Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:25](CC)CC)C.C(OC(Cl)=O)C(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([NH2:25])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 15 h

Procedure:
1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.22 g, 4 mmol) was combined with THF (40 mL) and cooled to -10° C. Triethylamine (0.61 mL, 4.4 mmol, 1.1 eq.) and isobutylchloroformate (0.57 mL, 4.4 mmol, 1.1 eq.) were added and the reaction was allowed to warm to ambient temperature and stir 15 h. The slurry was filtered and the solids were rinsed with THF. The filtrate was cooled to -10° C. and sparged with NH3 (gas) for 0.5 h. The slurry was allowed to warm to 20° C. and stir for 15 h. The slurry was filtered and the filtrate was diluted with ethyl acetate and washed with saturated NaHCO3 (3X). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a residue. The residue was recrystallized from diethyl ether to give the title compound:
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:6]([O-:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Sr+2:5].[C:6]([O-:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C([O-])c1ccccc1

Procedure:
Strontium carbonate (1.0 g, 6.77 mmol) and benzoic acid (1.65 g, 13.5 mmol) in water (30 ml) were stirred for 4 hours at 70° C. The mixture was filtered and the fitrate was evaporated to dryness and dried in vaccuo at ambient temperature. The title compound was isolated. Yield 1.8 g (81%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[N:17]=[CH:16][C:15]([C:18](O)=O)=[N:14]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:33]2[CH:34]=[N:35][C:36]([F:39])=[CH:37][CH:38]=2)([NH2:32])[C@@H:29]([NH2:31])[CH3:30])=[CH:24][CH:23]=1.[Yb]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2([C:33]3[CH:34]=[N:35][C:36]([F:39])=[CH:37][CH:38]=3)[C@H:29]([CH3:30])[NH:31][C:18]([C:15]3[CH:16]=[N:17][S:13][N:14]=3)=[N:32]2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1cnsn1
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Yb]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1NC(c2cnsn2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Triethylamine (23 mg) and 1,1′-carbonyldiimidazole (37 mg) were added to a solution of 1,2,5-thiadiazole-3-carboxylic acid (30 mg) in tetrahydrofuran (3 mL) in this order, and the mixture was stirred at room temperature for one hour. A solution of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (50 mg) described in Reference Example 5-1 in tetrahydrofuran (1 mL) was added to the above reaction mixture, and the resultant mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, and then the obtained residue was dissolved in ethyl acetate. Then the solution was washed with water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained crude product was dissolved in toluene (0.5 mL). Ytterbium triflomethanesulfonate (12 mg) was added to the solution, and then the mixture was stirred at 100° C. for 10 hours. The reaction mixture was diluted with ethyl acetate, and the dilution was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order. The mixture was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:3) to give the objective compound (37 mg) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:57])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:57])=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1c(Br)cccc1C(=O)N1CCN(C)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(C)CC4)c3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (174 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-(4-methyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-148) as a pale yellow powder (54 mg, 56%).
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][C:3]1([CH3:16])[CH:2]2[O:8][CH:7]2[C:6]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: CC1(C)Oc2ccc(C=O)cc2[C@@H](O)[C@@H]1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2ccc(C=O)cc2C2OC21
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
A mixture of trans-3-bromo-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran-6-carbaldehyde (6.9 g), potassium carbonate (6.7 g), and dimethylformamide (24 ml) was stirred at room temperature for 48 hours and followed by at 35° C. for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by recrystallization from diisopropyl ether to give 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6-carbaldehyde (2.9 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>CO>[CH2:1]([NH:8][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:26][O:25][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncnc(OCC3CCC(=O)CC3)c2c1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(OCC3CCC(NCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzylamine (1.08 ml, 10 mmol) and sodium cyanoborohydride (2.2 g, 11 mmol) were added to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexanone (2.87 g, 10 mmol) in methanol (50 ml). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dissolved in saturated potassium carbonate solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×50 ml), and the combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc/MeOH 9/1).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[C:13](=[O:22])[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1)([CH3:3])[CH3:2]>[OH-].[Na+].C1COCC1>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]([CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[C:13](=[O:22])[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)n1c(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2c(-c3ccccc3)oc(=O)n2C(C)C(=O)O)ccc1=O
Temperature: 52.5 °C
Yield: 82 %

Procedure:
A solution of ethyl 2-[4-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-5-phenyl-oxazol-3(2H)-yl]-propanoate (3.32 g) in a mixture of 1N aq. NaOH (25 ml) and THF (25 ml) was heated at 50-55° C. for 2 hours. After removal of THF, the mixture was acidified with 1N aq. HCl, extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was recrystallized from a mixture of CHCl3 and n-hexane to give 2-[4-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-5-phenyl-oxazol-3(2H)-yl]propanoic acid as a solid (2.53 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:18](=[O:26])[NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:4]1>CO.[Pd]>[CH3:1][O:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:18]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:26])[CH2:4]1
Reactant: CO[C@H]1C[C@@H](C(=O)Nc2cnccn2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CN[C@H](C(=O)Nc2cnccn2)C1
Yield: 102.3 %

Procedure:
To a solution of (2S,4S)-benzyl 4-methoxy-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 18C (550 mg, 1.54 mmol) in methanol (200 mL) was added palladium on carbon (10%, 80 mg) under nitrogen. The suspension was hydrogenated at 55 psi overnight. The resulting suspension was filtered through a pad of celite and washed with methanol. Concentration of the filtrate gave the product (18D) as an oil (350 mg, 100%) which was used without purification in the next step. LC/MS [M+H]+: 223; Ret time (Method F): 0.76 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.[CH3:23]I>CN(C=O)C.CCOC(C)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:23])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: CI
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A solution of NaH (60% dispersion in mineral oil) (2.1 g, 53 mmol) in DMF (100 mL) in a 500 mL round bottom flask was cooled 0° C. A solution of ethyl 2,2-bis(4-chlorophenyl)acetate (5.47 g, 18 mmol) and MeI (3.3 mL, 53 mmol) in DMF (50 mL) was added dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for 20 hours. A mixture of products was observed by LC/MS. The solution was diluted with EtOAc (200 mL), and then washed with 10% HCl(aq) (200 mL), with deionized water (200 mL), and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 10.11 g crude product which was purified by flash column chromatography (silica, 0-100%, hexane/EtOAc) to give 2,2-bis(4-chlorophenyl)propanoic acid (3.05 g).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH2:11][CH2:12][C:13](F)(F)F)(=[O:9])=[O:8])[CH3:6])C.[CH3:19][Si](C)(C)[O-].[K+].Cl>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:19])(=[O:8])=[O:9])([CH3:6])[C:4]([OH:3])=[O:18]
Reactant: C[Si](C)(C)[O-]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCCC(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CCS(=O)(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109 %

Procedure:
To a solution of 170 g (0.59 mol) of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethyl ester in THF (3.4 L) are added 225.4 g (1.76 mol) of potassium trimethylsilanolate in portions over 0.5 h. The reaction is stirred at room temperature for 18 h. The reaction mixture is acidified with 2 M aq. HCl solution (2 L) to pH 2 and extracted with DCM (2×2 L). The combined organic extracts are dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure to afford 143 g of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid.
Reaction SMILES: [C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3]([O:20][C:17](=[O:19])[CH3:18])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 10.0 g of product from Example 317 in 250 ml of acetic acid is added 15.0 g mercuric acetate. The mixture is stirred at room temperature for 22 hours, concentrated in vacuo, and purified by chromatography (Silica gel: methylene chloride -5% methyl alcohol/methylene chloride) to give 7.5 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2([N+:17]([O-])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO.Cl.[Zn]>[NH2:17][C:11]1([CH:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[OH:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])C1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: NC1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of (3,5-dichloro-phenyl)-(1-nitro-cyclohexyl)-methanol (5.87 g, 19.3 mmol) in methanol (40 mL) and concentrated HCl (10 mL), cooled to ˜5° C., was added zinc powder. The mixture was stirred at room temperature overnight and filtered through Celite. The filter cake was washed with methanol (2×100 mL) and the filtrate was evaporated to dryness. The residue was treated with 5% aqueous NaOH (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over Na2SO4 and evaporated to leave (1-amino-cyclohexyl)-(3,5-dichloro-phenyl)-methanol (4.36 g) as a white solid. 1H NMR (500 MHz, CDCl3) δ(ppm): 7.25 (s, 1H), 7.185 (s, 2H), 4.21 (s, 1H), 1.55 (m, 4H), 1.3 (m, 3H), 1.1 (m, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH:12]=[O:11])[CH2:14][CH2:15]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To 1.99 g of dimethyl sulfoxide in 45 ml CH2Cl2 at −78° C. was added 2.16 g of oxalyl chloride. After 10 min, 1.865 g of 4-hydroxymethyl-N-benzoyl piperidine (step B) in 15 ml of CH2Cl2 was added at −78° C. and stirred for 30 min. DIEA (5.49 mL) was added and this mixture was stirred for an additional 30 min. at −78° C. and then warmed to room temperature and stirred another 30 min. The reaction was quenched with 50 mL H2O and extracted with 3×50 ml CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was chromatographed with 2:1 hexane:EtOAc, followed by 1:1 hexane: EtOAc to give 1.445 g of the title compound. 1H NMR (500 MHz) 1.72 (m, 2H), 1.90 (m, 1H), 2.14 (m, 1H), 2.58 (m, 1H), 3.21 (m, 2H), 3.68 (m, 1H), 4.41 (m, 1H), 7.39 (m, 5H), 9.72 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][C:4]=5[CH3:10])=[O:9])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C(=O)O)c(C)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C)s1
Yield: 63.1 %

Procedure:
In the same manner as in Example 18-4 and using 2,5-dimethyl-1,3-thiazole-4-carboxylic acid (314 mg, 2.00 mmol), tetrahydrofuran (50 mL), oxalyl chloride (191 μL, 2.20 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (283 mg, 63%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@H:9]([NH:14]C(=O)C3C=CC=CC=3CO)[C@H:10]2[OH:13])=[CH:6][CH:5]=1)[CH3:2]>C(O)(=O)C>[NH2:14][C@H:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C@@H:10]1[OH:13]
Reactant: CCOc1ccc2c(c1)[C@H](O)[C@@H](NC(=O)c1ccccc1CO)C2
Solvent: CC(=O)O
Product: CCOc1ccc2c(c1)[C@H](O)[C@@H](N)C2
Reaction time: 18 h

Procedure:
N-[(1S,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamide and N-[(1R,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamnide (XVII, Example 16, 200 mg, 0.61 mmol) is dissolved in acetic acid (2.5 mL). The reaction mixture is stirred for 18 hr at 80°. Then the mixture is partitioned between methylene chloride and water. The aqueous phase is separated and adjusted to pH=10 using aqueous ammonium. The product is extracted with methylene chloride. The organic layers are concentrated to give the same title compound (VII) as EXAMPLE 6 and its cis-diastereomer.
Reaction SMILES: [CH2:1]1[CH2:12][O:11][CH:3]([CH:4]([CH3:10])[CH2:5][C:6](OC)=[O:7])[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:1]1[CH2:12][O:11][CH:3]([CH:4]([CH3:10])[CH2:5][CH2:6][OH:7])[O:2]1
Reactant: COC(=O)CC(C)C1OCCO1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CCO)C1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of methyl 4,4-ethylenedioxy-3-methylbutanoate (63.2 g) in ether (200 ml) is added dropwise to a mixture of lithium aluminum hydride (13.8 g, 0.363 m) in ether (500 ml) at 0° C. under nitrogen. The resulting mixture is stirred for 2 hr., treated with 5% sodium bicarbonate solution (100 ml), allowed to warm to room temperature and filtered. The filtrate is dried (Na2SO4) and the solvent is evaporated in vacuo to give the crude product (26 g). This material is further purified by column chromatography on silica gel (300 g, 20% ethyl acetate in hexane) to give 4,4-ethylenedioxy-3-methyl-1-butanol as a colorless liquid (14.9 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]3[N:22]([C:18]([C:17]([F:34])([F:35])[F:16])=[N:19][N:20]=3)[N:23]=2)[CH2:28][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: Oc1cccc(OCc2ccccc2)c1
Product: FC(F)(F)c1nnc2ccc(N3CCC(Oc4cccc(OCc5ccccc5)c4)CC3)nn12
Yield: 40 %

Procedure:
Obtained in 40% yield by an analogous procedure to Example 430, preparation of starting materials, starting from 3-(benzyloxy)phenol and 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol.
Reaction SMILES: [OH:1][C:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][CH3:13])[CH2:8][CH2:7]1)=[O:4].Br[CH2:25][CH2:26][OH:27].C(N(CC)CC)C.BrC(O)C>C(#N)C.C1COCC1>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:25][CH2:26][OH:27])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Reactant: OCCBr
Agent: CC(O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(CCO)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 300 mg; 0.85 mmol), 2-bromoethanol (0.145 ml; 2.05 mmol) and triethylamine (0.36 ml; 2.58 mmol) in 4.5 ml of acetonitrile and 3.5 ml of THF was stirred at 80° C. in a sealed vessel for 16 hr. Additional amounts of bromoethanol (0.145 ml; 2.05 mmol), triethylamine (0.36 ml; 2.58 mmol), acetonitrile (3.5 ml) and THF (3.5 ml) were added and the stirring and heating prosecuted for 24 additional hours. The solution was evaporated to dryness, dissolved in dichloromethane, washed with brine, dried and concentrated. Purification by preparative reversed-phase HPLC (Cl3CH/MeOH from 1:0 to 9:1) gave 76% of the title product as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl.CCOC(C)=O>[CH3:27][C:26]1([CH3:28])[O:34][CH:25]1[C:14]1[CH:15]=[C:16]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)[C:11]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:12][CH:13]=1
Reactant: COc1ncc(Nc2ncc(C=C(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ncc(Nc2ncc(C3OC3(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methylprop-1-enyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (380 mg, 0.996 mmol) in DCM (9.9 mL) was cooled to 0° C., and 3-chlorobenzoperoxoic acid (268 mg, 1.196 mmol) was then added. The resulting mixture was stirred at 0° C. for 1.5 h and then allowed to warm to ambient temperature and stir for 2 h. The reaction mixture was then diluted with 200 mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 1 time with 150 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. m/z (ESI, +ve ion) 398.2 (M+H)+.