Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=[C:14]3[NH:24][CH:25]=[CH:26][C:13]=23)[CH2:8][CH2:7]1)=[O:5].[CH3:27][C:28]([CH3:30])=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.CCOCC.CN(C=O)C.C(Cl)CCl>[CH:28]([NH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=[C:14]3[NH:24][CH:25]=[CH:26][C:13]=23)[CH2:8][CH2:7]1)=[O:5])([CH3:30])[CH3:27]
Reactant: CC(C)=O
Reactant: NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOCC
Product: CC(C)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
3-Amino-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propan-1-one (0.040 g, 0.095 mmol, see Example 21) and acetone (0.0696 mL, 0.947 mmol) were placed in 1:1 dichloroethylene (“DCE”):DMF (2 mL). DIEA (d 0.742; 0.0495 mL, 0.284 mmol) was then added, followed by the addition of NaBH(OAc)3 (0.0401 g, 0.189 mmol). The reaction was then stirred for 30 minutes. The reaction was then poured into aqueous Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The residue was purified by chromatography (9:1 DCM:MeOH) to give the pure product. The solid was then dissolved in minimal MeOH, and then 1M HCL in ether was added. The precipitate was collected, washed with ether and dried to give 3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.005 g, 11.4% yield) as the dihydrochloride salt. MS ESI (+) m/z 392 detected.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH:25](=[O:27])[CH3:26]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:27][CH:25]([C:11]([CH3:14])([CH:12]=[CH2:13])[C:10]([N:5]1[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]1=[O:9])=[O:15])[CH3:26]
Reactant: C/C=C(\C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A cooled (−78° C.) solution of (S)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (the enantiomer of the previously described compound 77a) (2.316 g, 10.962 mmol) in anhydrous dichloromethane (50 mL) was treated with a solution of titanium(IV) chloride (1 M, 12 mL, 11.510 mmol) in dichloromethane. After stirring the orange solution for 5 minutes, the mixture was treated with N,N-diisopropylethylamine (4.8 mL, 27.405 mmol). After stirring at −78° C. for 2 h, the purple solution was treated with acetaldehyde (4.3 mL, 76.374 mmol). After stirring at −78° C. for 1.5 h and at room temperature for 50 minutes, the reaction was quenched with a saturated solution of ammonium chloride (60 mL). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 1:1 to afford the title compound (1.742 g, 62%) as a 1:1.13:1.85:2.60 mixture of diastereoisomers and as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH3:16]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCC[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-butyl magnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.3 %

Procedure:
To a solution of (3,5-dichloro-phenylethynyl)-trimethyl-silane (1.97 g, 8.1 mmol) in methanol (40 mL) was added a solution of potassium hydroxide (6.8 mg, 0.12 mmol) in H2O (0.24 mL). After stirring at ambient temperature for 40 minutes, the reaction mixture was diluted with water (40 mL), and extracted with hexane until the extracting solvent showing no product by TLC. The combined organic layer was dried over MgSO4, and concentrated to give the title compound (1.21 g, 87% yield) as a white solid. 1H NMR (CDCl3) δ 7.37-7.34 (m, 3H), 3.15 (s, 1H).
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:43]([NH:45][C:46]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[F:34])=[S:47])=[O:44]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 64%). Mass spectrometry value (ESI-MS, m/z): 547 (M++1)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:13](Cl)(Cl)[C:14](Cl)=[O:15].P(Cl)(Cl)(Cl)=O>C(O)(=O)C.C(OCC)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:14](=[O:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=C1CC(COCc2ccccc2)C1
Reaction time: 0.03 h
Yield: 31.3 %

Procedure:
Into a 200 ml four-necked flask, copper(II) acetate monohydrate (0.16 g) was added and dissolved in 5 ml of acetic acid. Zinc powder (2.8 g) was added to this solution, and after allowing the mixture to stir for 90 seconds, decantation was carried out. Acetic acid (1 ml) was added to the residue and decantation was repeated five times. Dry diethyl ether (6 ml) was added to the residue and decantation was repeated three times. The atmosphere in the reaction vessel was completely replaced with argon gas by operating a three-way stopcock that was connected to an aspirator. Allyl benzyl ether 6.3 g (6.3 ml, 40.5 mmol) dissolved in 60 ml of dry diethyl ether was placed in this reaction vessel. Trichloroacetyl chloride 5.0 ml (45 mmol) and phosphoryl trichloride 4.1 ml (45 mmol) that were dissolved in 40 ml of dry diethyl ether were added dropwise to the above solution over a period of one hour. This reaction solution was refluxed and stirred for 21 hours. After the reaction solution was returned to room temperature, it was filtered. The filtrate was quenched by the addition of water and washed with water and brine. The organic layer was dehydrated over anhydrous sodium sulfate and then concentrated. Acetic acid (33 ml) and zinc powder (13.3 g) were added to the residue, and the mixture was stirred under reflux for 4 hours. This reaction solution was filtered and the filtrate was concentrated. This residue was dissolved in ethyl acetate, and zinc powder precipitated upon neutralization with a saturated NaHCO3 solution was separated by filtration using Celite. The filtrate was separated into two layers and washed with a saturated NaHCO3 solution and brine. The organic layer was dehydrated over sodium sulfate and then concentrated. The unreacted allyl benzyl ether was removed by evaporation under reduced pressure in a glass tube oven. The residue was purified by silica gel chromatography (toluene:ethyl acetate=96:4) to obtain 3-(benzyloxymethyl)cyclobutanone (2.41 g, 29%) as a clear oil. A clear oil: b.p. 115° C./1.0 mmHg. (TLC; Rf=0.20 (G):(M))
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:20][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC1=NS(=O)N=C1OCC
Solvent: CCO
Product: CCOC1=NS(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Yield: 882.3 %

Procedure:
A solution of 3,4-diethoxy-1-oxo-1,2,5-thiadiazole (1 g, 0.52 mmol) and L-tyrosine t-butyl ester (1.25 g, 0.52 mmol) in ethanol (25 mL) was stirred at room temperature for 60 hr. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, hexane:EtOAc 1:1 to give the title intermediate (1.75 g, 88%)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([C:5]1[CH:19]=[CH:18][C:8]2[CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[C:12]3[C:13](=[O:14])[C:7]=2[CH:6]=1)=[O:4].[OH:22]O>C(O)(=O)C>[F:21][C:2]([F:1])([F:20])[S:3]([C:5]1[CH:19]=[CH:18][C:8]2[CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[C:12]3[C:13](=[O:14])[C:7]=2[CH:6]=1)(=[O:22])=[O:4]
Reactant: OO
Reactant: O=C1c2cc(S(=O)C(F)(F)F)ccc2CCn2cccc21
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)(=O)C(F)(F)F)ccc2CCn2cccc21

Procedure:
A solution of 2 gm. of 9-trifluoromethylsulfinyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 20 ml. of acetic acid containing 5 ml. of 90% hydrogen peroxide is stirred at 25° C. for 4 days. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. After washing the organic solution with 2 × 25 ml. of 1N Na2CO3, it is dried and evaporated, and the residue chromatographed on silica gel to yield 9-trifluoromethylsulfonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35](O)=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccc(OC)c(OC)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (3,4-dimethoxy-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(3,4-dimethoxyphenyl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 296 (ester elimination ion); RT=7.486 min LCMS Method III
Reaction SMILES: [CH:1]1([C:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:9]1[CH:10]=[C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[S:7][CH:8]=1
Reactant: O=C(c1cccs1)C1CC1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Br)cs1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl(2-thienyl)methanone (Aldrich, 1.5 g, 9.9 mmol) was diluted in chloroform (10 mL). Aluminum chloride (2.96 g, 22.2 mmol, 2.3 eq) was added, followed by the dropwise addition of bromine (0.56 mL, 11 mmol, 1.1 eq) in chloroform (10 mL). The mixture was stirred at rt overnight, then poured onto ice water (100 mL). The whole was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give brown oil. The crude product was purified by isco combiflash, 120 g column, eluting with 0-15% ethyl acetate in hexanes. Yellow oil was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](C(=O)C)[C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=[O:5])[CH3:2].C(O)C>O>[NH2:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(N)c2ccc(-c3ccccc3)cc2n1C(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(-c3ccccc3)ccc2c1N
Temperature: 0 °C
Yield: 90 %

Procedure:
Reflux a mixture of 3-amino-1-(ethanoyl)-6-phenyl-1H-indole-2-carboxylic acid ethyl ester (7.3 g, 22.6 mmol) 20% aqueous potassium carbonate (100 mL) and ethanol (100 mL) for 1.75 h. Let the reaction stand at ambient temperature overnight and dilute with water (500 mL). Cool at 0° C. and collect a purple solid. Wash the solid with water and dry at 40° C. under vacuum and obtain 5.7 g of a purple solid. Triturate the solid with dichloromethane (40 mL) filter and wash the solid with dichloromethane and ethyl acetate, and then dry at 40° C. under vacuum to obtain 2.5 g of the title compound as a solid:
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]#[N:46])=[C:40]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C:45]#[N:46])=[C:40]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:39]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CC#N
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(CC#N)c(S(C)(=O)=O)c2)cc1)C(N)=O
Temperature: 75 °C
Yield: 76.7 %

Procedure:
A mixture of (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate (92 mg), 2-(4-bromo-2-(methylsulfonyl)phenyl)acetonitrile (75 mg), bis(1,2-bis(diphenylphosphino)ethane)-palladium(0) (8.29 mg, 9.17 μmol) and 2 N aqueous potassium carbonate (0.229 mL) in dioxane (3 mL) was heated at 75° C. for 14 h. The mixture was poured onto an Isolute HM-N cartridge, eluting with DCM, collecting about 100 mL of eluent. The eluent was concentrated in vacuo to leave a brown oil. The residue was purified by flash silica chromatography, eluting with ethyl acetate to give the subtitle compound as a white solid (80 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][NH:18][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=4)[C:10](=[O:17])[N:11]=3)=[CH:28][C:25]=2[C:26]#[N:27])=[CH:31][C:32]=1[C:37]([F:38])([F:39])[F:40]
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.1 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.201 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(4-chloro-3-trifluoromethyl-phenoxy)-benzonitrile (110 mg, 1.6 eq) were heated in a sealed vial at 130° C. for 20 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/20% MEOH in DCM solvent system (gradient 5-50% of 20% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with cyclohexane and diethyl ether to obtain 2-(4-chloro-3-trifluoromethyl-phenoxy)-5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-benzonitrile (36 mg, yield=29.7%, purity=90%) in form of tain coloured powder. MS: [M+H]+=541.34. 1H NMR (300 MHz; CDCl3) δ/ppm 2.65 (s, 3H), 2.94 (t, J=7.02 Hz, 2H), 3.57 (s, 2H), 3.59-3.68 (m, 2H), 5.49 (br.s., 1H), 6.89 (d, J=8.61 Hz, 1H), 7.15 (dd, J=8.30 Hz, J=2.98 Hz, 1H), 7.38 (d, J=2.76 Hz, 1H), 7.44 (dd, J=8.82 Hz, J=1.91 Hz, 1H), 7.51 (d, J=8.51 Hz, 1H), 7.60 (d, J=2.02 Hz, 1H), 7.71 (s, 1H), 8.53 (s, 2H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH:6]=1)=[CH2:2].C(O)C.O>O1CCCC1>[CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)=[CH2:2]
Reactant: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.3 %

Procedure:
—Sodium borohydride (8.54 g) was added to a solution of (7α)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (8.72 g) in a mixture of tetrahydrofuran (161 ml), ethanol (161 ml), and water (26.4 ml). The reaction mixture was stirred at room temperature for 50 min. and then poured into water. The product was extracted into ethyl acetate; the combined organic phases were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (7α,17β)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (8.45 g).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:16]=[C:17](Br)[CH:18]=1)[C:9]([O:11][C:12](C)(C)C)=[O:10]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:3]#[C:2][CH2:1][OH:4])[CH:18]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)cc(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Pd(Ph3P)4 (1.08 g), CuBrSMe2 (0.41 g) and propargyl alcohol (2.95 g, 50.2 mmol) are added successively to a solution of methyl 3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (5.7 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (7.5:2.5)], Rf=0.15.
Reaction SMILES: [CH2:1]([C:6](Cl)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:9]1([C@H:15]2[NH:18][C:17](=[O:19])[C@@H:16]2[O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:6]([N:18]1[C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:16]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[C:17]1=[O:19])=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)CC(C)(C)C)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using neopentylcarbonyl chloride, and (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one were converted to the title product: 1H NMR (CDCl3) δ 0.19-0.62 (m, 15H), 0.88 (s, 3H), 2.43 (d, 1H, J=13.8 Hz), 2.62 (d, 1H, J=14.1 Hz), 4.90 (d, 1H, J=5.7 Hz), 4.95 (d, 1H, J=6.0 Hz), 7.05-7.17 (m, 5H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15](Cl)=[O:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2.N1C=CC=CC=1>C(Cl)Cl>[OH:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:19][NH:18][C:15]([C:10]1[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=1[CH2:12][CH2:13][CH3:14])=[O:16])[CH:29]=[CH:28]2
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Reactant: NCc1ccc2cc(O)ccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(C(=O)NCc2ccc3cc(O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A solution of 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (2.0 g, 8 mmol) in 20 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-aminomethyl-naphthalen-2-ol (1.63 g, 9.42 mmol), prepared in step 1 of Example 8, and 75 mL of anhydrous pyridine. The reaction stirred at room temperature for 17 h (overnight). The reaction was diluted with methylene chloride and extracted with 1N HCl. The aqueous layer was separated and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. The solid was recrystallized from ethyl acetate and then again from isopropanol. The crystals were collected by filtration and dried under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (0.767 g, 25%) as a tan solid, mp 189-190° C.