Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.CCOC(C)=O>[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[N:27]=1
Reactant: OCc1csc(Br)n1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (239 mg), (2-bromothiazol-4-yl)methanol (330 mg) and triphenylphosphine (669 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (597 mg), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc, washed with water and brine successively, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (185 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[C:3]([NH2:9])[CH:2]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C(O)(C)C.[Pd]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]2[NH:8][C:4]3[C:5]([NH2:7])=[CH:6][N:1]=[CH:2][C:3]=3[N:9]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1cncc(N)c1N
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2nc3cncc(N)c3[nH]2)cc1
Yield: 37 %

Procedure:
Pyridine-3,4,5-triamine 3 (100 mg, 0.81 mmol) was dissolved in isopropanol (4 ml) with Pd/C (20 mg of 10% powder). 4-t-butyl benzaldehyde (150 mg, 0.92 mmol) was added, and this mixture was refluxed for 48 hours. The reaction mixture was filtered through CELITE to remove the palladium, and the crude was purified by HPLC (Method E) to yield the title compound 4 (81 mg (37%), 0.3 mmol). 1H NMR (DMSO-d6): δ 8.64 (bs, 1H), 8.18 (d, J=8.6 Hz, 2H), 7.75 (s,1H), 7.69 (d, J=8.6 Hz, 2H), 6.30-6.61 (bs, 2H), 1.35 (s, 9H). MS (ESI-POS): [M+H]+=266.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([O:26]C)[CH:24]=[CH:25][C:11]1=2)[CH3:9].O>CO.ClCCl>[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:11]1=2)[CH3:9]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A 1.0 M boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg) at 0° C., and stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction with the mixture solvent (dichloromethane:methanol=10:1) was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (156.4 mg) as a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:17])=[C:10]2[C:13]([F:16])([F:15])[F:14])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[NH2:17][C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2ccc(N)c(C(F)(F)F)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc2ccc(O)cc2c1C(F)(F)F
Temperature: -78 °C
Yield: 69 %

Procedure:
To a solution of 7-methoxy-1-(trifluoromethyl)naphthalen-2-amine (2 g, 8.29 mmol) in dichloromethane (20 ml) was added dropwise BBr3 (4 ml, 42 mmol, 5 eq.) with stirring at −78° C. The resulting solution was stirred overnight at room temperature and then quenched by ice—water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford 7-amino-8-(trifluoromethyl)naphthalen-2-ol as a brown solid (1.3 g, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27])=[O:11]
Reactant: CCc1nc2ccccc2c(=O)n1N
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Product: CCc1nc2ccccc2c(=O)n1NC(=O)C[C@@H]1CC[C@H]2C[C@@H]1C2(C)C

Procedure:
The product from Example 1C and 3-amino-2-ethylquinazolin-4(3H)-one (Aldrich) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (d, J=9.5 Hz, 1H) 1.09 (s, 3H) 1.24 (d, 3H) 1.34 (t, J=7.3 Hz, 3H) 1.55-1.68 (m, 2H) 1.85-2.03 (m, 4H) 2.08-2.26 (m, 1H) 2.32-2.45 (m, 1H) 2.51-2.70 (m, 2H) 2.70-2.86 (m, 2H) 7.44 (t, J=7.3 Hz, 1H) 7.66-7.72 (m, 1H) 7.76 (t, J=7.1 Hz, 1H) 8.21 (d, J=7.9 Hz, 1H); MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: [ClH:1].[CH:2]([C:4]1[O:5]C(=O)[C:7](=[O:9])[N:8]=1)=[CH2:3]>ClC1C=CC=CC=1Cl>[C:4]([N:8]=[C:7]=[O:9])(=[O:5])[CH:2]=[CH2:3].[Cl:1][CH2:3][CH2:2][C:4]([N:8]=[C:7]=[O:9])=[O:5]
Reactant: Cl
Reactant: C=CC1=NC(=O)C(=O)O1
Solvent: Clc1ccccc1Cl
Product: C=CC(=O)N=C=O
Product: O=C=NC(=O)CCCl
Reaction time: 0.5 h

Procedure:
To 2-vinyloxazoline-4,5-dione hydrochloride (100 g), o-dichlorobenzene (400 g) was added, and the resultant mixture was heated at 110° to 120° C. while stirring for about 30 minutes. After cooling with ice, the reaction mixture was distilled under reduced pressure to give acryloyl isocyanate (8.9 g; b.p., 82° to 83° C./760 mmHg) and betachloropropionyl isocyanate (56.4 g).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:24])=[O:8])C>O1CCCC1.O>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:24])([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccn(-c2ccnc3ccccc23)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccn1-c1ccnc2ccccc12
Yield: 98.6 %

Procedure:
2.226 g (53 mmol) of lithium hydroxide monohydrate, in portions of 0.742 g every 24 hours, are added at 20° C. to 2.48 g (8.4 mmol) of 3-ethoxycarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 75 mL of tetrahydrofuran and 75 mL of water. After stirring at reflux for 72 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 mL of water and then triturated with 10 mL of 5N hydrochloric acid for 0.2 hour. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 2.09 g of 3-carboxy-2-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a pinkish solid. Mass spectrum (EI): m/e 252 (M+.), m/e 207.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.ClCCl.N[C:22]1[CH:38]=[CH:37][C:36]2[C:27]3[NH:28][C:29](=[O:35])[C:30]4[N:31]([CH:32]=[CH:33][N:34]=4)[C:26]=3[CH2:25][C:24]=2[CH:23]=1.C[N:40](C)C=O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:40][C:32]2[N:31]3[C:26]4[CH2:25][C:24]5[CH:23]=[CH:22][CH:38]=[CH:37][C:36]=5[C:27]=4[NH:28][C:29](=[O:35])[C:30]3=[N:34][CH:33]=2)=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCCCc1ccccc1)Nc1cnc2c(=O)[nH]c3c(n12)Cc1ccccc1-3

Procedure:
The preparation is carried out as in Example 12, from 5 g of 5-phenylvaleric acid, 2.5 ml of thionyl chloride, 60 ml of dichloromethane, 1 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one and 75 ml of dimethylformamide. After refluxing for 7 hours, the insoluble material is filtered and recrystallized from dimethylformamide. After filtration, washing with water and drying under reduced pressure (1 mm Hg, 0.13 kPa) at 80° C., there is obtained 0.58 g of 8-(5-phenylvalerylamino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a yellow solid which decomposes at 170° C. (Analysis C24H22N4O2.0.41DMF, % calculated C: 72.34, H: 5.56, N: 14.06, % found C: 72.0, H: 5.6, N: 13.8).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[NH:11])=[CH:5][CH:4]=1.C([O:15][C:16](=O)[CH:17]([NH:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:18](OCC)=[O:19])C>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[N:12]=[C:16]([OH:15])[C:17]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[C:18]([OH:19])[N:11]=2)=[CH:7][CH:8]=1
Reactant: N=C(N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: O=C(Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 129 %

Procedure:
2.25 g of sodium were dissolved in 140 ml of ethanol at 60° C. to give a solution of sodium ethoxide. 6.9 g of 2-(4-chloro-phenyl)acetamidine hydrochloride were added while the temperature was maintained at 60° C. The mixture was stirred for 10 min, and then a solution of 10 g of 2-(3-fluoro-benzoylamino)-malonic acid diethyl ester in 20 ml of ethanol was added. The reaction mixture was stirred at 60° C. for 3 h and then evaporated to dryness. The residue was dissolved in the minimum amount of water, and the pH was adjusted to 1-2 by addition of concentrated aqueous hydrochloric acid. The precipitate was filtered off and dried in an infrared dryer until constant weight. 8.9 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23]C3CCCNC3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].N[CH:37]1[CH2:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]1>>[C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:42]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCCNC3)c(=O)n3ccccc23)CC1
Product: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCNCC3)c(=O)n3ccccc23)CC1

Procedure:
1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-4-yl-4H-quinolizine-3-carboxamide was prepared by the procedure described for the synthesis of 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-3-yl-4H-quinolizine-3-carboxamide in Example 19, substituting tert-butyl 4-aminopiperidine-1-carboxylate for tert-butyl 3-aminopiperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].CS([C:21]1[N:33]=[C:24]2[N:25]=[C:26]([CH2:31][CH3:32])[CH:27]=[C:28]([CH2:29][CH3:30])[N:23]2[N:22]=1)(=O)=O>O1CCCC1>[CH2:31]([C:26]1[CH:27]=[C:28]([CH2:29][CH3:30])[N:23]2[N:22]=[C:21]([O:11][CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:13][OH:14])[N:33]=[C:24]2[N:25]=1)[CH3:32]
Reactant: OCCN(CCO)c1ccc(F)cc1
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(CC)n2nc(OCCN(CCO)c3ccc(F)cc3)nc2n1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of 2-[(4-fluorophenyl)(2-hydroxyethyl)amino]ethan-1-ol (200 mg, 1.01 mmol) and tetrahydrofuran (5 mL) was added to a 50 mL RBF under a nitrogen atmosphere with a magnetic stirring bar. The flask was cooled in an ice bath. Sodium hydride (60% dispersion in mineral oil) (40 mg, 1.01 mmol) was added (Effervescence). The reaction was warmed to room temperature and stirred for 10 minutes before 2-methanesulfonyl-5,7-diethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (213 mg, 0.84 mmol) was added (Effervescence). Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The title compound eluted with a retention time of 4.1 min. After 90 minutes the reaction was concentrated then partitioned between dichloromethane (30 mL) and water (5 mL). The aqueous layer was extracted once more with dichloromethane (20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The title crude material was purified by silica gel column chromatography using a gradient elution of 1-10% isopropanol in dichloromethane to afford the title compound as an oil that crystallized upon standing overnight (135 mg, 43% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.09 (s, 1H), 6.99 (t, 2H), 6.78 (m, 2H), 4.69 (t, 1H), 4.48 (t, 2H), 3.77 (t, 2H), 3.53 (q, 2H), 3.43 (t, 2H), 3.01 (q, 2H), 2.82 (q, 2H), 1.32 (t, 3H), 1.26 (t, 3H). EM (calc.): 373.2; MS (ESI) m/e: 374.3 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:29][CH3:30])=[C:7]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:15]2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-aminobutyrylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.588 g, 1.39 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.333 g, 1.39 mmol), and DIPEA (0.71 mL, 4.15 mmol) in n-butanol (6 mL) was stirred in a sealed vial at 100° C. for 16 h. After cooling to RT, volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording the title compound as a light brown gum (0.516 g, 59%). LCMS (Method B): RT 2.47 min [M+H]+ 625.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:35]1([C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:2][CH2:3]5)(=[O:5])=[O:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)=[O:33])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carboxylic acid (0.155 g) in N,N-dimethylformamide (5 mL) were added morpholine (0.056 mL), triethylamine (0.135 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (93 mg) and 1-hydroxybenzotriazole (74 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.106 g, yield 60%) as colorless crystals. MS: 550 (MH+). melting point 114-116° C.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:31]([OH:33])[CH3:32])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:24]4[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=4[CH:18]=3)[N:16]=2)[CH2:8][CH2:7]1)=O.B.CO>C1COCC1>[NH2:1][C@H:2]([CH2:3][NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:24]4[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:30])[C:19]=4[CH:18]=3)[N:16]=2)[CH2:10][CH2:11]1)[C@H:31]([OH:33])[CH3:32]
Reactant: C[C@@H](O)[C@H](N)C(=O)NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](N)CNC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
115 mg (0.18 mmol) of (2S,3R)-2-amino-3-hydroxy-N-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-yl}butyramide was dissolved in 3 ml of THF, and 272 μl (0.54 mmol) of 2M borane dimethyl sufide solution in THF were added at 70° C. under nitrogen atmosphere, and the mixture was subsequently stirred at 70° C. for 2 hours. In order to decompose the excess borane, 1 ml of MeOH was added dropwise. The reaction mixture was evaporated, and 1 ml of water and 1 ml of conc HCl were added to the oily residue. The mixture was stirred at room temperature for 2 h, rendered alkaline using 2 molar NaOH and extracted with ethyl acetate. The organic phase was dried and purified by column chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]1([C:24]#[CH:25])[CH2:23][CH2:22]1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:21]1([C:24]#[C:25][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C#CC1CC1
Yield: 95.4 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.70 g, 2.23 mmol) with cyclopropyl acetylene (0.30 g, 4.46 mmol) using Pd(PPh3)2Cl2 and CuI in DMF at room temperature gave 0.49 g (96%) of the title compound (149) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.80-0.95 (m, 4H), 1.45-1.55 (m, 1H), 3.82 (s, 3H), 3.87 (s, 3H), 6.80 (dd, J1=8.9 Hz, J2=2.7 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 231 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.Cl[C:6]1C=CC(N2C(C)=C(CCC)C(=O)C(C(O)=O)=N2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:37][C:36](=[O:43])[C:35]([C:44]([OH:46])=[O:45])=[N:34]2)=[CH:29][CH:28]=1.O>CO>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:37][C:36](=[O:43])[C:35]([C:44]([O:46][CH3:6])=[O:45])=[N:34]2)=[CH:29][CH:28]=1
Reactant: CCCc1c(C)n(-c2ccc(Cl)cc2)nc(C(=O)O)c1=O
Reactant: CCCCc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCCCc1cc(=O)c(C(=O)OC)nn1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 25 ml of methanol, cooled to -5° C., there is added 2.38 g (0.02 mol) of thionyl chloride. To the ice cooled solution is added 2.85 g (0.0093 mol) of the mixture of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-n-propyl-6-methyl pyridazine-3-carboxylic Acid and 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-n-butyl pyridazine-3-carboxylic Acid dissolved in 25 ml of methanol. The solution is stirred at 0° C. for 1/2 hr. and at room temperature for 18 hrs. To the solution is added 250 ml of water and the oil suspension formed is stirred at room temperature for 1 hr. The suspension is extracted with 3 (100 ml) portions of methylene dichloride and the extract is dried over magnesium sulfate and concentrated in vacuo to afford 2.9 g of mixed products (oil). The mixture is separated using a silica gel dry column and ethyl acetate as eluent to afford 0.5 g (17% yield of example 30 (oil) and 0.5 g (17% yield) of example 29 (semi-solid).
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:6][CH:5]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH:35]([CH3:37])[CH3:36])[CH2:31][C:32](O)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]([CH:35]([CH3:37])[CH3:36])[CH2:31][C:32]([NH:17][CH2:16][CH:12]2[O:13][CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:18])[F:19])=[CH:9][CH:8]=3)[CH2:11]2)=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
(4-(4-(Trifluoromethyl)phenyl)morpholin-2-yl)methylamine hydrochloride (99 mg, 0.34 mmol), 2-[(4-fluoro-benzenesulfonyl)-isopropyl-amino]-acetic acid (96 mg, 0.35 mmol), BOP reagent (154 mg, 0.35 mmol) and TEA (0.2 mL) were combined in 5 mL of dichloromethane. The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was washed with sodium bicarbonate solution and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (11 g silica gel, ethyl acetate in hexanes 0% to 50%) to give the desired compound as a white solid (133 mg, 74%). [MH]+=517.9.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A stirred mixture of nonanedioic acid (18.8 g; 0.10 mol), benzyl alcohol (10.8 g; 0.10 mol), and p-toluenesulphonic acid (0.2 g) in toluene (200 mL) was refluxed through a Dean-Stark trap overnight. The mixture was cooled to ambient temperature and extracted with 10% aqueous N-methyl-D-glucamine (4×25 mL). The last extract was a milky emulsion. The first three extracts were combined, acidified with 1 M HCl (50 mL), and filtered to give recovered nonanedioic acid (3.8 g). The emulsion was acidified with 1 M HCl and allowed to separate overnight. The organic layer was evaporated and the residue dissolved in hexane (200 mL) and diethyl ether (50 mL). The solution was extracted with 10% N-methyl-D-glucamine (2×50 mL) (emulsions broken by adding a little ethanol). The organic solution was washed with water (1×25 mL) and the combined aqueous solution was acidified with 1 M HCl (150 mL). After extraction with dichloromethane-tetrahydrofuran (4:1) (5×10 mL), the combined extracts were dried (Na2SO4), filtered, and evaporated. 13.0 g (47%) product was obtained (oil that solidified on standing).