Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41]>ClCCl>[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:41]
Reactant: O=C(O)c1cccc(F)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In dichloromethane (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and dicyclohexylcarbodiimide (2.4 g), and a solution of 3-fluorobenzoic acid (1.6 g) dissolved in dichloromethane (10 ml) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Reactant: CN1CCC(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2[N+](=O)[O-])CC1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.45 g of 3-(1-methylpiperidin-4-yl)propan-l-ol in 40 ml of tetrahydrofuran are added 360 mg of sodium hydride. The white suspension formed is stirred for 15 minutes at 65° C., cooled and mixed with 1.45 g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, whereupon the mixture suddenly turns dark red. The reaction mixture is stirred first for 10 minutes at ambient temperature, then for 45 minutes at 65° C. As the reaction is not yet complete, a further 150 mg of sodium hydride are added and the mixture is stirred for a further 45 minutes at 65° C. The solvent is distilled off using a rotary evaporator and the brown residue is stirred with 50 ml of ice water. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.05). Yield: 1.30 g of (65% of theory); Rf value: 0.28 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=500, 502 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=O.B.C1COCC1>C1COCC1>[F:13][C:2]([F:1])([S:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)Sc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NCC(F)(F)Sc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2-difluoro-2-phenylsulfanylacetamide (1 g, 4.92 mmol) in THF at room temperature was treated with BH3.THF (1M, 25 mL), stirred for 18 hours, quenched with methanol (5 mL), and concentrated. The concentrate was treated with 2M HCl and heated to 80° C. for 30 minutes and concentrated The concentrate was partitioned between dichloromethane and saturated sodium bicarbonate, and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 190 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](O)([CH3:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(=O)CC.N#N>C1(C)C=CC=CC=1>[CH3:29][C:6]1[C@@H:7]2[C@@H:23]([C@:24]3([CH3:27])[C:4]([CH:5]=1)=[CH:3][C:2](=[O:1])[CH2:26][CH2:25]3)[CH2:22][CH2:21][C@@:20]1([CH3:28])[C@H:8]2[CH2:9][CH2:10][C@@H:11]1[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O)CC1=CC3(C)O
Agent: CC(C)[O-]
Agent: N#N
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.2 %

Procedure:
A mixture of methyl 7-hydroxy-7-methylchol-5-en-24-oate (8) (2.0 g, 4.78 mmoles), aluminum isopropoxide (1.17 g, 5.72 mmoles), 2-butanone (8.6 ml, 96 mmoles) in toluene (40 ml) was heated at 80° in a N2 atmosphere for 6 hrs. About 15 ml of solvent was distilled from the reaction mixture at atmospheric pressure. Toluene (30 ml) was added, and the mixture was extracted with 3N HCl (2 times), H2O (3 times) and dried with MgSO4. Evaporation in vacuo gave 1.7 g of an orange oil that was purified by flash chromatography on silica gel with hexane-EtOAc (7:2 and 2:1) to give 0.62 g of pure 9 as a colorless syrup. NMR (CDCl3): δ 0.76 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.08 (s, 3H, 19-Me); 3.67 (s, 3H, CO2Me); 5.59 (s, 1H, 4-H); 5.95 (s, 1H, 6-H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCc2ccc(C#N)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 16.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 4-(2-aminoethyl)benzonitrile (0.101 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.039 g, 16%). 1H NMR (500 MHz, CDCl3): δ 7.53-7.43 (m, 7H), 6.88-6.84 (m, 2H), 5.39-5.33 (m, 1H), 3.17-3.10 (m, 2H), 2.65-2.60 (m, 2H), 1.71 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.7, 143.2, 134.7, 132.7, 131.8, 130.1, 129.5, 129.1, 125.2, 118.8, 111.1, 108.1, 61.9, 44.5, 41.2, 36.2, 27.8; Mass Spectrum: M−H+ 410.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH2:8]Br>CN(C)C=O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH2:8][S:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1CSC
Reaction time: 16 h
Yield: 92.3 %

Procedure:
Sodium thiomethoxide (0.469 g) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.5 g) in dimethylformamide (25 ml). The mixture was stirred for 16 h, solvent removed at reduced pressure and the residue dissolved in ethyl acetate and washed with water and brine, dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (1.2 g) as a yellow solid
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:20][C:21]1([CH3:26])[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:23]3[CH2:24][CH2:25][C:21]([CH3:26])([CH3:20])[CH2:22]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: CC1(C)CCNC1
Product: CC1(C)CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.225 g) was reacted with 3,3-dimethylpyrrolidine via General Procedure B to afford quantitative yield of 4-(2-chloro-6-((3,3-dimethylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[N:6]1([C:4]([C:3]2[CH:20]=[C:21]([CH:22]=[CH:23][C:2]=2[F:1])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the solution of the crude tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepane-1-carboxylate (370 mg crude obtained from previous step) in DCM (20 ml) was added TFA (1 ml) and stirred for 14 h at room temperature. The reaction mixture was concentrated under vacuo to yield the crude product as yellow oil (300 mg), used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:6][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[C:3]#[CH:4].C([Mg]Br)C.[CH:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>C1COCC1>[OH:29][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]#[C:3][C:2]([CH3:1])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:8])=[O:9])[CH3:5]
Reactant: C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCC=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(O)C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In 2 ml of THF was dissolved 1.185 g (5 mmole) of 3-methyl-3-tosylamino-1-butyne, and a THF solution of ethylmagnesium bromide (12 mmole) was added thereto at room temperature, followed by refluxing for 1 hour. After cooling the solution to 0° C., a solution of 1.25 ml (8 mmole) of n -octanal in 3 ml of THF was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and water, and then dried. The solvent was removed by distillation, and the residual oily substance was purified by column chromatography to obtain 1.37 g (percent yield: 75%) of 5-hydroxy-2-methyl-2-tosylamino-3-dodecyne.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:13][CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (10.1 g). To the mixture was added under ice-cooling 65% sodium hydride (3.6 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature iodoethane (12.6 g),and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(ethoxymethyl)benzene (10.1 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(O)cc2s1
Reactant: c1ccc2ocnc2c1
Product: Cc1nc2ccc(OCC3CO3)cc2s1

Procedure:
Compound 51 was prepared in the manner of compound 6 substituting compound 50 for compound 8 in partC-5 of Example 1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH2:24][CH3:25])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]1[N:12]([CH2:24][CH3:25])[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)[N:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCN(CC(=O)c1ccc(F)c(C)c1)C(=O)COCc1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1COCc1ccccc1
Yield: 74.8 %

Procedure:
5.8 g 2-benzyloxy-N-ethyl-N-[2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-acetamide and 4 g ammonium acetate was melted at 200° C. for 30 min Dichlormethane was added and the mixture was washed with aqueous potassiumhydrogen carbonate solution. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (cyclohexane/ethyl acetate 4:1) to yield 4.1 g of the desired product. Rt: 0.74 min (method J), (M+H)+: 325
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]1([CH2:18][CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:18][CH:15]1[CH2:16][CH2:17]1)=[O:6]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(C(F)(F)F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-trifluoromethylbenzoic acid and 3-cycl opropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=3.11. [α]D20=+26.0 (c=2.0 mg/mL,CHCl3)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH:41]([CH3:43])[CH3:42])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([O:40][CH:41]([CH3:42])[CH3:43])=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CC(C)Oc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC(C)C)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207A). MS (ES+): m/z 608.27 (100) [MH+]; HPLC: tR=1.18 min (UPLC, purity).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][C:7]=1[C:13]1[C:19]([OH:20])=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([C:28]([CH3:36])([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]=1[OH:15])([CH3:5])[CH3:4])#[N:2].C([OH:46])C.[OH-].[Na+]>Cl>[NH2:2][C:1]([C:3]([C:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][C:7]=1[C:13]1[C:19]([OH:20])=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]([C:28]([CH3:35])([CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]=1[OH:15])([CH3:4])[CH3:5])=[O:46]
Reactant: CCO
Reactant: CCCCCCC(C)(C)c1c(Cc2ccccc2)c(O)c(C2=C(C(C)(C)C#N)CCC(C)C2)c(O)c1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC(C)(C)c1c(Cc2ccccc2)c(O)c(C2=C(C(C)(C)C(N)=O)CCC(C)C2)c(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A solution of 2.0 g. of 2-[2-(1-cyano-1-methylethyl)-5-methyl-1-cyclohexenyl]-5-(1,1-dimethylheptyl)-dibenzylresorcinol in 6 ml. of ethanol containing 10 ml. of fifty percent aqueous sodium hydroxide solution was heated at reflux and stirred for 32 hours. After cooling the reaction mixture to room temperature, the excess reaction solvent was removed by evaporation under reduced pressure to provide a residue which was next dissolved in aqueous hydrochloric acid. The product was extracted from the aqueous acid solution into diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent affered 2.0 g. of 2-[2-(1-aminocarbonyl-1-methylethyl)-5-methyl-1-cyclohexenyl]-5-(1,1-dimethylheptyl)dibenzylresorcinol as a solid. M.P. 113°-114° C. M+ 595.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(N(CC)CC)C>[CH3:1][N:2]([Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To a vigorously stirred solution of 73.1 g (1.0 mole) N-methylacetamide dissolved in 1400 ml of dry triethylamine was added 196 g (1.30 mole) of t-butyldimethylsilyl chloride. The flask was purged with dry nitrogen and then equipped with a drying tube. Hard stirring of the mixture was continued for 24 hours at room temperature. Then, under a layer of dry air, the reaction mixture was filtered to remove the precipitate of triethylamine hydrochloride. The resulting filter cake was then washed three times with 150 ml each of dry triethylamine. The filtrate and washings were combined and reduced in volume by distillation at 35 degrees C. at 10 mm Hg. The remaining straw colored liquid was then fractionally distilled.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17][C:18](=O)[C:19]([CH3:21])([CH3:20])[C@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[OH:24].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:18]2/[C:19]([CH3:21])([CH3:20])[C@:2]34[O:1][C@H:3]3[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17]/2)[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]2[OH:24])[CH2:28]1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Yield: 75 %

Procedure:
Prepared in 75% yield (51 mg) as described in Example 2 starting from 5α,6α-epoxy-17β-hydroxy-4,4-dimethylandrostan-3-one, (Preparation 8, 50 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 105 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[C:15](=[S:30])(OC1C=CC=CN=1)OC1C=CC=CN=1>ClCCl>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:7]([CH2:6][CH:5]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]=[C:15]=[S:30])[CH3:2]
Reactant: CCOC1=CCc2cccc(N)c2C1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: CCOC1=CCc2cccc(N=C=S)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product of Example 1E (200 mg, 1.06 mmol) in dichloromethane (2.5 mL) was added to a solution of O,O-dipyridin-2-yl thiocarbonate (246 mg, 1.06 mmol) in dichloromethane (5 mL) at room temperature. After stirring at room temperature for 18 hours, the mixture was concentrated, then filtered through silica gel and eluted with 5% ethyl acetate-hexane. Evaporation of the filtrate in vacuo afforded the title compound as a pale pink solid, 225 mg (92%). 1H NMR (DMSO-d6) δ 7.21-7.27 (m, 3H), 4.86 (t, 1H, J=3.6 Hz), 3.81 (q, 2H, J=7.0 Hz), 3.49 (q, 2H, 4.4 Hz), 3.35 (t, 2H, J=5.2 Hz), 1.27 (t, 3H, J=7.0 Hz); MS (DCI+) m/z 232 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:14]12[CH2:24][CH:17]([CH:18]([O:20][CH2:21][CH2:22][OH:23])[CH2:19]1)[CH2:16][NH:15]2.C(N(CC)CC)C.C(O)C>>[CH:11]([C:10]1[C:3]2[C:2]([N:15]3[CH2:16][CH:17]4[CH2:24][CH:14]3[CH2:19][CH:18]4[O:20][CH2:21][CH2:22][OH:23])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: OCCOC1CC2CC1CN2
Reactant: CC(C)c1csc2ncnc(Cl)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCO)c12
Temperature: 50 °C

Procedure:
4-Chloro-5-isopropyl-thieno[2,3-d]pyrimidine (0.35 g, 1.6 mmol), 2-(2-azabicyclo[2.2.1]heptan-5-yloxy)ethanol (0.39 g, 2.5 mmol), triethylamine (0.50 g, 0.70 mL, 4.9 mmol) and ethanol (3.95 g, 5 mL, 85.6 mmol) were combined and heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@@H:7]([C:16](O)=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@H:7]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=O.[NH2:29][NH2:30]>CCO>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([NH:29][NH2:30])=[O:2])[CH:28]=[CH:27][C:8]=2[N:9]=1
Reactant: NN
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Solvent: CCO
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)NN)cc3[nH]2)c1
Temperature: 90 °C
Yield: 66.6 %

Procedure:
To a suspension of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid methyl ester (37.5 mg, 0.1 mmol) in EtOH (1 mL) was added anhydrous hydrazine (32 mg, 1 mmol). The reaction mixture was heated at 90° C. for 18 h, cooled to the room temperature, filtered to get the solid precipitate that was dried under reduced pressure to afford the title compound (25 mg, 33%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 4.51 (br s, 2H, NH), 7.11-7.17 (2H), 7.63 (d, J=9 Hz, 1H), 7.71 (d, J=9 Hz, 1H), 7.79-7.85 (2H), 8.10-8.21 (2H), 8.29 (s, 1H), 9.87 (br, 1H, NH). ESI-MS m/z 376.3 (MH+).