Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc(C(C)=O)c(O)c1
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
In 60 ml of dimethylformamide were dissolved 5.0 g of 2',4'-dihydroxyacetophenone and 6.37 g of N,N-diisopropylethylamine, and 2.72 ml of chloromethyl methyl ether was gradually added to the solution under ice cooling. The mixture was stirred under ice cooling for 20 minutes and a reaction was carried out at room temperature for 1.5 hours. After the reaction, the reaction mixture was extracted with 300 ml of diethyl ether, and the diethyl ether layer was washed with water (100 ml×2 times), shaken with a saturated aqueous solution of sodium chloride (50 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the residue was subjected to the silica gel chromatography (3.5 cm in diameter; 72.8 g; n-hexane/ethyl acetate=4/1; 0.3 kg/cm2) to obtain 5.66 g (yield=87.8%) of 2'-hydroxy-4'-methoxymethoxyacetophenone in the form of a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[CH3:21]O>C(Cl)Cl>[CH3:21][O:19][C:18](=[O:20])[C@@H:16]([NH2:17])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1
Reactant: CO
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
Thionyl chloride (3.2 g, 2.0 mL, 26.8 mmol) was added dropwise to a suspension 3-(3,4-dimethoxyphenyl)-L-alanine 1 (2.0 g, 8.9 mmol) in anhydrous MeOH (50 mL) at 0° C. under a nitrogen blanket. The mixture was slowly warmed to room temperature, then stirred for 72 hours. The solvent was removed under reduced pressure to provide a solid. The crude product was taken up in CH2Cl2, then washed with saturated NaHCO3 and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to yield a light brown oil (1.97 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.CN.[BH3-][C:14]#[N:15].[Na+].Cl>CO.CCOCC.[Cl-].[Cl-].[Zn+2]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:15][CH3:14]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CO
Product: CNCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
To a stirred solution of 3,5-dichlorobenzaldehyde (9.0 g, 51 mmol) in methanol (100 mL) was added methanolic methylamine (2M, 100 mL, 200 mmol) and the resulting mixture stirred for 2 h at room temperature. To this was added a solution of ZnCl2 (3.402 g, 25 mmol) slowly and NaCNBH3 (3.142 g, 50 mmol) in methanol (100 mL). After 24 h, the reaction mixture was concentrated, and the resulting residue taken up in dilute aq NaOH (0.5 N, 200 mL) and extracted with CH2Cl2 (5×50 mL). The combined CH2Cl2 extracts were dried over anhydrous Na2SO4, filtered and concentrated to give a yellow viscous liquid. The crude product was dissolved in ether (200 mL) to which was added 29 mL of 2N HCl (in ether). The resulting white 3,5-dichlorobenzyl-methylamine hydrochloride salt was filtered and dried under vacuum to give 11.20 g (97% yield) of product. 1HNMR (300 MHz, DMSO-d6) δ: 9.48 (2H, s), 7.68 (3H, s), 4.13 (2H, s), 2.50 (3H, s). MS calcd for C8H10C12N (M+H): 190.02. found: 190.05.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Reactant: CC(C)N
Product: Cc1cccc(-c2noc(C)c2COc2ccc(C(=O)NC(C)C)cn2)c1
Yield: 74 %

Procedure:
As described for example 249f, 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.6 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (160 mg, 74%) which was obtained as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])#[CH:11].C(OCC)(=O)C>CCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:11]#[C:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:20])[F:21])[CH:3]=1
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: Nc1ccc(Cl)cc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodoaniline (500 mg, 1.97 mmol) and 1-ethynyl-2-(trifluoromethyl)benzene (330 μl, 2.37 mmol). Off white solid. Rf 0.3 (1:9 Ethyl acetate:heptane) as an intense blue spot under UV light.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([OH:29])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:3])[CH3:2].[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([O:29][C:42](=[O:45])[CH2:43][CH3:44])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)O[C@H]1[C@@](C)(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@]1(F)COc1ccc2ccccc2c1O[P+]([O-])=N[C@@H](C)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
To a solution of (S)-2-[[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester prepared in Example 2 (86 mg, 144 μmol) in THF (10 mL) were added propionyl chloride (66.6 mg, 720 μmol) and DMAP (87.9 mg, 720 μmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 0-15% MeOH in DCM) to give the title compound as white solid (45 mg, 48%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:5][N:4]=[N:3]1.[Cl-].[OH:16][NH3+:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][OH:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=O)c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: Cn1nnnc1C(=NO)c1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
(1-methyltetrazol-5-yl)phenylmethanone (11.1 g, 59.1 mmol) and hydroxylammonium chloride (10.3 g, 148 mmol) were added to 100 ml of pyridine, followed by stirring at 45° C. for 24 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and water and ethyl acetate were added to the resulting residue, and then the reaction product was extracted. The organic layer was washed in turn with dilute hydrochloric acid, water and an aqueous sodium hydrogencarbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer to obtain (1-methyltetrazol-5-yl)phenylmethanoneoxime (12.0 g, yield: 100%) represented by the formua:
Reaction SMILES: C([N:3]([CH:13]([CH3:15])[CH3:14])[C:4]([C:6]1[NH:7][C:8]([Cl:12])=[C:9]([Cl:11])[N:10]=1)=[O:5])=O>S(=O)(=O)(O)O>[CH:13]([NH:3][C:4]([C:6]1[NH:7][C:8]([Cl:12])=[C:9]([Cl:11])[N:10]=1)=[O:5])([CH3:15])[CH3:14]
Reactant: CC(C)N(C=O)C(=O)c1nc(Cl)c(Cl)[nH]1
Agent: O=S(=O)(O)O
Product: CC(C)NC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 72 %

Procedure:
25 g (0.1 mol) of 4,5-dichloro-imidazole-2-carboxylic acid N-formyl-isopropylamide were stirred with 200 ml of concentrated sulphuric acid for about 15 minutes at 50°-70° C. After cooling, the mixture was poured onto ice and the product was filtered off, washed with water until neutral and dried. In this way, 16 g (72% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid isopropylamide with a melting point of 150° C. were obtained.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][CH2:28][C@:29]([C:32]3[CH:37]=[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][C:33]=3[F:43])([CH3:31])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:39]([NH:38][C:36]1[CH:35]=[CH:34][C:33]([F:43])=[C:32]([C@:29]2([CH3:31])[CH2:28][O:27][CH2:26][C:25]([NH2:24])=[N:30]2)[CH:37]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNc1ccc(F)c([C@]2(C)COCC(NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)=N2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNc1ccc(F)c([C@]2(C)COCC(N)=N2)c1

Procedure:
A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-5-(5-butylamino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine (26 mg, 44.7 mol) in dichloromethane 2.5 ml) was treated at room temperature with trifluoroacetic acid (17.1 1, 223 mol) for 20 hours. The reaction mixture was evaporated at reduced pressure and the crude product purified by flash chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. The title compound was obtained as a light yellow oil (58%); (calculated) C15H22FN3O [279.350]; (found) [M+H]+=280.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10]/[CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9](/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])\[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(=C\C=O)c2ccccc2OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1ccccc1OC
Yield: 76.1 %

Procedure:
As described in Example 99, (E)-3-(2-methoxyphenyl)-3-(4-methoxyphenyl)-2-propenal (5 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (6.83 g) in a mixture of carbon tetrachloride (50 ml) and dichloromethane (25 mL) for 4 days at room temperature. The crude ester was isolated in the usual way and was crystallized from 2-propanol-hexane to provide 4.6 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester. Recrystallization of a sample from the same solvents gave the analytical specimen, mp 99.5°-102.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:3][CH:4]=3)[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9]2=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Reactant: Nc1ccccc1
Solvent: CO
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.49 g; 1.21 mmol) (from Example 5a supra) and aniline (0.50 mL; 5.49 mmol) (Aldrich) was heated to 110° C. for one hour. Methanol was added to the hot mixture and the solution was then cooled. The solid that precipitated out of solution was collected and recrystallized from methanol to yield (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a white solid. (Yield 0.35 g; 62.2%). Melting Point: 224–228° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](O)=O)=[CH:25][C:20]=2[NH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:26]([C:24]2[CH:23]=[CH:22][C:21]3[NH:17][CH:18]=[N:19][C:20]=3[CH:25]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]cnc3c2)o1
Yield: 5 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (400 mg, 1.84 mmol) was converted using benzimidazole-5-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=70:20:10:0 to 0:80:10:10, 33 mg, 5%) which was obtained as an off-white solid. MS: m/e=344.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26]([NH2:33])=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(4-(2-chlorophenyl)-1H-pyrazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 274.
Reaction SMILES: C1CO[C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[CH:5]([C@@H:6]([CH2:31][OH:32])[C:7](=[O:30])[C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[O:22][Si](C(C)(C)C)(C)C)[C:4]2([CH3:34])[CH3:33])[O:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:33][C:4]1([CH3:34])[C:3](=[O:2])[CH2:20][CH2:19][C@@:18]2([CH3:21])[CH:5]1[C@@H:6]([CH2:31][OH:32])[C:7](=[O:30])[C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[OH:22]
Reactant: CC1(C)C2[C@@H](CO)C(=O)[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC12OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C(=O)CC[C@@]2(C)C1[C@@H](CO)C(=O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 95 %

Procedure:
3,3-(ethylenedioxy)-4,4-dimethyl-6α-hydroxymethyl-17β-tert-butyl-dimethylsilyloxyandrostan-7-one (100 mg) was dissolved in dioxane (2 ml) then 1N HCl (2 ml) was added and the mixture stirred at RT for 5.5 h. 5% NaHCO3 was added and the solvent evaporated to dryness. The water phase was extracted with DCM, dried over Na2SO4 and evaporated to dryness to give 4,4-dimethyl-6α-hydroxymethyl-17β-hydroxyandrostan-3,7-dione in 95% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])=[N:10][N:11]([CH3:17])[C:12]=1[O:13][CH:14]([F:16])[F:15].Br[CH2:28][C:29]1[O:30][CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35].[Cl-].[Na+]>CC(C)=O>[Cl:25][C:21]1[CH:20]=[C:19]([F:26])[C:18]([C:9]2[C:8]([Cl:7])=[C:12]([O:13][CH:14]([F:15])[F:16])[N:11]([CH3:17])[N:10]=2)=[CH:23][C:22]=1[O:24][CH2:28][C:29]1[O:30][CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CCOC(=O)c1ccoc1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccoc1COc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reaction time: 2 h
Yield: 98.1 %

Procedure:
2.32 g (16.81 mmoles) of potassium carbonate are added to a solution prepared with 5 g (15.28 mmoles) of 4-chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-difluoromethoxy-1-methylpyrazole, 3.92 g (16.81 mmoles) of ethyl 2-bromomethyl-3-furancarboxylate and 100 ml of acetone. The mixture is heated to reflux temperature under stirring for 2 hours. The raw product is then poured into 500 ml of a saturated solution of sodium chloride and extracted with ethyl acetate (3×150). The joined organic phases are washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated under vacuum. The raw product is purified by means of silica gel chromatography using a mixture of hexane/ethyl acetate: 8/2 as eluant. 7.18 g of ethyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxymethyl]-3-furancarboxylate (Compound Nr. 2) are obtained (yield 98%), as a white solid having a melting point of 59-61° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([O:46][CH:47]([CH3:49])[CH3:48])[C:32]([F:45])=[C:33]([CH:44]=1)/[CH:34]=[N:35]/[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1)[CH3:27]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([N:35]([CH2:34][C:33]2[CH:44]=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=[C:31]([O:46][CH:47]([CH3:49])[CH3:48])[C:32]=2[F:45])[C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2ccnc2-c2ccccc2)cc1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cnc(-c3ccccc3)n2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
To a solution of Intermediate 15.1 (100 mg, 0.378 mmol) in 2 mL THF at 0° C., was added sec-BuLi (0.81 M in cyclohexane, 514 μL, 0.416 mmol). The mixture was stirred at 0° C. for 10 min, then a solution of Intermediate 7.3 (123 mg, 0.378 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min and rt 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 53.7 mg of Intermediate 15.2.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37]O)=[N:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:37][C:34]4[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:25]5[O:26][CH2:27][CH2:28][O:24]5)=[CH:36][N:35]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: OCc1ccc(OCC2OCCO2)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(OCC3OCCO3)cn2)cc1
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (3.1 g, 10 mmol) in dry THF (200 mL) at 25° C. was added [5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol (2.4 g, 11 mmol), triphenylphosphine (2.9 g, 11 mmol) and di-tert-butyl azodicarboxylate (2.6 g, 11 mmol). The solution was stirred for 16 hours, then the solvent was evaporated and the residue dissolved in ethyl acetate/methanol (19:1, 50 mL) and purified by chromatography on silica, eluting with a gradient of 5-20% methanol in ethyl acetate, to give the title compound as a white solid (3.8 g, 76%). NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 3.85 (m, 2H), 3.92 (m, 2H), 4.10 (m, 2H), 5.20 (m, 3H), 7.12 (d, 2H), 7.30 (d, 1H), 7.45 (s, 2H), 7.62 (dd, 1H), 7.78 (s, 1H), 7.95 (d, 2H), 8.30 (s, 1H), 8.35 (d, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [CH2:1]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[C:14]([C:28]([OH:30])=[O:29])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].OC1C=CC(C(OCC2C=CC=CC=2)=O)=CC=1.C(Cl)(=O)CCCCCCCCCCC>[Pd]>[CH2:1]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[C:14]([C:28]([OH:30])=[O:29])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(C(=O)OCc2ccccc2)c(C(=O)O)c1
Agent: [Pd]
Agent: CCCCCCCCCCCC(=O)Cl
Agent: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: CCCCCCCCCCCc1ccc(C(=O)O)c(C(=O)O)c1
Yield: 102.5 %

Procedure:
By customary procedures, 3.5 g of benzyl 4-undecylcarboxybenzoate was prepared from 2.3 g of benzyl 4-hydroxybenzoate and 2.5 g of lauric acid chloride, and this ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2.8 g of 4-undecylcarboxybenzoic acid. The acid was converted to 4-undecylcarboxybenzoic acid chloride by thionyl chloride and the acid chloride was reacted with 1.8 g of benzyl 4-hydroxybenzoate to form benzyl 4-(4-undecylcarboxybenzoyloxy)benzoate. The ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to isolate the benzyl group and obtain 3.0 g of 4-(4'undecylcarboxybenzoyloxy)benzoic acid.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C[O:7][C:8]([C:10]1[O:11][C:12]([Br:15])=[CH:13][CH:14]=1)=O.Cl>C1COCC1>[Br:15][C:12]1[O:11][C:10]([C:8](=[O:7])[CH2:4][C:3]#[N:5])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Br)o1
Yield: 74.7 %

Procedure:
To 1.95 g (48.8 mmol, 60% dispersion in mineral oil) sodium hydride in a 2-necked flask fitted with a reflux condenser was added dropwise 30 ml THF and the mixture was then heated to reflux. A solution of 6.4 ml (122 mmol) acetonitrile and 5.00 g (24.4 mmol) 5-bromo-furan-2-carboxylic acid methyl ester in 20 ml dry THF was added dropwise and the reaction mixture heated at reflux for 5 hours. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixture was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 2/3) afforded 3.90 g (75%) 3-(5-bromo-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 215 (M{81Br}+, 27), 213 (M{79Br}+, 28), 175 ([M{81Br}—CH2CN]+, 100), 173 ([M{79Br}—CH2CN]+, 100), 38 (59).