Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23](O)=[O:24])=[C:5]([O:26][C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([NH2:39])=[O:24])=[C:5]([O:26][C:27]([F:28])([F:30])[F:29])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)O)=C(C)N2
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.477 mmol) of the compound from Example 37A are introduced into 5 ml of ethyl acetate and, after addition of 96.7 mg (0.596 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight (TLC check: insufficient reaction). Then 1 ml of DMF is added, and the mixture is stirred at room temperature for a further night (TLC check: complete conversion). The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 663 μl of ammonia (28% by weight solution in water, 4.77 mmol) are added, and the reaction mixture is heated at 100° C. in a closed vessel overnight. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 140 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.[CH2:8](I)[CH3:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7])[CH3:9]
Reactant: CCI
Reactant: O=C(O)C1=CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 108.4 %

Procedure:
To a solution of 3.2425 g (33.09 mmol) of 1-cyclobutenecarboxylic acid in 60 ml of dimethylformamide were added 12 ml (150 mmol) of ethyl iodide and 5.53 g (40 mmoL) of potassium carbonate, followed by 20 hours of stirring at room temperature. The reaction solution was poured into water and extracted with ether. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, 4.5267 g of the title compound was obtained as a mixture with ethyl iodide and ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:9]
Reactant: CO
Reactant: Cc1cc(C(=O)O)no1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)on1

Procedure:
2,5-Hexanedione, 9 is the starting material for the process. 2,5-Hexanedione 9 is nitrated and oxidized with nitric acid to form 5-methyl-3-isoxazolecarboxlic acid 8, (isoxazole acid). Isoxazole acid 8 is esterified by treating it with methyl alcohol and sulfuric acid to give 5-methyl-3-isoxazolecarboxylic acid methyl ester, isoxazole ester 7. Isoxazole ester 7 is reacted with Benzylhydrazine 5 which itself is prepared from the reaction of benzaldehyde 6 with hydrazine and then reduced with hydrogen to form Benzylhydrazine 5.
Reaction SMILES: CC1(C)[NH:6][CH:5]([PH:7](=[O:9])[OH:8])[C:4]([CH3:11])([CH3:10])[S:3]1>O>[NH2:6][CH:5]([PH:7](=[O:8])[OH:9])[C:4]([SH:3])([CH3:11])[CH3:10]
Reactant: CC1(C)NC([PH](=O)O)C(C)(C)S1
Solvent: O
Product: CC(C)(S)C(N)[PH](=O)O
Temperature: 0 °C

Procedure:
0.5 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)phosphinic acid (prepared as described in Example 2) was dissolved in boiling water and the solution was concentrated by boiling. The solution was cooled to 0° C. and the white crystalline solid was collected. There was obtained 0.15 g of DL-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 205°-207° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1cc(C(=O)O)c(C)c(C)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)c(C)c(C)c1C
Reaction time: 3.5 h
Yield: 142.8 %

Procedure:
A 3 L 3-necked flask is equipped with a condenser, argon inlet, thermowell, magnetic stirrer. The flask is purged with argon then charged with 2,3,4,5-tetramethylbenzoic acid (138.3 g, 0.776 mol), methylene chloride (1.5 L), thionyl chloride (73.5 mL, 1.01 mol) and N, N-dimethylformamide (2.0 mL, 0.026 mol). The resulting suspension is heated to reflux, after a clear solution is formed, heating is continued for 3.5 hours. The solution is allowed to cool then concentrated in vacuo. Last traces of thionyl chloride are removed by co-distillation with toluene (2×100 mL). The remaining oil is dried under high vacuum then used without further purification. Additional reactions are carded out to produce a total of 218 g of 2,3,4,5-tetramethylbenzoyl chloride.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[N:32]2[N:33]=[C:34]([SH:36])[N:35]=[C:31]2[N:30]=[CH:29][CH:28]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:31]4[N:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1ccnc2nc(S)nn12
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4nccc(C)n4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([OH:28])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([O:28][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][NH:12]2)=[CH:6][N:5]=1.[CH2:17](Cl)[C:18]#[CH:19]>CC(N(C)C)=O>[Cl:3][C:4]1[N:14]=[C:13]2[C:7](=[CH:6][N:5]=1)[N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][N:12]2[CH2:19][C:18]#[CH:17]
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 15 mg, 0.38 mmol) in DMA (1 mL) was carefully added a solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 65 mg, 0.31 mmol) in DMA (1.5 mL). The reaction mixture was allowed to stir, under nitrogen, on an ice bath for 1 hour prior to addition of propargyl chloride (34 mg, 0.47 mmol). The reaction mixture was left to stir at ambient temperature overnight and then quenched by addition of saturated aqueous ammonium chloride solution (0.5 mL) and stirred for 15 minutes. The resultant mixture was partitioned between DCM (10 mL) and water (10 mL). The organic phase was separated by filtration through PTFE filter cup. The aqueous phase was re-extracted with DCM (5 mL) and the combined organic solutions evaporated to dryness to yield the title compound as a beige coloured solid (52 mg, 67%)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC(C)(CN)CO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC(C)(C)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 83.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 3-amino-2,2-dimethyl-1-propanol (TCI-US) (0.2 g, 2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.2 g, 1.6 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide as a white solid (0.16 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C=Cc1ccccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccccc1OCCCBr
Yield: 89.4 %

Procedure:
To a solution of methyl 2-hydroxycinnamate (1.31 g; 7.33 mmol) in 50 ml acetone was added 1,3-dibromopropane (1.50 ml; 14.8 mmol) and K2CO3 (4.36 g; 13.4 mmol). The mixture was heated to reflux for 12 h, cooled to r.t, diluted with hexane (50 ml), filtered and finally concentrated to afford the title product (1.96 g; 50% pure), which was used as such in the next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[CH:12][C:11]=1[O:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(O)c2ccccc2)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To 2-(tert-Butyldimethylsilanyloxymethyl)-5-bromoanisole (500 mg, 1.51 mmol) in THF (10 ml) at -78° C. was added n-BuLi (1.13 ml of a 1.6M solution in penthane, 1.81 mmol) and the mixture allowed to stir for 1 h at -78° C. Benzaldehyde (176 mg, 1.66 mmol) was added and the mixture allowed to warm to room temperature and stirred for 1 h. Water (20 ml) was added and the mixture extracted with ether (3×10 ml). The combined extracts were washed with water (10 ml), brine (10 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was purified by chromatography (SiO2, 50% ether/petrol) to give the title compound as a colourless oil (303 mg, 56%).
Reaction SMILES: [OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C=O.F[C:26](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C:10](=[CH2:26])[CH2:9]3
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2C=C[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 3.5 h
Yield: 43.5 %

Procedure:
500 mg of 17β-hydroxy-17α-methylandrosta-4,15-dien-3-one in 8.3 ml of tetrahydrofuran is stirred at 60° C. under argon with 348 mg of paraformaldehyde and 2.2 g of N-methylanilinium trifluoroacetate. After 3.5 hours, the mixture is diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under vacuum. After the crude product has been chromatographed on silica gel with a pentane-diethyl ether gradient, 226 mg of 17β-hydroxy-17α-methyl-6-methyleneandrosta-4,15-dien-3-one is obtained, mp 162° C. (from isopropyl ether).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C:27]([C@@H:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:29][C@:13]12[CH3:14])=[C:26]1[C:21](=[CH:22][C:23](=[O:39])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9].O.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CO>[C:8]([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C:27]([C@@H:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:1](=[O:3])[CH3:2])[CH2:29][C@:13]12[CH3:14])=[C:26]1[C:21](=[CH:22][C:23](=[O:39])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](CCCCCCCCO)C[C@]12C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCC[C@H]1C[C@]2(C)[C@@H](OC(C)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CCC3=C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.6 cm3 of acetic anhydride and 95 mg of 4-(dimethylamino) pyridine are added to a solution of 1.4 g of 17beta-(acetyloxy) 11beta-(8-hydroxy octyl)-estra-4,9-dien-3-one (obtained by a similar process to Stage D of the preparation of Example 50 of the European Patent Application EP 384 842) in 10 cm3 of pyridine. The solution is agitated for one hour at ambient temperature, 5 cm3 of water and 5 cm3 of methanol are added, followed by agitation for ten minutes at 0°/+5° C., the whole is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure after having entrained the pyridine with toluene. 1.61 g of crude product is obtained which is chromatographed on silica, eluant: ethyl acetate-cyclohexane 3-7. In this way 1.28 g of desired product is collected.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.CCOCC>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.30 mmol) was added to a suspension of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 0.165 g, 0.43 mmol) in CH2Cl2 (10 mL). The mixture was cooled to 0° C. in an ice bath, and isopropyl chloroformate (1.0M in toluene, 0.48 mL, 0.48 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirred for 1.5 h, then diluted with ether, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column eluted with 45 to 50% EtOAc/hexane to give 0.152 g (82%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.97 (d, 2H, J=8.3 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.90-4.80 (m, 1H), 4.20-4.10 (m, 2H), 3.90 (d, 2H, J=6.1 Hz), 3.13 (s, 3H), 2.95-2.75 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 432 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([OH:25])=O)=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:26]#[N:27].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:17][CH2:18]3)[C:14]3[C:19]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:25])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:26]#[N:27]
Reactant: NC1CCCC1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)c2n1C1CC1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)NC3CCCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid (132 mg, 0.36 mmol) in DMF (3 mL) was added cyclopentanamine (0.10 mL, 1.0 mmol), N-ethyl-N-isopropylpropan-2-amine (0.060 mL, 0.36 mmol) and 1 h-benzotriazol-1-yl-oxytripyrrolidinophosphonium (190 mg, 0.36 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent gave 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-cyclopentyl-1-cyclopropyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, MeOH-d4) δ 8.03 (1H, s), 7.70 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.28 (1H, t, J=8.0 Hz), 6.03 (1H, q, J=8.0 Hz), 4.45-4.38 (1H, m), 4.11 (1H, dd, J=8.0, 4.0 Hz), 3.53-3.44 (1H, m), 2.15-2.05 (2H, m), 1.88-1.78 (2H, m), 1.75-1.60 (4H, m), 1.38-1.10 (3H, m), 1.00-0.92 (1H, m); LC-MS (ESI) m/z 431.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7])[CH:2]([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:7])=[CH:16][CH:15]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: CC(C)COC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)OCC(C)C)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A solution of 4-(1-isobutoxyethyl)benzoic acid (132 mg, 0.59 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulphate, concentrated. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-isobutoxyethyl)benzamide (83 mg, 40%) as white solid. LRMS (M+H+) m/z: calcd 356.13. found 356. HPLC Purity (214 nm): 97%. 1H NMR (300 MHz, CD3OD) δ 7.76 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 6.10 (s, 1H), 4.49-4.43 (m, 3H), 3.14-3.00 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.84-1.79 (m, 2H), 1.39 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.6 Hz, 6H).
Reaction SMILES: C([N:9]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH3:31])[CH2:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:10]1)(=O)C1C=CC=CC=1>CO.[Pd]>[CH3:31][N:14]([C@@H:11]1[CH2:12][CH2:13][NH:9][CH2:10]1)[CH2:15][C:16]([N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:17]
Reactant: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
To a solution of (R)-2-[(1-benzoyl-pyrrolidin-3-yl)-methyl-amino]-N,N-diphenyl acetamide(0.68 g, 1.70 mmol) in CH3OH (30 ml) was added Pd/C 20% (170 mg). The resulting slurry was hydrogenated at 50 psi for 24 hours. The catalyst was filtered through Celite and filtrate evaporated under reduced pressure to give 0.5 g of desired product.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O.[BH4-].[Li+]>CCOCC>[CH3:11][C:7]1([CH3:10])[N:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@H:5]([CH2:3][OH:2])[CH2:9][O:8]1
Reactant: CCCCCCC(=O)N1[C@H](C(=O)OC)COC1(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](CO)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8a (296 mg, 1.09 mmol) in dry ether (1 mL) is treated with lithium borohydride (2M solution in THF, 0.55 mL, 1.09 meq) under an argon atmosphere. The mixture is stirred for 3 hr at reflux and 18 h at room temperature. The resulting mixture is diluted with ether and quenched with methanol. The volatiles are removed and the residue is taken up in EtOAc/H2O. Workup provides the crude alcohol which is purified by chromatography (2:1 hexane/EtOAc): NMR δ 0.88 (m, 3 H), 1.30 (m, 6 H), 1.54 (s, 3 H), 1.62 (s, 3 H), 2.35 (m, 2 H), 3.30-4.40 (complex m, 6 H); MS (HR-E1) m/z 243.1837 (M calcd. for C13H25NO3 243.1840); [α]D26 =-5±1 (CHCl3).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([F:18])[F:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:12]([O:14][C:15](=[O:20])[C:16]([F:18])([F:17])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:13]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Ic1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
To a suspension of 6-iodo-quinoline (1.0 g, 4 mmol) and Cu(0) (559 mg, 8.8 mmol) in dry DMSO was added bromodifluoro-acetic acid ethyl ester (893 mg, 4.4 mmol). The reaction mixture was stirred under N2 at 55° C. for 15 h. The mixture was poured in a solution of K2CO3 and extracted with EtOAc. The organic layer was collected and dried over MgSO4. The crude was purified by silica gel column to give the title compound as a red oil (310 mg, 30%). 1H-NMR (400 MHz, CDCl3) δ ppm 1.33 (t, 3H), 4.334 (q, 2H), 7.52 (m, 1H), 7.93 (m, 1H), 8.15 (s, 1H), 8.20-8.23 (m, 2H), 9.03 (s, 1H).