Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.Cl[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[OH-].[Na+]>CO.O>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]=[C:7]1[NH:8][CH2:9][CH2:10][NH:11]1
Reactant: Nc1ccccc1Cl
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccccc1N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To 2-chloroimidazoline bisulfate (60.0 g, 300 mmoles) in methanol (600 ml) and water (150 ml) is added with stirring 2-chloroaniline (81.1 g, 67 ml, 636 mmoles). The heterogeneous mixture is stirred at ambient temperature overnight. After 20 hours the mixture is poured into ice water, made strongly alkaline with sodium hydroxide and extracted with dichloromethane twice. The organic extracts are washed once with water and once with saturated sodium chloride solution and then extracted with 2 N acetic acid (2×1 liter). The combined acid extracts are backwashed with dichloromethane, made strongly alkaline with sodium hydroxide, and once again extracted with dichloromethane twice. The dichloromethane extracts are combined, washed with water and then sodium chloride solution and finally dried and evaporated in vacuo. The solid residue (31 g) is dissolved in hot toluene, filtered, and diluted with hexane (total volume 3 liters). Colorless crystals separate which are filtered, washed with hexane and air-dried, to give 28.2 g of 2-(2-chlorophenylimino)imidazolidine, m.p. 133°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Se](=O)=[O:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]2[C:9]([CH:12]=[O:14])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1cccc2occ(C)c12
Solvent: C1COCCO1
Product: COc1cccc2occ(C=O)c12

Procedure:
To a solution of 4-methoxy-3-methyl-benzofuran (J. Chem. Res. Synopses (1996), 132) (4 g, 24.66 mmol) in 40 ml of dioxane is added selenium dioxide (3.39 g, 29.59 mmol) and the mixture is heated under reflux for 24 hours. It is then cooled and filtered. The solvent is evaporated and the crude red solid is used as such in the next step.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>C1(C)C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19]
Reactant: CCC(C)NC
Reactant: O=C(O)c1nc(-c2ccccc2)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCC(C)N(C)C(=O)c1nc(-c2ccccc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 19, starting from 2.5 g of 4-phenyl quinazoline 2-carboxylic acid, 10 ml of thionyl chloride, 25 ml of toluene and 10 ml of N-methyl 2-butanamine. 2.2 g of N-methyl N-(1-methyl propyl) 4-phenyl quinazoline 2-carboxamide, melting at 128° C., are obtained.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCC([OH:35])C>>[OH:35][CH:11]([CH3:12])[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(O)CN
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-amino-2-propanol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 317 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, s) 10.22 (1H, s) 7.99 (1H, d, J=5.47 Hz) 7.94-7.98 (1H, m) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.27 Hz) 7.28 (1H, dd, J=3.42, 2.44 Hz) 6.77 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.42, 1.85 Hz) 4.70 (1H, d, J=4.69 Hz) 3.69-3.79 (1H, m) 3.09-3.20 (2H, m) 1.01 (3H, d, J=6.05 Hz)
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1>>[Cl:27][C:23]1[N:22]=[C:21]([NH:20][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:26]=[N:25][CH:24]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH:13]=1
Reactant: N#CC1CCC1
Reactant: Fc1cc(Br)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cc(Br)ccn2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
LiHMDS (1M in toluene, 17.7 mL, 17.7 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) solution of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol) and cyclobutanecarbonitrile (1.39 g, 17.1 mmol, 3 eq) in toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 5 h, quenched by addition of a saturated solution of NaHCO3 (50 mL) and filtered through a pad of celite. The filtrate is extracted with EtOAc (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 933 mg of the title compound as a yellow oil: ESI-MS: 237.0/239.0 [M+H]+; tR=4.27 min (System 1); TLC: Rf=0.30 (Hex/EtOAc, 9:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][C:32](=[O:34])[CH3:33])[C:6]([Cl:11])([Cl:12])[C:7]([F:10])([F:8])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1C(O)C(Cl)(Cl)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of 954 mg (2.00 mmol) of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 4, in 2 ml of pyridine, 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography (silica gel, dichloromethane/hexane =1/1) to obtain 1.02 g of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CCCCCC.O1CCCC1.[Cl-].[Na+]>[O:26]=[C:25]([CH2:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CP(=O)(OC)OC)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a mixture cooled at -78° C. of 50 ml of 2.1M n-butyl lithium solution in hexane and 100 ml of tetrahydrofuran, was added dropwise 12.4 g of dimethyl methylphosphonate. The mixture was stirred at -78° C. for 30 minutes, and thereafter 22.4 g of methyl 3-(3,4-dimethoxyphenyl)propionate [synthesized from 3,4-dimethoxycinnamic acid in 2 steps: (a) esterification (HCl--CH3OH) and (b) reduction (Pd/C--H2)] and 100 ml of tetrahydrofuran were added dropwise to the mixture. Then, the reaction was continued at -78° C. for 22 hours. The reaction mixture was poured in 500 ml of saturated aqueous sodium chloride solution. After neutralization and extraction with dichloromethane, the extract was dried and concentrated to give crude product. By purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=1:4), 9.0 g of the above caption compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>C(Cl)(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][S:13][CH2:14]2)=[CH:5]1
Reactant: C1CSCN1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: ClC(Cl)Cl
Product: c1ccc2c(CCN3CCSC3)c[nH]c2c1
Temperature: 25 °C

Procedure:
3-(2-Bromo-ethyl)-indole (3.00 g, 13.4 mmol) and thiazolidine (2.38 g, 26.8 mmol) were stirred in abs. CHCl3 (25 ml) at a bath temperature of 75° C. for 5 h. The mixture was cooled to RT and extracted with dilute sulfuric acid (2×30 ml). The acidic aqueous phase was rendered alkaline with 5N NaOH, while cooling with ice, and extracted with ether (3×30 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue was purified by flash chromatography with CHCl3/MeOH (20:1→4:1→MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nccs2)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
4-Cyclohexyl-4-formyl-piperidine-1-carboxylic acid tert-butyl ester, 3, (296 mg, 1.0 mmol) and 2-aminothiazole (103 mg, 1.0 mmol) are dissolved in toluene (15 mL), and the mixture was refluxed using a Dean-Stark apparatus overnight. The solution is then cooled to room temperature and sodium triacetoxyborohydride added. The reaction is stirred at room temperature for three hours and then diluted with ethyl acetate. The reaction mixture is washed with aqueous sodium bicarbonate and brine. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to afford 312 mg (82% yield) of the desired compound. MS (ESI) m/z 380 (M+H+)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][C:2](=[O:3])[N:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH3:6])[CH:8]=[CH:9]2)[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: Cn1ccc2cc(Nc3ccncc3)ccc21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(c1ccncc1)c1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl chloroformate (1.3 g) in 5 ml DCM was added to a solution of 1-methyl-5-(4-pyridinylamino)-1H-indole (2.5 g) in 120 ml DCM and 6 ml triethylamine (4.4 g). After stirring one hour at ambient temperature the reaction mixture was washed with water and saturated sodium chloride, dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 3.1 g of a solid. Recrystallization from methanol yielded 2.4 g of crystals, mp 157°-159° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1>>[ClH:1].[ClH:14].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][N:30]([C:2]4[C:3]5[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CCn4c(nnc4C(N)c4ccc(Cl)cc4)C3)c21
Yield: 64 %

Procedure:
Using the procedure from Example 8, Step 5, using (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (100 mg, 0.30 mmol) to afford (4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (75 mg, 0.19 mmol, 64%): LCMS APCI+(M+H+): 396 (60%), 398 (20%), rt 2.48 min. HPLC purity at 254 nm>99%, rt=1.68 min. 1H NMR (400 MHz, d6-DMSO) □ 9.51 (s, 3H), 8.85 (d, J=9.4 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 6.08 (br d, J=9.0 Hz, 1H), 5.42 (dd, J=26 Hz, 16 Hz, 1H), 5.19 (dd, J=21 Hz, 18 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 3.79 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.32 (m, 1H), 1.82 (m, 1H), 1.15 (t, J=6.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:25]2[N:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[CH:27][CH:26]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(C)C)Oc2ccc(Cl)nc2)cc1
Product: CC(C)CCCC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 515.2 [M−H]−.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:37].N(C(OCC)=O)=NC(OCC)=O>>[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:44][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCC=C(c1ccccc1)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccccc2)c2ccncc2)cc1)OCC
Yield: 42.5 %

Procedure:
Reaction of 3-phenyl-3-pyridin-4-yl-prop-2-en-1-ol (0.50 g, 2.37 mmol), triphenylphosphine (0.68 g, 2.61 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.68 g, 2.84 mmol) and diethyl azodicarboxylate (0.46 g, 2.63 mmol) in an identical manner to example 1 gave the title compound (435 mg, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](N)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[BrH:14].N#N.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:14])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)c1nc(C)cnc1N
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nc(C)cnc1Br
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C) (2.0 g, 11 mmol), 4 mL water and 3.7 mL (33.1 mmol) hydrobromic acid 48% was cooled to 5° C. 2.5M NaNO2— solution in water (5.3 mL, 13.2 mmol) was added drop wise at 5° C. (N2-evolution!). The reaction mixture was stirred for 1 hr and poured then into ice-water. The reaction mixture was neutralized with Na2CO3 and extracted two times with ethyl acetate (200 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->50:50 gradient). The desired compound was obtained as a colorless liquid (0.53 g, 20%), MS: m/e 245.1 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5]([CH3:8])([OH:7])[CH3:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.O>CN(C)C=O>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:7][C:5]([CH3:8])([CH3:6])[C:4]([F:10])([F:9])[F:3])[CH:14]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(OCc1cccc(Cl)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a suspension cooled to 0° C. of sodium hydride (126 mg, 60 wt. % oil dispersion) in N,N-dimethylformamide (5 ml) was added dropwise, 1,1,1-trifluoro-2-methylpropan-2-ol (320 μL) under argon atmosphere, and the mixture was stirred for 15 minutes. To this reaction mixture was added dropwise 1-bromomethyl-3-chlorobenzene (320 μL), and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 40/1) to give the titled compound (389 mg).
Reaction SMILES: [H-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:7]=1[N+:13]([O-:15])=[O:14].C[CH2:17][O:18]C(C)=O>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:18][CH3:17])[C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 100 mL three-necked flask containing 10 mL of THF and 0.255 mL of MeOH. The mixture is stirred at room temperature for 1 hour, and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of THF is added. The reaction medium is left at room temperature for 16 hours. 10 mL of EtOAc are added and the resulting mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 is obtained (cream-coloured solid).
Reaction SMILES: [CH3:1][CH:2]([C:4]1([S:14][CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:3].Cl[CH2:17][CH2:18][O:19]C1CCCCO1>>[OH:19][CH2:18][CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH:2]([CH3:1])[CH3:3])([S:14][CH3:15])[C:5]1=[O:13]
Reactant: CSC1(C(C)C)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CSC1(C(C)C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-(1-methylethyl)-3-methylthio-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1ccccn1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccn1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromopyridine as described in Example 14. The compound was isolated by chromatography as in Example 14 and was crystallized from ethyl acetate to give colorless crystals with m.p. 179°-181° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](Cl)(Cl)([Cl:44])[Cl:43]>ClCCl.[Zn]>[CH3:1][C:2]([CH3:22])([CH:3]=[C:42]([Cl:44])[Cl:43])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C=O)COCc1ccc(F)c(Cc2ccccc2)c1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C=C(Cl)Cl)COCc1ccc(F)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)propan-1-al (0.4 g), triphenylphosphine (0.77 g), zinc dust (0.10 g) and carbon tetrachloride (3 cm3) in dichloromethane (3 ml) was heated at the reflux temperature for five hours. After cooling to the ambient temperature (ca 25° C.), the mixture was allowed to stand for 14 hours where upon it was triturated with diethylether. The solvent was evaporated under reduced pressure and the residue was passed through a short plug of silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent to give 2,2-dimethyl-1-(3-benzyl-4-fluorobenzyloxy)-4,4-dichlorobut-3-ene (0.44 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH:21]=O)=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH2:21][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1
Reactant: O=Cc1csc2ccc(Cl)nc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1csc2ccc(Cl)nc12
Yield: 30.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-6, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (1.98 g, 13.4 mmol) was reacted with 5-chlorothieno[3,2-b]pyridine-3-carbaldehyde (Compound XIX-1) (1.98 g, 10 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=98:2 to 95:5) to obtain the title compound (996 mg, 30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][OH:17])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][O:17][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[Cl:19])[CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N(CCO)[C@H]1CC[C@H](C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(N(CCOCc2ccccc2Cl)C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a mixture of (2-hydroxy-ethyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 2.91 mmol) and 2-chlorobenzylbromide (0.90, 4.37 mmol) in DMF (8 mL) was added NaH (60% in mineral oil, 0.23 g, 5.83 mmol) and the reaction mixture was stirred for 16 h. H2O (4 mL) was added and the mixture was extracted with diethyl ether (3×5 mL). The organic phase was collected and the solvent was removed in vacuo to give the crude product of [2-(2-chloro-benzyloxy)-ethyl]-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester. This was dissolved in DCM (4 mL) and TFA (4 mL) was added and the mixture was stirred for 2 hs before the volatiles were removed in vacuo.