Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.[CH2:16]([NH:18][CH2:19]C)C>S(Cl)(Cl)=O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:16])=[O:5]
Reactant: CCNCC
Reactant: Nc1ccccc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1ccccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-aminobenzoic acid (1.0 g, 7.3 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Excess of thionyl chloride was removed. And the residue was treated with toluene (3×10 mL) to remove the excess thionyl chloride. To the crude product obtained was added THF (20 mL) and the resulting solution was cooled to 0° C. Diethyl amine (3.78 mL, 36 mmol) was added and the resulting solution was stirred for 2 hrs at room temperature. The solvent was removed under reduced pressure and residue was taken into dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (3×20 mL), water (20 mL), dried over sodium sulfate and concentrated to provide the desired product as brown oil. This crude product was used in Step 2 without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH3:26][N:27]=[C:28]=[O:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:28]([NH:27][CH3:26])=[O:29])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CN=C=O
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Product: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(=O)NC
Yield: 74 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and methyl isocyanate, afforded the title compound as a white solid (194 mg, 74%); LCMS (method B): RT=3.38 min, M+H+=306; 1H NMR (CDCl3, 300 MHz): 8.42 (s, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.39 (dt, J=8.2, 6.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.15 (dt, J=9.9, 2.3 Hz, 1H), 6.99 (tdd, J=8.3, 2.4, 0.9 Hz, 1H), 4.71-4.65 (m, 1H), 4.31 (q, J=7.1 Hz, 2H), 2.90 (d, J=4.9 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:29])=[N:9]2)=[CH:4][CH:3]=1.C[O:31]CCOC.O1CCCC1.[OH-].[K+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:20]([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]([OH:31])=[O:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: COCCOC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 30 °C
Reaction time: 34 h
Yield: 85 %

Procedure:
To a reactor was charged racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone (170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). The slurry was heated to 30° C. and a solution of potassium hydroxide (140 Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34 hours. The solution was cooled to 20° C. and the lower aqueous layer was removed and replaced with water (1000 L). The solution was adjusted to pH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at 30° C. to remove the THF. Water (550 L) was added and the pH of the reaction was adjusted to 11.5 with 2N potassium hydroxide. The solution was filtered to remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone. To the liquors was added methylene chloride (1200 L) and the pH was adjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organic layer was washed with water (700 L) and the water was discarded. The organic layer was concentrated under vacuum and replaced with methanol (500 L). The slurry was cooled to 10° C., water was added (500 L), and the mixtrue was cooled to 0° C. The resulting precipitate was isolated by filtration and dried under vacuum at 50° C. to afford 150 kg (85%) of racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl ]-benzoic acid as a white solid. DCl/MS: M+H+ at 426, 100%. M.P. 173–4° C. UV maxima at 236 nm, 268 nm, and 353 nm.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[F:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[NH:1][C:23]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:25])=[C:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:24]=2)=[O:6]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(OCc2ccccc2)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(F)c(OCc3ccccc3)cc2[nH]1

Procedure:
A mixture of methyl 2-azidoacetate, 4-benzyloxy-3-fluoro-benzaldehyde and sodium methanolate (in methanol) in toluene was reacted for 3 h at 0° C. The residue after filtration of the suspension was washed with methanol, partitioned between ethyl acetate and ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, evaporated to dryness and the residue taken up in p-xylene and brought to reflux temperature for 2 h. After concentration the mixture was left to crystallize and the formed crystals were filtered off and washed with toluene. The title compound was after drying at 40° C. under vacuum obtained as yellow crystals. MS (m/e): 300.3 (MH+, 100%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Reaction time: 12 h
Yield: 49.4 %

Procedure:
The crude 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (21.1 mg, 0.066 mmol) (Example 2) was suspended in dichloromethane (8 mL) and treated with diisopropylethyl amine (46 uL, 0.264 mmols), DMAP (8 mg, 0.065 mmol), and 4-(methyloxy)benzenesulfonyl chloride (21 mg, 0.1 mmols) at 0° C. After 12 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (10 mL), and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified via preparative HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (16 mg, 55%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH3:18])[CH:5]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccco2)c(C)c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-2methylphenyl ester (1.19 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added 2-(tributylstannyl)furan (1.81 g, 5.05 mmol), lithium chloride (0.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol) under nitrogen. The mixture was heated at reflux temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/10) to give title compound (0.845 g, quant).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].C(S[C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1)CC.O>O1CCCC1>[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][O:6][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1
Reactant: COCC(F)(F)CO
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(F)(F)COc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 29 mg) in tetrahydrofuran (5 ml) was added 2,2-difluoro-3-methoxypropan-1-ol (151 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (8 mg).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].CS(C)=O.[S-:24][C:25]#[N:26].[K+]>O>[S-:24][C:25]#[N:26].[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Agent: N#C[S-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1ccc(C(C)=O)c(O)c1CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 10.65 g. of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl bromide in 60 ml. of dry dimethylsulfoxide were added 6.5 q. of potassium thiocyanate. The solution was stirred overnight at room temperature and then was poured into water. The solution was extracted twice with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The resulting oil was vacuum distilled to provide the title compound in 95% yield as a yellow viscous oil, b.p. about 205° C. at 0.45 torr.
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:53])C=2)C1)=O)(C)(C)C>>[ClH:53].[Cl:1][C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[N:24]=2)[CH:22]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1Cl)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 1-hexanal (22 μl, 0.18 mmol) and sodium (triacetoxy)borohydride (175 mg, 0.83 mmol), to obtain 28.4 mg of the title compound as a colorless oily substance (80%).
Reaction SMILES: C[O:2][C:3]1[C:12](=O)[N:11]([CH3:14])[C:10]2[N:9]=[CH:8][N:7]=[C:6]([N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C:5]=2[N:4]=1.[OH2:32].[OH-].[Li+].Cl>O>[CH3:14][N:11]1[C:12]([C:3]([OH:32])=[O:2])=[N:4][C:5]2[C:10]1=[N:9][CH:8]=[N:7][C:6]=2[N:15]1[CH2:31][CH2:30][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][NH:20][C:19]2=[O:29])[CH2:17][CH2:16]1
Reactant: O
Reactant: COc1nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc2n(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(C(=O)O)nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc21
Temperature: 60 °C
Reaction time: 48 h

Procedure:
6-Methoxy-8-methyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)pteridin-7(8H)-one (1 g, 2.37 mmol) was treated with lithium hydroxide monohydrate (0.281 g, 4.74 mmol) tetrahydrofuran (2.5 mL) and water (2.5 mL). This mixture was stirred at 60° C. for 48 hours. The reaction mixture was cool to room temperature acidified to pH 4 with 1 M hydrochloric acid (8 mL) and evaporated under reduced pressure. The resulting crude material was then used in the next step without any further purification. MS (EI) for C20H21N7O3: 408 (MH+), 364 (MH+−44 (—CO2)).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH3:51])[C:48]([NH2:50])=[O:49].Cl.NCC(N)=O>>[C:48]([C:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[CH:36][CH:35]=1)=[O:41])([CH3:52])[CH3:51])(=[O:49])[NH2:50]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(N)=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[CH2:7]([O:14][C:15]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-alanine is reacted (12.5 g., 0.14 mol) with 26 g., 0.14 mol + 2 g. excess. of benzyloxycarbonyl chloride and 0.28 mol of sodium hydroxide. The D-alanine is dissolved in one equivalent of sodium hydroxide solution, cooled in ice, and treated slowly with the acid chloride and the second equivalent of sodium hydroxide while maintaining pH 10-12. The reaction is stirred for an additional hour with cooling and is worked up by extraction with ether and acidification of the aqueous solution. A precipitate soon solidifies and is collected and dried; 23.5 g.; m.p. 82°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)=[O:4]>C1(C)C=CC=CC=1.C(OC(N(C)C)OC(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][C:5]([CH3:6])([CH3:13])[CH3:3])=[O:15])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2[nH]c(C(=O)OC(C)(C)C)cc2c1

Procedure:
To 13 g 1H-Indole-2,5-dicarboxylic acid 5-methyl ester in 300 ml toluene, 59 ml Di-tert-butoxymethyl-dimethyl-amine were added dropwise at 80° C. Then, the reaction mixture was heated under reflux for additional 6 h. After removal of the solvents under reduced pressure the residue was dissolved in 300 ml DCM and washed with sat. aqueous NaHCO3 solution (2×100 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a n-heptane/ethyl acetate gradient. The fractions containing the product were collected and concentrated under reduced pressure.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](I)=[N:16][CH:17]=1>CN1C(=O)CCC1.[Cu]I>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:5]([F:8])([F:7])[F:6])=[N:16][CH:17]=1
Reactant: Clc1ccc(I)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of KF (53 mg, 0.91 mmol, 1.10 equiv) in NMP (3 mL), CuI (175 mg, 0.92 mmol, 1.10 equiv), trimethyl(trifluoromethyl)silane (119 mg, 0.84 mmol, 1.00 equiv) and 5-chloro-2-iodopyridine (as prepared in the previous step, 200 mg, 0.84 mmol, 1.00 equiv). The reaction mixture was stirred overnight at 60° C. The reaction was then quenched by the addition of 20 mL of ammonia (12%). The resulting solution was extracted with 2×20 mL of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried (Na2SO4), and concentrated to yield 5-chloro-2-(trifluoromethyl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[BH4-].[Na+]>CO.[OH-].[Na+].O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CO)ccc1F
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (5 g) in methanol (25 ml) was added dropwise sodium borohydride (368 mg) in 0.1N sodium hydroxide aqueous solution (5 ml) in water bath and the whole was stirred for 1 hour. After the mixture was evaporated under reduced pressure, ethyl acetate and water were added thereto. The organic layer was separated and the water layer was further extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give 4-fluoro-3-methoxybenzyl-alcohol (5.22 g) as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:25][C:24]4[CH:23]=[C:22]([CH2:21][OH:20])[CH:29]=[CH:28][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cccc(CO)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: OCc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(hydroxymethyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give [3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][N:19]([CH3:22])[CH:20]=O>C(OCC)(=O)C>[CH3:8][C@H:6]1[CH2:20][N:19]([C:22]2[CH:9]=[CH:10][CH:11]=[CH:5][N:4]=2)[CH2:18][CH2:3][N:7]1[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CN(C)C=O
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 3 h
Yield: 46 %

Procedure:
The product of Example 25B (0.24 g, 1.33 mmol) in N,N-dimethylformamide (10 mL) was treated with 2-chloromethyl-1H-benzimidazole (0.21 g, 1.27 mmol) and cesium carbonate (0.41 mmol, 1.27 mmol) at 23° C. with stirring for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1–3% methanol/dichloromethane gradient) to afford 178 mg (46% yield) of the title compound as a light yellow solid. mp 149–151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5; C, 70.33; H, 6.89; N, 22.78. Found: C, 70.21; H, 6.77; N, 22.62.