31]2[C:27]([NH:28][CH:29]=[N:30]2)=[N:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:33][C:32]1[N:24]=[CH:25][N:26]=[C:27]2[C:31]=1[N:30]=[CH:29][N:28]2[CH:2]([C:4]1[O:5][C:6](=[O:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1)n1cnc2c(N)ncnc21
Yield: 36.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-(dimethylamino)phenyl)-1H-isochromen-1-one (intermediate C8, 86 mg, 0.231 mmol), 9H-purin-6-amine (46.8 mg, 0.347 mmol) and K2CO3 (47.9 mg, 0.347 mmol) to give the title compound (36 mg, 37%). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%). The resulting product was further purified by Preparative HPLC (method 1) to give the title compound (12 mg, 12%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 3.44 g (16.4 mmol) 2,4-dichloro-benzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 2.5 g (79%) of the title compound.
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.I[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]>C1COCC1.C(OCC)(=O)C>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC1=NC(C(C)C)C(OC)=NC1
Reactant: FC(F)(F)CCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirred solution of 2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (1 mL, 5.58 mmol) in THF (13.5 mL) under argon at −78° C. was added a solution of n-butyllithium (2.5 M, 2.3 mL, 5.75 mmol). The solution was stirred at −78° C. for 30 minutes. A solution of 1-Iodo-3,3,3-trifluoropropane (925 μL, 5.87 mmol) in THF (11.5 mL) was added slowly. The resulting solution was stirred at −78° C. for 5 hours, warmed to room temperature and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NH4Cl solution, water and brine. The organic layer was then dried (MgSO4), concentrated and purified by flash chromatography to yield 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine (915 mg, 59%). 1H-NMR: 400 MHz, (CDCl3) δ: 4.04-3.99 (m, 1H), 3.98-3.95 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.29-2.20 (m, 1H), 2.18-2.04 (m, 3H), 1.94-1.84 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C(O)CCC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][CH2:18][OH:19])([O-:14])=[O:13]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated till reflux. Stirring at reflux is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is acidified with a hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleumether. The product is filtered off and dried, yielding 141 parts (100%) of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH2:12][CH3:13])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([OH:11])[CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CCOC(=O)CBr
Reactant: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol and 200 ml of 2-butanone is added a mixture of 7.35 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 7.4 g of potassium carbonate and 3.3 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 3 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are washed, dried over anhydrous magnesium sulfate, filtered and the solvent removed to give an oil which solidifies on cooling. Recrystallization from ethyl ether and hexane gives 10 g of ethyl [(6,7-dichloro-2-(1-hydroxypropyl]benzo[b]thien-5-yl]oxy]acetate, mp 69°-70°.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[H-].[Na+].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH:24]=[CH2:25]>O>[CH2:24]([C:23]([CH2:22][CH2:21][CH:20]=[CH2:19])=[CH:10][C:8]([O:7][CH3:6])=[O:9])[CH3:25]
Reactant: C=CCCC(=O)CC
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=CC(=O)OC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (25 mL) solution of trimethyl phosphonoacetate (4.67 g, 25.1 mmol) was added dropwise at 0° C. over 1 hour to a tetrahydrofuran (25 mL) suspension of sodium hydride (1.04 g, 63%, 27.4 mmol). To the mixture, tetrahydrofuran (25 mL) was further added, and the mixture was then stirred at 0° C. for 1 hour. To this solution, a tetrahydrofuran (25 mL) solution of 6-hepten-3-one (2.56 g, 22.8 mmol) was added dropwise at 0° C. over 20 minutes, and the mixture was stirred at room temperature for 2.5 hours and subsequently stirred at 65° C. for 3 hours. The mixture was treated with water, and volatile portions were then distilled off under reduced pressure, followed by extraction with hexane. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (3.04 g, 79%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].F[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:26][CH2:25][CH2:24][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCS
Reactant: Fc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%) (0.75 g, 19 mmol) was added to a solution of ethanethiol (2.1 ml, 1.7 g, 28 mmol) in N,N-dimethylformamide (15 ml) at 0° C. under an argon atmosphere. After stirring for 0.5 hours, 2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]-imidazole (3.5 g, 12.5 mmol) of Example 2 was added and the resulting solution heated to 95° C. for 6 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue partitioned between 1N aqueous sodium hydroxide and dichloromethane. The organic layer was washed successively with water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel eluting with 25:1 chloroform/methanol. Fractions containing product were combined, the solvent evaporated and the residue recrystallized from ethyl acetate to afford the titled compound; mp. 124°-125° C. Anal. Calcd. for C19H19N3S: C,70 99; H, 5.96; N, 13.08; S, 9.97: Found: C, 70.99; H, 5.92; N, 13.07; S, 9.81.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:13][CH2:12][CH2:11]1)=[O:9])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:11][CH2:12][CH2:13]1)(=[O:23])=[O:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)S(=O)N1CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)(=O)N1CCC1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of 4.62 g (21 mmol) of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acid ethyl ester in DCM (100 mL) at room temperature are added 5.46 g (32 mmol) of meta-chloroperbenzoic acid. The reaction is stirred for 1 h before Ambersep 900-OH resin (2.9 g) is introduced. The suspension is shaken for 2 h and then filtered. The filtrate is concentrated under reduced pressure. The residue is dissolved in DCM (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic layer is dried (Na2SO4) and filtered. The solvent is removed under reduced pressure to provide 5 g of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid ethyl ester as an orange oil, which is used in the next step without further purification. Yield 100%, ES-MS: m/z 236 [M+H].