Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]1=[O:25].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[C:14](=[O:25])[CH:15]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccc(Cl)cc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccc(Cl)cc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 11 g of the product of Step C and 3.5 ml of benzoyl chloride were reacted to obtain 13 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:19])[NH:14][C:15](=O)[CH2:16]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:10][S:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:16]=[C:15]([NH:14][C:13]([O:12][CH3:11])=[O:19])[N:1]=2)[CH:4]=1)=[O:9]
Reactant: COC(=O)NC(=O)CCl
Reactant: CS(=O)c1ccc(N)nc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(S(C)=O)ccc2n1

Procedure:
A suspension of 2-amino-5-(methylsulfinyl)pyridine (7.9 mmol) and methyl(chloroacetyl)carbamate (11.6 mmol) in 12 ml of HMPT is treated in a manner similar to that described in Example 1D to yield the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)C)[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N2CCC(N)C2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 83.3 %

Procedure:
24 g (0.0911 mol) of N-[1-(3-methyl-4-nitrophenyl)pyrrolidin-3-yl]acetamide (1) are introduced into a solution containing 75 ml of 37% hydrochloric acid and 165 ml of water in a 500 ml three-necked flask. The reaction medium is heated at 90° C. for 2 hours 30 minutes. After cooling, the medium is neutralized carefully with 75 ml of aqueous 35% sodium hydroxide (pH=approximately 8). The resulting solid is then filtered off, after which-it is washed with water until the washing waters are neutral. The product is then dried under vacuum over P2O5. 16.8 g (83%) of 1-(3-methyl-4-nitrophenyl)pyrrolidin-3-ylamine (2) are thus obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:64]([O:71][C:72](=[O:78])[C@@H:73]1[CH2:77][CH2:76][CH2:75][NH:74]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:74]3[CH2:75][CH2:76][CH2:77][C@H:73]3[C:72]([O:71][CH2:64][C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[O:78])=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3cccc(F)c3)n2)CC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[5-carboxymethoxy-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.506 g HOBt, 1.2 ml DIPEA and 0.798 g L-proline benzyl ester hydrochloride at RT. Then 0.633 g EDC was added portionwise and the suspension stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Fc1ccc(I)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2-methylimidazole (13.6 g, 165 mmol) in DMF (500 ml) was added sodium hydride (6.60 g, 165 mmol, 60% dispersion in mineral oil) in portions. The resulting white suspension was stirred at room temperature for 30 min, 4-fluoroiodobenzene (33.3 g, 150 mmol) added and the mixture heated at 100° C. After 16 hr, the bulk of DMF was removed by evaporation. The residue was then partitioned between a mixture of ethyl acetate-toluene (2:1, 500 ml) and water(250 ml). The organic layer was separated and washed with water (250 ml). Product was extracted with 10% aqueous hydrogen chloride (2×200 ml) and the combined aqueous extracts neutralized with 30% aqueous potassium hydroxide. The resulting suspension was extracted with a mixture of ethyl acetate-toluene (2:1, 3×250 ml) and the combined organic extracts washed with water (2×250 ml), brine (250 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was recrystallized from toluene to afford the titled compound as off-white solids (21.9 g, 51%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>CCO>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[CH:11]=1
Reactant: Brc1cc(Br)c2ccccc2n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
A solution of 2,4-dibromoquinoline (273 mg, 1.0 mmol) in EtOH (15 mL) was treated with aqueous dimethylamine (40%, 0.4 mL, 3 mmol), stirred at room temperature for 16 h, concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (119 mg, 50%) as a cream solid: IR νmax (Nujol)/cm−1 2924, 2854, 1598, 1546, 1510, 1463, 1379 and 754; NMR δH (400 MHz, CDCl3) 3.21 (6H, s), 7.21 (1H, s), 7.23-7.26 (1H, m), 7.55 (1H, t, J 8.2 Hz), 7.68 (1H, d, J 8.5 Hz) and 7.94 (1H, d, J 7.1 Hz); M/Z 251 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([F:26])[CH3:25])=[O:10])[C:2]1C=CC=C[CH:3]=1.[H][H]>CO.Cl.[Pd].C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([F:26])[CH3:25])=[O:10])[CH:2]=[CH2:3]
Reactant: CC(F)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCC(C)F
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-fluoropropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (950 mg) in a mixture of methanol (20 ml) and concentrated hydrochloric acid (one drop) was hydrogenated under atmospheric pressure of hydrogen in the presence of 30% palladium on carbon as a catalyst at ambient temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (100 ml) and water (40 ml). The aqueous layer was separated and tetrahydrofuran (40 ml) was added thereto To the solution was added dropwise allyl chloroformate (320 μl) while keeping the pH between 8-9 with 4N sodium hydroxide at 0° C. and the mixture was stirred at the same condition for one hour after addition of allyl chloroformate (320 μl). The mixture was extracted with ethyl acetate (100 ml), washed with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (100 ml) eluting with a mixture of hexane and ethyl acetate (2:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-fluoropropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (360 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[O:9])[CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:13][C:12]=2[CH3:17])=[O:9])[CH:3]=1
Reactant: Cc1ccccc1NC(=O)c1cc(Cl)ncn1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cooled (0° C.) solution of 6-chloro-N-(2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 18; 14.00 g; 56.52 mmol) in DCM (280 ml) was treated dropwise with a solution of chlorosulfonic acid (37.8 ml; 565 mmol) in DCM (100 mL). The reaction mixture was allowed to warm from 0° C. to room temperature, then it was stirred at room temperature overnight. The mixture was cooled to 15° C., a mixture ice/water was added and it was stirred for a few minutes. Phases were separated and the organic layer was washed with cold water, brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)nc2c(-c3ccncc3)cnn12
Yield: 37.7 %

Procedure:
Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (79 mg, 38%). MS (ISP) 421.2 [(M+H)+]; mp 289° C.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]1([CH3:22])[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH3:51])[C:30]2[O:36][C:35]3[C:37]([Cl:47])=[CH:38][C:39]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:40][C:34]=3[CH2:33][S:32](=[O:49])(=[O:48])[C:31]=2[CH:50]=1)=[O:26]>CN(C=O)C>[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH3:51])[C:30]2[O:36][C:35]3[C:37]([Cl:47])=[CH:38][C:39]([N:41]4[CH2:42][CH2:43][N:44]([C:19](=[O:20])[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=5[CH3:22])[CH2:45][CH2:46]4)=[CH:40][C:34]=3[CH2:33][S:32](=[O:48])(=[O:49])[C:31]=2[CH:50]=1)=[O:26]
Reactant: Cc1ccccc1C(=O)O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(=O)c4ccccc4C)CC3)cc(Cl)c1O2
Temperature: 22 °C
Reaction time: 1 h

Procedure:
Carbonyl diimidazole (0.074 g 0.55 mmol) was added to a solution of 2-toluic acid (0.111 g, 0.67 mmol) in DMF (3 mL) and stirred at 22° C. for 1 h. To this, a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.2 g, 0.45 mmol) in DMF (2 mL) was added and stirred at 22° C. for 1 h. Solvent was removed and ice water (5 mL) was added. The solid separated was filtered, washed with water. The crude product obtained was purified by column chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 0.093 g (53%); mp: 201-204° C.; 1H NMR (DMSO-d6, 500 MHz): δ 2.23 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.28 (s, 2H, CH2), 3.34 (s, 2H, CH2), 3.39 (s, 2H, CH2), 3.87 (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.12 (s, 1H, Ar), 7.16 (s, 1H, Ar), 7.20 (m, 4H, Ar), 8.11 (s, 1H, Ar), 8.16 (s, 1H, Ar); MS: m/e (ES+) 555 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[Na].[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:24][CH3:25])[CH3:22]>CO.C1(C)C=CC=CC=1>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)[CH3:22]
Reactant: Oc1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCN(CC)CCCCl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A solution of 4.9 g. (0.023 mol.) of 2-p-hydroxyphenylbenzofuran in 75 ml. of toluene and 5 ml. of methanol was added to a sodium methoxide solution prepared by dissolving 0.54 g. (0.023 g.-atom) of sodium in 25 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation and 3.48 g. (0.023 mol.) of diethylaminopropyl chloride was added and the resulting reaction mixture was refluxed for four hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran, m.p. 86°-88°.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[O:9]([C:16]1[CH:17]=[C:18]([N:22]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34](OC)=[O:35])[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN([Al]CCl)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[C:31]([CH2:30][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:32]=1
Reactant: CNC
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: CN(C)[Al]CCl
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution of trimethylaluminum in toluene (3.2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. was slowly added the (N,N-dimethylamino)chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl) amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C25H25F3N2O3.0.5 H2O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMS calcd. 459.1896 [M+H]+, found: 458.1887. 1H NMR (C6D6) δ 7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H). 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 3H), 2.14 (bs, 3H). 19F NMR (C6D6) δ −78.69 (d, 3F).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[C:14]([F:17])([F:16])[F:15])C.[OH-].[Na+].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: CCOC(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(CNCC(F)(F)F)OCC
Temperature: 125 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 1 g (7.5 mmol) of 1-amino-2,2-diethoxyethane, 1.26 g (7.9 mmol) of trifluoroacetaldehyde ethyl hemiacetal and 1 pellet of NaOH in 15 ml of toluene was heated at 110° C. with a Dean-Stark trap for 3 hours. The mixture was heated at 125° C. for a further 3 hours. The reaction mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 25 ml of methanol, and 1.13 g (30 mmol) of sodium borohydride were added. The reaction mixture was then heated to 70° C. and stirred overnight, concentrated in vacuo and partitioned between water and ethyl acetate. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 740 mg of the desired amine were obtained as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[O:9][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(I)cc1Cl
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(I)cc1Cl)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 2-chloro-4-iodophenol (351.2 g, 1.38 moles) in toluene (1750 ml) under nitrogen, was added triethylamine (168 g, 1.66 moles), dimethylaminopyridine (8.5 g, 0.069 moles) and chlorotriisopropylsilane (320 g, 1.66 moles), then stirred for 16 hours. After this time the reaction was quenched by the addition of aqueous hydrochloric acid (2M, 1000 ml) and the organic phase washed with water (1000 ml). The solution was dried by azeotropic distillation of toluene, to give the title compound as a clear oil (497 g, 87%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[O:28][CH:29]=2)[N:3]=1.[NH2:37][CH2:38][CH2:39][OH:40]>C1COCC1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH2:38][CH2:39][OH:40])[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Reactant: NCCO
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25 mg (0.046 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-[3-fluoro-4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile (Example 125A) are initially charged in 1 ml of THF, 6 μl of 2-aminoethanol are added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is then purified directly by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5). This gives 24 mg (94% of theory) of the target compound.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][CH:3]=2)=[CH:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 65 °C

Procedure:
To a stirred solution of sodium (2.51 g, 105 mmol, 7 eq) in absolute methanol (50 mL) was added the indole (15.0 mmol) and N-t-butoxycarbonyl-4-piperidone (8.96 g, 45.0 mmol 3.0 eq). The resulting reaction solution was heated at reflux (65° C.) under nitrogen for 3-24 hours, depending on the indole used. The resulting reaction solution was evaporated under reduced pressure, and the residue was partitioned between a saturated solution of sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was removed, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was purified either by trituration in diethyl ether or by column chromatography to afford the desired 3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole.
Reaction SMILES: [OH:1][CH:2]([CH2:30]O)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22]([O:28]C)=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6].[ClH:32]>>[Cl:32][CH2:30][CH:2]([OH:1])[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22](=[O:28])[NH:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6]
Reactant: Cl
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(O)CO)c2n1
Product: O=C(NCC(O)CCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C

Procedure:
A mixture of N-(2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HCl (4 N, dioxane, 5.8 mL) was sealed in a pressure tube and heated at 85° C. overnight. After the clear solution was decanted, the crude product was obtained as a brownish oily residue, which was vacuum-dried and used directly in the next step without further purification. MS (apci) m/z=435.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[C:13](C)=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[OH:16])=[O:7].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:15][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[CH:10][C:9]=1[OH:16])=[O:7]
Reactant: C1=COCCC1
Reactant: COC(=O)CCC(=O)c1c(C)cc(O)cc1O
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(OC2CCCCO2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a mixture of 4-(2,4-dihydroxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (1.0 g, 4.20 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (0.38 mL, 8.40 mmol) and pyridium p-toluenesulfonic acid (0.010 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-[2-hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-oxo-butyric acid methyl ester (1.1 g, 81%). 1HNMR (400 MHz, CDCl3): 12.40 (s, 1H), 6.95 (s, 1H), 6.90 (s, 1H), 5.90 (br s, 1H), 3.27 (t, J=7.8 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.30 (s, 3H).