Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][NH:12][CH2:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2sc3ncnc(Cl)c3c2C1
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CNCC4)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 12A from tert-butyl 4-chloro-7,8-dihydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidine-6(5H)-carboxylate from Example 75A (122 mg, 0.37 mmol) and 3,4-dichloroaniline (64 mg, 0.39 mmol) to yield 127 mg (91%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1)=[CH2:2].[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14]>C1COCC1>[F:11][C:12]([F:18])([F:17])[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)=[O:14]
Reactant: COC(=O)C(F)(F)F
Reactant: C=Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
The (4-vinylphenyl)magnesium bromide solution of Example 1 was cooled to −78° C. using a dry ice /acetone bath and a solution of methyl trifluoroacetate (20.00 g, 156.19 mmol) in THF (25 mL) was added dropwise over 15 min. The reaction mixture was stirred in the cooling bath for 1 h, then quenched by pouring into cold 1N H2SO4. The aqueous solution was extracted with ether and the combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 17.81 g of a pale yellow oil. This material was purified by vacuum distillation to provide 12.65 g (46%) of a colorless oil: bp 59-60° C. (1.4 mm); 1H NMR (CDCl3) δ 8.05 (d, 2ArH), 7.55 (d, 2ArH), 6.79 (dd, CH═), 5.97 (dd, ═CHH), 5.51 (dd ═CHH).
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26]>O1CCCC1>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)#[N:26]
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: N#CCCCCBr
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: N#CCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0° is added dropwise over 20 minutes a solution of 2-(3-pyridyl)indole (1.9 g) in 12 ml of tetrahydrofuran. The mixture is stirred at 0° for 0.5 hour and is then treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of tetrahydrofuran. This mixture is stirred at 0° for 1 hour, then at room temperature for 1 hour, and is then poured into 125 ml of ice-water. This is extracted with 2×50 ml of ether, the extract is washed with water, dried, evaporated to dryness and purified to give 3-(4-cyanobutyl)-2-(3-pyridyl)indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:9]([NH:16][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Yield: 40.3 %

Procedure:
Acid, 3-oxocyclobutanecarboxylic acid (10 g, 0.087 mol), benzylamine (10.5 mL, 0.96 mol), and triethylamine (38 mL, 0.26 mol) were dissolved in DMF (100 mL). BOP (38.7 g, 0.087 mol) was added at 0° C. under stirring in argon. The mixture was stirred at 20° C. for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was purified by chromatography (silica gel, 63-100 μm, 1 L, CCl4→CHCl3, CHCl3/MeOH 100:0→95:5). The title compound (7.12 g, 40%) was obtained as a colorless oil. 1H NMR-data (DMSO-d6): 8.62 (br.s, 1H, NH); 7.21-7.36 (m, 5H, Ph); 4.32 (d, 2H, CH2, J=6.1 Hz); 3.10-3.28 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[N:4]=1.[S:21](=[O:36])(=[O:35])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][O:33][CH3:34])[NH2:22].N12CCCN=C1CCCCC2>C(#N)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12](=[O:20])[NH:22][S:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:36])=[O:35])[N:6]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COCCOc1ccccc1OS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
1.74 g (0.0063 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are dissolved in 80 ml of acetonitrile, and 1.48 g (0.006 mol) of 2-(2-methoxyethoxy)phenyl sulfamate are added at room temperature. 1.0 g (0.0066 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the reaction mixture is then stirred at room temperature for 18 hours, concentrated, diluted with H2O and acidified with 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.4 g (93% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[2-(2-methoxyethoxy)phenoxysulfonyl]urea of melting point 106°-108° C. are obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])S[CH2:4][CH2:3]1.OO.[S:19]([O-:22])(O)=[O:20].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:19](=[O:22])(=[O:20])[CH2:4][CH2:3]1
Reactant: O=S([O-])O
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2C
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2C
Yield: 98 %

Procedure:
A 30-ml eggplant type flask was charged with 0.75 g (3.2 mmol) of the 4,5,8-trimethylthiochroman-6-carboxylic acid, 1.1 g (9.5 mmol) of 30% hydrogen peroxide and 1 ml of acetic acid, and the mixture was allowed to react at 100° C. for 2 hours. The reaction mixture was poured into a sodium hydrogensulfite aqueous solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the solvent was distilled off to give 0.76 g (yield 98%) of 4,5,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[N:27]1([N:33]=[CH:25][C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: NN1CCCCC1
Solvent: CCO
Solvent: ClCCl
Product: C(=NN1CCCCC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Yield: 107 %

Procedure:
To a solution containing 342 mg (1.01 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde and 100 mg (1.0 mmol) of piperidin-1-ylamine are added 3.5 mL of ethanol and 1.5 mL of dichloromethane. The reaction medium is heated at 80° C. for 1 hour. The solvents are evaporated off and 450 mg of a powder are obtained and used in the following step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1C(C1C=C(C)C=CC=1N1N=CC=N1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[N:35]1[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[N:36]1)=[O:33]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)O)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in Example A68 using 5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid. MS (ESI) 394 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[O:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[O:25][C:24]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])o4)nc23)CC1
Yield: 61.5 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0093 mL (0.053 mMol) 5-nitro-2-furoyl chloride, 0.010 gm (64%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH:7]([F:9])[F:8]>ClCCCl>[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([Cl:3])=[O:15])[CH:7]([F:9])[F:8]
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1cccc(OC(F)(F)C(F)F)c1
Reaction time: 3 h

Procedure:
39.4 parts by weight of thionyl chloride are added to a suspension of 65 parts by weight of m-(1,1,2,2-tetrafluoroethoxy)-benzoic acid in 500 parts by volume of 1,2-dichloroethane and the mixture is stirred for 3 hours under reflux. It is then concentrated under reduced pressure, and after filtering off a small amount of starting material which has precipitated, m-(1,1,2,2-tetrafluoroethoxy)-benzoyl chloride is obtained as a yellowish oil. The IR spectrum shows C=O bands at 1,770 and 1,748 cm-1 and fluoroalkoxy bands at 1,225, 1,190 and 1,125 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[C:6][C:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1)[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][N+:2]([O-:31])([CH2:4][C:5]#[C:6][C:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1)[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Solvent: ClC(Cl)Cl
Product: C[N+](C)([O-])CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2 g. of N,N-dimethyl-3-(8-chloro-dibenzo [b,f]thiepin-10-yl)-2-propynylamine in 100 ml. chloroform is treated at -50° C. with 1.2 g. of m-chloroperbenzoic acid. The solution is stirred for 15 minutes at this temperature, warmed to room temperature and chromatographed on basic aluminum oxide using chloroform/methanol (9:1) as the eluant, whereby there is obtained N,N-dimethyl-3-(8-chloro-dibenzo [b,f]thiepin-10-yl)-2-propynylamine N-oxide, which melts at 68°-69° C. after recrystallization from ethyl acetate/petroleum ether.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:15]O>C(O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:15]
Reactant: NO
Reactant: COc1ccc(C=O)c(F)c1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(C#N)c(F)c1OC
Reaction time: 2.5 h

Procedure:
4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride are heated under reflux for 5 hours together with 30 ml of ethanol. The reaction mixture is subsequently evaporated and the residue, dried in a high vacuum at 23°, is introduced into 40 ml of phosphorus oxychloride. After stirring at 23° for 2.5 hours the reaction mixture is evaporated, the residue is treated with ice-water, the precipitate which thereby forms is filtered off, washed with water, taken up in methylene chloride, the methylene chloride solution is dried over sodium sulfate and evaporated. By recrystallization of the residue from methylene chloride/hexane there is obtained 2-fluoro-3,4-dimethoxybenzonitrile of m.p. 64°-65°.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH:3]=[CH2:4].CCN(CC)CC.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:26]1([CH2:25][O:32][C:33](=[O:34])[NH:17][CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:2]([CH3:1])([CH3:5])[CH:3]=[CH2:4])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC(C)(C)c1[nH]c2ccccc2c1CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,1-dimethyl-2-propenyl)-1H-indole-3-ethanamine (0.707 g, 3.07 mmol) in dry CH2Cl2 (30 mL) at 0° C. under argon was added NEt3 (0.98 mL, 6.93 mmol) and BnOC(O)Cl (1.10 mL, 7.32 mmol). The reaction was permitted to warm to rt while stirring overnight. It was diluted with CH2Cl2, and extracted with cold H2O. The CH2Cl2 layer was separated. The H2O layer was re-extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with satd aq NaHCO3 and brine, dried, filtered and concentrated to give an oil. This oil was purified by silica chromatography to provide the title compound: TLC Rf=0.34 (CH2Cl2); MS (EI) m/z 362.3, 254, 211, 198, 182. 168, 167, 108, 91, 77, 65, 51; 1H NMR (300 MHz, CDCl3) δ 7.89 (1H), 7.56 (1H), 7.33-7.26 (6H), 7.10 (2H), 6.12 (1H), 5.18-5.12 (2H), 5.12 (2H), 4.87 (1H), 3.47 (2H), 3.07 (2H), 1.53 (6H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccnc1S
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cn1ccnc1SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 49 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1-methylimidazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 49% yield.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:12][CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:14][C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1>>[CH2:12]([C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:14][C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1)[CH3:13]
Reactant: CCC(C)=CCCC(=CCBr)CC
Reactant: Oc1ccc2c(c1)OCC2
Product: CCC(C)=CCCC(=CCOc1ccc2c(c1)OCC2)CC

Procedure:
1-bromo-3-ethyl-7-methyl-2,6-nonadiene and 6-hydroxy2,3-dihydrobenzofuran are reacted to form 6-[(3-ethyl-7-methyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 132° C. -134° C./0.001 mmHg; nD20 = 1.5346;
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][C:12]#[N:15])=[CH:7][CH:6]=1
Reactant: C=CC#N
Reactant: Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: N#CCCOc1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
5.4 g of sodium methylate were added portionwise at 60° C. to 112.1 g of 4-fluoro-phenol. After 10 minutes, the mixture was treated with 500 ml of acrylonitrile, boiled in an oil-bath for 48 hours, thereafter poured into 3 l of water and extracted with chloroform. After drying the organic phase with sodium sulfate, it was concentrated completely in vacuo. There was obtained 3-(4-fluoro-phenoxy)propionitrile as a viscous oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:29]([CH3:30])[CH3:28])[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 3.7 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using dimethylamine hydrochloride (232 mg, 2.85 mmol) and N,N-diisopropylethylamine (294 mg, 2.28 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 8 mg, 4%) which was obtained as a light brown solid. MS: m/e=377.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C@@H:6]([NH:14]C(OC(C)(C)C)=O)[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:3])[CH3:2].[ClH:29]>CCOCC>[ClH:29].[C:1]([O:4][C@@H:5]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C@@H:6]([NH2:14])[C:7](=[O:13])[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](c1ccc(F)cc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)O[C@@H](c1ccc(F)cc1)[C@@H](N)C(=O)N1CCCC1

Procedure:
A solution of (1S,2R)-2-(tert-butoxycarbonylamino)-1-(4-fluorophenyl)-3-oxo-3-(pyrrolidin-1-yl)propyl acetate, CCH 23140-2 (104 mg, 264 μmol), in Et2O (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirbar was stirred for 1 h at RT in presence of a stream of HCl. The reaction mixture was concentrated and dried for 3 days under vacuum to obtain (1S,2R)-2-amino-1-(4-fluorophenyl)-3-oxo-3-(pyrrolidin-1-yl)propyl acetate hydrochloride, Compound 17, as a white solid (86 mg, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12.CC(C)([O-])C.[K+].[CH3:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:29]4[N:28]([CH3:27])[C:32]5=[N:33][CH:34]=[CH:35][CH:36]=[C:31]5[N:30]=4)=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 4-(5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (238 mg) in DMA (4 ml) was added potassium tert-butoxide (112 mg) at room temperature. After stirring for 10 min, 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (211 mg) was added, and the obtained mixture was stirred at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (THF) and recrystallized from hexane/THF to give the title compound (229 mg).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C1(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
An ozone stream (2.5 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70° of 12.7 g (RS)-2-(2-buten-1-yl)-3,3,6-trimethyl-1-indanone in 200 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 6.12 ml of dimethyl sulfide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 150 ml of dichloromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 11.3 g (94%) of (RS)-2-(2-oxoethyl)-3,3,6-trimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][OH:12]>N1C=CC=CC=1>[O:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][O:12][S:1]([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCCO1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Mesylchloride (12.1 g) was added to a mixture of (S)-1-(Tetrahydro-furan-2-yl)-methanol (10.0 g) and pyridine (55 mL) at −15° C. and stirred for 1.5 hours at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with a solution of potassium hydrogensulfate (20%) and with a solution of saturated sodium hydrogencarbonate, dried over magnesium sulfate and concentrated.