Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)C1C=CC=CC=1.C(O)C>[C].[Pd].O>[ClH:1].[C:17]([O:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(OCC1CNCCO1)c1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
10% Palladium-carbon (40 g) and 4-benzyl-2-benzoyloxymethylmorpholine hydrochloride (202 g) are added to a mixture of ethanol (600 ml) and water (200 ml), and the mixture is stirred under hydrogen pressure of 10 kg/cm2 at 40° C. for 5 hours. Palladium-carbon is filtered off, and the solvent is distilled off under reduced pressure. To the residue is added ethanol, and the mixture is distilled under reduced pressure. This procedure is repeated three times. The resulting crystals are washed with ether and recrystallized from chloroform-ethanol to give the title compound (91 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O=S(Cl)[Cl:16].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-methylsulphonylbenzoic acid (100 mg, 0.48 mmol) in DCM (2 mL) was added SOCl2 (52 μL, 0.73 mmol) and toluene (2 mL) and the resulting reaction was stirred at 60° C. for 20 hours. A further charge of SOCl2 (100 μL, 1.45 mmol) was added and the reaction was heated at 80° C. for a further 24 hours. Volatiles were removed at reduced pressure and the crude product used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 317 (M+, 66), 92 (100), 65 (55).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:35]1[C:36]([N:41]=[CH:42][N:43]([CH3:45])C)=[N:37][CH:38]=[CH:39][CH:40]=1)#N>>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:45]2[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][C:36]=3[N:41]=[CH:42][N:43]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1
Yield: 24 %

Procedure:
The product of Example 64A was reacted with the product of Example 29A using the procedure of Example 13D substituting the product of Example 64A for the product of Example 13C and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title compound (31 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.48 (s, 9 H) 7.01 (d, J=8.46 Hz, 1 H) 7.32 (m, 4 H) 7.54 (d, J=8.46 Hz, 2 H) 7.71 (m, 2 H) 7.82 (d, J=7.72 Hz, 1 H) 8.01 (s, 1 H) 8.08 (s, 1 H) 8.64 (s, 1 H) 8.96 (d, J=8.09 Hz, 1 H) 9.11 (d, J=2.94 Hz, 1 H) 9.61 (s, 1 H) 10.35 (s, 1 H) 10.36 (s, 1 H); MS (ESI+) m/z 643/645 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[N:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:36])[CH3:35])=[CH:30][C:29]=1[CH3:37])=[O:27].BrC(Br)=O>CS(C)=O.O>[OH:36][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:14]2[C:13](=[O:17])[CH:12]=[C:11]([O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)[CH:16]=[N:15]2)=[C:29]([CH3:37])[CH:30]=1)[CH3:35]
Reactant: COc1ccc(COc2cn[nH]c(=O)c2)nc1
Reactant: Cc1cc(C(C)O)ccc1C(=O)CBr
Agent: O=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)O)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b, 2.00 g, 8.58 mmol) in DMSO (20 mL) is added cesium carbonate (5.59 g, 17.2 mmol) and the mixture is stirred 10 min at room temperature. Then 2-bromo-1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]-ethanone (preparation 10b, 2.21 g, 8.58 mmol) is added in portions and the mixture is stirred overnight at room temperature. An additional 0.5 g of the bromoketone is added and the mixture is stirred for 3 h at room temperature. After addition of water, the reaction mixture is extracted with ethyl acetate. The combined organic layer is dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:30][C:18]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A mixture of 179 (50 mg, 0.17 mmol), NBS (33 mg, 0.18 mmol) and K2CO3 (28 mg, 0.20 mmol) in MeCN (3 mL) was heated at 60° C. under N2 for 30 min. The solvent was removed under reduced pressure and the residue was purified by chromatography eluting with petroleum ether/EtOAc (9:1) followed by recrystallization (petroleum ether) to give methyl 8-bromo-7-[(tert-butoxycarbonyl)amino]-2-naphthoate (180) (57 mg, 90%) as colorless crystals: mp 137-140° C.; 1H NMR (CDCl3) δ 8.89 (d, J=1.2 Hz, 1H), 8.49 (d, J=9.1 Hz, 1H), 8.01 (dd, J=8.6, 1.7 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.35 (br s, 1H), 4.00 (s, 3H), 1.57 (s, 9H). Anal. (C17H18BrNO4) C, H, N, Br.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:16][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCCc1ccccc1

Procedure:
5 ml of triethylamine were added to a solution of 3.64 g of phenethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.63 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which it was stirred for 30 minutes whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, after which ethyl acetate was added to the residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 4.96 g of the title compound as pale yellow-brown needles melting at 62°-65° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH2:16][O:17][CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:39][C:40]([O:42][CH3:43])=[O:41])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:16][O:17][CH3:18])=[CH:39][C:40]([O:42][CH3:43])=[O:41])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC(=O)c1cccc(OCc2ccccc2)c1
Solvent: c1ccccc1
Product: COCC(=CC(=O)OC)c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 53.4 %

Procedure:
To a solution of 102.A (0.17 g, 0.66 mmol) in benzene (7 mL) was added methyl (triphenylphosphoranylidene)acetate (available from Aldrich) (2.2 g, 6.6 mmol) at room temperature. The mixture was stirred for 72 hours at reflux (100° C.), cooled to room temperature, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 102.B (mixture of geometric isomers) (0.11 g, 53% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 39b (177 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (214 mg, 85%). LCMS (Method 4): Rt 3.65 min, m/z 765 [MH+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1COCC1>[N:7]1([C:13]2[S:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1csc(N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1csc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluene was diluted with 10 ml of THF, cooled to 0° C., and treated with a solution of 1.7 g (7.0 mmol) of ethyl 2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resulting solution was stirred for 1 h, quenched cautiously with aqueous Rochelle's salts, diluted with chloroform, filtered, dired over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 2-4% methanol in chloroform provided 856 mg (61%) of the desired compound, Rf 0.16 (4% methanol in chloroform). 1H NMR (CDCl3) δ 2.44 (br, 1H), 3.46 (t, J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: NC1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>O>[CH3:29][N:30]([CH3:33])[C:31]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc(-c3ccc(N)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cccc2cc(-c3ccc(N(C)C)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.6 g of methyl 2-(4-aminophenyl)benzofuran-7-carboxylate, 1.52 ml of methyl iodide, 6.72 g of potassium carbonate and 25 ml of dimethylformamide is stirred at room temperature for 1 hour. 2.2 ml of methyl iodide are added to the mixture and the mixture is stirred for 2 hours. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:4) to give 2.0 g of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate as orange needles.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:25]1[CH:26]=[C:19]([F:18])[C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:28])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1F
Reaction time: 0.25 h
Yield: 188.7 %

Procedure:
To a suspension of NaH (2.6 g, 64 mmol, and 60.0% dispersion in oil) in DMF (80 mL) was added a solution of di-tert-butyl malonate (3.57 g, 16.50 mmol) in DMF (20 mL) at 0° C. and this was stirred for 15 min. Subsequently, 2,4,5-trifluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 h at 80° C. and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give 10.0 g of di-tert-butyl(4-cyano-2,5-difluorophenyl)propanedioate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J=5.5, J=5.4 Hz, 1H), 7.37 (dd, J=5, J=6 Hz, 1H), 4.84 (s, 1H), 1.50 (s, 18H). LC-MS (IE, m/z): 298.2 [(M+1)]+-t-Bu].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][N:13]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:10])=[O:17])=[CH:14][N:13]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)c(C)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(C)c1

Procedure:
6-Chloro-N-(4-methoxy-2-methyl-phenyl)-nicotinamide was prepared from 4-methoxy-2-methyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O2Cl [M+H]+: 277.0739. Found: 277.0738.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]=1[CH3:22])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.[CH3:35][O:36][C:37]([C:39]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:40]1)=[O:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:17][C:12]1[CH:11]=[C:10]([CH:9]2[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]([CH3:22])=[C:4]2[C:1]([NH:48][CH2:47][CH2:46][CH2:45][N:42]2[CH2:41][CH2:40][C:39]([C:37]([O:36][CH3:35])=[O:38])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:3])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: COCN1C(C)=NC(C)=C(C(=O)O)C1c1ccc(F)c(F)c1
Reactant: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCN1C(C)=NC(C)=C(C(=O)NCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine (0.13 g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.82 mmol.) and CH2Cl2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.17 g, 0.62 mmol.), the mixture was refluxed overnight. To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution. After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 80:20 v/v ethyl acetate- methanol) to give the title compound in 32% yield (0.075 g) as a pale yellow solid: mp 53-57° C. Anal. Calcd. for C31H38F2N4O4.0.25CHCl3: C, 62.71; H, 6.44; N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]([Cl:20])=[CH:4][N:3]=1.ClC1C=C(O)C=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>>[Cl:20][C:5]1[CH:6]=[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[C:2]([O:37][C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[Cl:29])=[N:3][CH:4]=1
Reactant: O=C(c1cc(Cl)cnc1Cl)N1CCCc2ccccc21
Reactant: Oc1cc(Cl)ccc1Cl
Agent: Oc1cccc(Cl)c1
Product: O=C(c1cc(Cl)cnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 25, Step 2, replacing (2-chloro-5-fluoro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanon with (2,5-dichloro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone and 3-chloro-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). MS (ISP): 433.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].[Br:26]N1C(=O)CCC1=O>ClCCl>[Br:26][C:9]1[CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]2([CH3:6])[C:4]=1[S:3][CH2:1][CH3:2])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCSC1=C(Br)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (11β)-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4,16-trien-3-one (181 mg) in dichloromethane (10 ml) containing N-bromosuccinimide (98 mg) is stirred at room temperature for 2 hours and the reaction mixture is subjected to preparative thin layer chromatography on silica gel plates to isolate the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([OH:19])[CH2:14][NH:15][CH:16]3[CH2:18][CH2:17]3)[O:11][C:10]([CH3:21])([CH3:20])[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:36]([O:43][C:44]([N:15]([CH2:14][C@@H:13]([C@@H:12]1[O:11][C:10]([CH3:21])([CH3:20])[N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:8]1[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:19])[CH:16]1[CH2:17][CH2:18]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CNC2CC2)OC1(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CN(C(=O)OCc2ccccc2)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.9 %

Procedure:
A mixture of 180 mg (0.45 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, 0.126 ml (0.98 mmol) of triethylamine and 136 mg (0.545 mmol) of N-(benzyloxycarbonyloxy)succinimide in 5 ml of methylene chloride is stirred at room temperature for 2 hours. Subsequently, the residue is poured on to ice and 2N sodium bicarbonate solution and then extracted three times with 150 ml of ether each time. The organic phase is washed with 70 ml of water, then dried over magnesium sulphate and evaporated. There are obtained 296 mg of tert-butyl (4S,5R)-5-[(S)-2-[1-(benzyloxy)-N-cyclopropylformamido]-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a colourless oil; MS: 531 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[IH:12].[PH2](O)=O.[OH-].[Na+]>O>[I:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:3]([OH:2])=[O:11])[CH:9]=1
Reactant: I
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: O=[PH2]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(I)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydriodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL) was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight. The mixture was cooled to 95° C. At this temperature were added in 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL), followed by the addition of water (15.2 mL). The mixture was cooled to rt, stirred for 1 h during which time product precipitates. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give a yellow solid 11a, 4-Iodopicolinic acid (3.5 g, 66%): 1H NMR (300 MHz, DMSO d6) δ 8.39 (d, J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS): 250.2 [M+H]+.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]=[O:10]>CCOCC>[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]([OH:10])[CH3:5]
Reactant: CI
Reactant: CC1=CCCC(C)(C)C1C=CC(C)C=O
Agent: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Product: CC1=CCCC(C)(C)C1C=CC(C)C(C)O
Temperature: 30 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A solution of methylmagnesium iodide, prepared from 11 g of magnesium shavings and 76 g of methyl iodide, in 700 ml of absolute ether is added dropwise at -10° C. under nitrogen to a solution of 62 g of 2-methyl-4-(2,6,6-trimethyl-2-cyclohexenyl)-3-butenal in 700 ml of ether. The mixture is stirred for 4 hours at 30° C. and then poured on to an excess of ice-cold ammonium chloride solution. The mixture is extracted with ether in the usual manner, the extract is washed neutral with water and dried over anhydrous sodium sulphate to give, after removal of the solvent, 66 g of a yellow, slightly viscous oil which, after distillation in vacuo, yields 52 g of 3-methyl-5-(2,6,6-trimethyl-2-cyclohexenyl)-4-penten-2-ol; b.p.0.008 = 90°; nD20 = 1.4890. This alcohol has a very fine, tenacious sandalwood odour.