Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH:19]=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:29]([S:33]([NH2:35])=[O:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:1][C:2]1([CH3:28])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:21][S:22]([C:24]([CH3:26])([CH3:27])[CH3:25])=[O:23])/[CH:19]=[N:35]/[S:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:34])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(C=O)NS(=O)C(C)(C)C)cc2)O1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(/C=N/S(=O)C(C)(C)C)NS(=O)C(C)(C)C)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-formyl-butyl}-amide in THF (20 ml) is added tert-butyl sulfinamide (323 mg, 2.7 mmol) followed by titanium ethoxide (1.0 ml, 4.8 mmol). The yellow solution formed is stirred at room temperature overnight. The solution is quenched with 1N NaOH (50 ml) and EtOAc (50 ml) and stirred for 30 minutes at room temperature. The resultant mixture is filtered through Celite™ (filter material) and the organic phase separated and dried (MgSO4). Concentration gives 2-Methyl-propane-2-sulfinic acid (4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-butyl)-amide as a mixture of diastereomers as a yellow oil; [M+H]+ 515.38
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:3]=12.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:26]1.N#N>O1CCOCC1.C([O-])(O)=O.[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:3]=23)[C:27]([C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[N:26]1
Reactant: C[Si](C)(C)c1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc([Si](C)(C)C)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 105 °C
Yield: 36 %

Procedure:
A mixture of 4-bromo-1-(phenylsulfonyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (37 mmol) and 1-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mmol) in 1,4-dioxane (300 ml) and saturated NaHCO3(aq) (100 ml) was degassed with N2 for 10 minutes after which time tetrakis(triphenylphosphine) palladium(0) (1.85 mmol) was added and the resulting mixture was heated at 105° C. overnight. The reaction was then concentrated, diluted with CHCl3 (200 ml) and EtOAc (200 ml), sonicated for 10 minutes, filtered through Celite 545, and concentrated to yield a red oil which was purified on 400 g silica gel (CHCl3/EtOAc w/0.1% MeOH) to give the title product as a light yellow foam (36%). ESMS [M+H]+: 532.0.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:10][CH2:9]2)[O:6][CH:7]=1.[K].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>CN(C=O)C>[CH:8]1([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:16]3[C:12](=[O:22])[C:13]4[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:15]3=[O:17])[N:4]=2)[CH2:10][CH2:9]1
Reactant: ClCc1coc(C2CC2)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To the stirred solution of 4-chloromethyl-2-cyclopropyl-oxazole (4.0 g, 25.38 mmol) in dry DMF (30 mL), was added potassium salt of phthalimide (4.7 g, 25.38 mmol) at rt. The resulting mixture was stirred for 24 h at rt and monitored through TLC. After completion of the reaction, water (200 mL) was added and the crude was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtained crude residue which was purified via column chromatography (100-200 silica gel, elution with 20% EtOAc in hexane). 3.5 g of 2-(2-cyclopropyl-oxazol-4-ylmethyl)-isoindole-1,3-dione was obtained as a white solid, 269.2 (M+H)+, which contained phthalimide. This compound was used for the next step as such.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(O)(=O)C1C=CC=CC=1.ClC1C=C(O)[C:28]2[N:32]=NN[C:29]=2[CH:33]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.C1(N)CC1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:32][CH:28]2[CH2:29][CH2:33]2)=[O:8])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1C(F)(F)F
Reactant: Oc1cc(Cl)cc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.50 g (1 eq, 5.57 mmol) of 4-bromo-2-(trifluoromethyl)benzoic acid (synthesis analogous to EP1445253 Yamanouchi Pharmaceutical Co. by bromination of the benzoic acid) were dissolved in 5 ml of dichloromethane. Then 954 mg (1.0 eq, 5.57 mmol) of 6-chlorohydroxybenzotriazole, 1.28 g (1.2 eq, 6.69 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.45 ml (1.5 eq, 8.63 mmol) of N-ethyldiisopropylamine were added thereto, and the mixture was stirred at RT for 20 min. Subsequently, 477 mg (1.5 eq, 8.36 mmol) of cyclopropylamine were added thereto, and the reaction mixture was stirred at room temperature for 12 h. Thereafter, the mixture was concentrated under reduced pressure and the crude product dissolved in ethyl acetate (EA). The solution was washed 2× with buffer solution (0.5 M phosphate buffer pH=7) and then dried over MgSO4. The purification was effected by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 100% EA). This gives 831 mg (48%) of 4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:30])[C@@H:27]([NH:28][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])[CH3:29]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)c1nc(Cl)c2ccccc2c1O

Procedure:
1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, 1.5 ml of triethylamine, 0.55 g of DECI, and 0.56 g of (L)-Alanine methyl ester hydrochloride were stirred in 15 ml of methylene chloride at room temperature for 72 h. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated and successively washed with 1M aqueous HCl, satd. aqueous NaHCO3, and satd. aqueous NaCl. The organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum to afford 0.133 g of off-white solid product: MS-(+)-ion, M+1=308.9 Daltons.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[OH-].[K+].C1(C)C=CC=CC=1.[C:17](Cl)(Cl)=[O:18]>O>[CH3:6][CH:5]([C@H:2]1[CH2:3][O:4][C:17](=[O:18])[NH:1]1)[CH3:7]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 0.5 h

Procedure:
A mixture of 9.4 grams (0.091 mole) of (S)-2-amino-3-methyl-1-butanol, 36 grams (0.0546 mole) of 85% potassium hydroxide, 175 mL of toluene, and 240 mL of water was stirred rapidly as 140 mL (0.273 mole) of a toluene solution containing 20% phosgene was added dropwise during a 15 minute period. Upon completion of addition, the resulting hot solution was stirred an additional 30 minutes. The reaction mixture was cooled, and the organic and aqueous layers were separated. The organic layer was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 15.0 grams of (S)-4-(1-methylethyl)-2-oxazolidinone as a solid. Recrystallization from cyclohexane yielded purer compound, m.p. 71.5°-72.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]O.C(O)(=O)CC>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: CCC(=O)O
Solvent: O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 100 parts of 3,3-dimethylacrolein, 200 parts of prenol and 150 parts of propionic acid is heated for three hours at 130° C, the water formed being distilled out azeotropically. The reaction product is worked up. 24 parts of citral is obtained. This is equivalent to a yield of 51% of theory at a conversion of 26% (based on 3,3-dimethylacrolein).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:7]=2[CH:27]=1>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH2:13])[CH3:12])[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7]=2[CH:27]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1

Procedure:
4.0 M HCl in 1,4-dioxane (1.0 mL) was added to a solution of (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethylcarbamate (12 mg, 0.034 mmol) in DCM (1 mL). After ˜2 h the reaction mixture was concentrated under reduced pressure to dryness. The resulting solid was partitioned between DCM and satd. aq. NaHCO3 solution. The aq. layer was extracted with DCM. The organic layers were combined, dried with Na2SO4, filtered and concentrated under reduced pressure to give (S)-1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine: LC-MS (ESI) m/z 256.1 [M+H]+. The product was carried on crude without purification.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([C:17]([NH:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:52][CH2:53][CH:54]1[CH2:56][CH2:55]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.CCOC(C)=O>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][NH:19][C:17](=[O:18])[C:16]1[CH:50]=[CH:51][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
(S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (180 mg, 0.2 mmol) was dissolved in HCl 4M in EtOAc and stirred overnight at 0° C. The solvent was evaporated under vacuum, and the crude product was purified by Preparative reverse-phase HPLC to give 12 mg of the final product (Yield: 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CCO>[CH2:4]([O:10][C:8]1[CH:9]=[C:2]([Cl:1])[C:3]([CH2:4][OH:5])=[C:6]([Cl:11])[CH:7]=1)[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Suspend 2,6-dichloro-4-hydroxy-benzaldehyde in 3 L EtOH and cool in an ice bath at 0° C. Add 32.97 g (871.45 mmol) NaBH4 caplets portionwise. Remove the ice bath and stir for 2 hours. Carefully add the reaction mixture to 8 L sat'd. NH4Cl solution and stir until fully quenched. Extract with CH2Cl2 (2×2 L) and dry the combined organic extracts over Na2SO4. Filter and concentrate under vacuum to yield 247 g (100%) of (4-benzyloxy-2,6-dichloro-phenyl)methanol as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC#N>[CH:25]1([NH:31][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCCCC3)n2)cc1
Yield: 52 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.50 g, 1.31 mmol) in MeCN (10 ml) was added cyclohexylamine (0.50 ml) and the resultant solution heated under reflux for 26 h. The cooled reaction mixture was concentrated in vacuo and the residue partitioned between 2N HCl and ethyl acetate. The organic phase was separated, washed with 2N HCl then water and concentrated in vacuo to an off-white solid. This solid was crystalised from 5% AcOH/MeOH and dried in vacuo to give the title compound as a white solid (0.27 g, 52%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])[CH3:22])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14].C(=O)C.Cl>O1CCCC1>[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])/[CH:22]=[CH:1]/[CH3:2])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14]
Reactant: CC[C@H]1CC=C[C@H](C)[C@@H]1C(C)=O
Reactant: CC(C)NC(C)C
Agent: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)[C@@H]1[C@@H](CC)CC=C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
At −78° C., a solution of diisopropylamine (6.6 g, 34 mmol) in tetrahydrofuran (23 ml) was treated with n-butyl lithium (21 ml, 1.6M in hexane, 34 mmol). The resulting solution was warmed to 0° C., cooled to −78° C., and treated with a solution of 1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)ethan-1-one (4.5 g, 27 mmol) in tetrahydrofuran (23 ml). The resulting solution was stirred 20 min. at −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (1.8 g, 41 mmol) in tetrahydrofuran (23 ml). After 1 h stirring, aqueous 1 N HCl (50 ml) was added and the reaction mixture warmed to 20° C. The aq. phase was extracted with diethyl ether and the combined org. phases dried (MgSO4), and concentrated. A solution of the residue (4.9 g) in toluene (4.9 ml) was treated with para-toluene sulfonic acid monohydrate (20 mg) and refluxed overnight. The reaction mixture was cooled, treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (MgSO4) and concentrated. FC (550 g SiO2, hexane/diethyl ether 9:1) of the crude product gave (2E)-1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)but-2-en-1-one (2.9 g, 56%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])C(O)=O)#[N:8].CN(C=O)C>C(Cl)Cl>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.224 ml, 2.56 mmol) was added to a stirred solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (which can be prepared as described in WO2005/58848, 500 mg, 2.437 mmol) in DCM (10 ml), followed by DMF (20 μl) and the resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated to give the title compound (545 mg, 100%) as an olive green solid which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]([C:13]([OH:15])=O)=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:38][CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][C:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[C:48]([Cl:54])[CH:47]=2)=[N:42]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:54][C:48]1[CH:47]=[C:46]([C:43]2[CH:44]=[CH:45][N:41]([CH2:40][CH2:39][NH:38][C:13]([C:4]3[NH:5][N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2](=[O:1])[CH:3]=3)=[O:15])[N:42]=2)[CH:53]=[CH:52][C:49]=1[C:50]#[N:51]
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(=O)n(-c4ccccc4)[nH]3)n2)cc1Cl
Yield: 17.3 %

Procedure:
5-Oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylic acid (0.05 g; 0.24 mmol), HOBt (0.049 g; 0.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.07 g; 0.37 mmol) were added to 2.5 ml of DCM. To this a mixture of 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.06 g; 0.24 mmol) and DIPEA (0.064 ml; 0.37 mmol) was added dropwise and the mixture was stirred overnight after which 10 ml of DCM was added. The mixture was washed with 3×5 ml of water and the combined water phases were extracted with 2×5 ml of DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The product was purified with flash chromatography using DCM/MeOH as gradient eluent. The combined fractions gave 18 mg of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.23 (s, 1H), 3.65-3.70 (m, 2H), 4.37 (t, 2H), 5.83 (s, 1H), 6.97 (d, 1H), 7.31-7.35 (t, 1H), 7.45-7.49 (t, 2H), 7.76 (d, 2H), 7.85-7.89 (m, 2H), 7.94-7.96 (m, 1H), 8.09 (d, 1H), 8.28 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:31]=O>>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:23]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Reactant: C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(C)CC3)cc1
Yield: 5 %

Procedure:
6-Methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (8 mg, 5%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 419.2 (M+H)+
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Mg]Br>>[CH3:22][C@@H:8]1[CH:9]=[C:10]2[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[CH2:11]2)[C@@H:17]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Mg]Br
Product: C[C@@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Alkylation of androsta-4,6-dien-3,17-dione 17 ketal 1 with methyl magnesium bromide in the presence of cuprous chloride, proceeds via conjugate addition to yield 7α-methylandrost-5-en-3,17-dione 17 ketal 2. Allylic bromination of 2 using N-bromosuccinimide in carbon tetrachloride yields the 6β-bromo-7α-methylandrost-4-en-3,17-dione 17 ketal 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield 4. Deprotection of the C-17 ketone with aqueous acid yields 3β-hydroxy-7α-methylandrost-5-en-17-one, 5. Higher homologues may be synthesized using the substituted Grignard reagent i.e. R=CH3, C2H5, C3H7. The 7β-epimer can be synthesized by treatment of 2 with DDQ-dichlorodicyanoquinone to generate another olefin at C-7. Catalytic reduction of this olefin should occur from the α face of the steroid to yield the 7β-methyl steroid i.e. 7β-methylandrost-5-en-3,17-dione 17 ketal. Following the same sequence as above yields 3β-hydroxy-7β-methylandrost-5-en-17-one. ##STR20##
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH3:26])[C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH3:22])=[N:19][CH:18]=2)=[C:13]([O:23][CH3:24])[CH:12]=1)=O.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#[N:60])C>C(OCC)(=O)C.C(=O)([O-])O.[Na+].C(OCC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:5]2([CH3:26])[CH2:4][CH2:3][CH2:2][N:60]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:8]=[C:6]23)=[CH:32][CH:31]=1
Reactant: COc1cc(C(=O)NNC(=O)C(C)(CCCCl)c2ccc(Cl)cc2)ccc1-c1cnc(C)o1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(Cl)cc2)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of N′-[5-chloro-2-(4-chlorophenyl)-2-methylpentanoyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.0 g) and carbon tetrachloride (1.57 mL) in acetonitrile (25 mL) was added triphenylphosphine (8.56 g), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). Another lot synthesized similarly was combined and the mixture was dissolved in diethyl ether. The insoluble material was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of the purified product in DMSO (50 mL) was added sodium azide (1.88 g), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, water and saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (50 mL)/water (5 mL) was added triphenylphosphine (7.60 g), and the mixture was stirred at 60° C. for 2.5 hr. The solvent in the reaction mixture was evaporated under reduced pressure. Acetic acid (25 mL) was added to the residue, and the mixture was stirred under heating with reflux for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.80 g).