Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Si:14]([O:21][CH2:22][C@@H:23]([N:30]=[CH:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:24][S:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.C(OCC)C>[Si:14]([O:21][CH2:22][C@@H:23]([NH:30][C@@H:31]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:32]([F:41])([F:42])[O:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[CH2:24][S:25][CH2:26][CH:27]1[CH2:28][CH2:29]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N=CC(F)(F)Oc1ccc(F)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 4-fluorobromobenzene (0.589 ml, 5.36 mmol) in anhydrous THF (5 ml) at −78° C., under nitrogen, a solution of 2.5 M of BuLi in hexanes (2.1 ml, 5.36 mmol) was added. After stirring the reaction mixture for 1 h at −78° C., a solution of [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethylethyl]-[2,2-difluoro-2-(4-fluorophenoxy)ethylidene]amine (0.8 g, 1.78 mmol) in THF (5 ml) was added. After stirring for 2 h at −40° C., the reaction mixture was diluted with ethyl ether and the solution was washed with 10% ammonium chloride solution, brine and dried over sodium sulfate. Concentration under vacuum followed by column chromatography over silica gel with ethyl acetate/hexanes (1/10) gave [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethylethyl]-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)-ethyl]amine (0.75 g, 77%) as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:9]([CH3:26])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[ClH:27].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[C:9]([CH3:26])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To tert-butyl 4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (1.490 g, 4.15 mmol) was added Hydrochloric acid solution (8.72 mL, 34.9 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et2O (10 mL), filtered, rinsed with Et2O (3×5 mL), and the resulting solid was dried in vacuo to provide N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.37 g, 4.15 mmol, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.61 (m, 2H) 0.61-0.70 (m, 2H) 2.28 (s, 3H) 2.82 (tq, J=7.41, 3.99 Hz, 1H) 3.02-3.13 (m, 4H) 3.14-3.29 (m, 4H) 7.05 (d, J=8.34 Hz, 1H) 7.62-7.69 (m, 2H) 8.32 (d, J=4.29 Hz, 1H) 9.38 (br. s., 2H). ESI-MS: m/z 260.2 (M+H)+. mp=171.5-172.8° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]3[CH3:34])=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: CC1CCCCN1CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3C)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)butyric acid hydrochloride and dicyclohexylcarbodiimide in methylene chloride are stirred at room temperature for 16 hours. The reaction mixture is cooled and the solid removed by suction filtration. The methylene chloride is evaporated to give a residue which is dissolved in methylene chloride and diethyl ether. After removing the resulting crude product, the solvents are evaporated and the gummy resin is dried, triturated with diethyl ether, and dried to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[O:28])[CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[H-].[Na+].[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35].Cl>O1CCCC1.O>[O:28]=[C:7]([CH:8]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC=CC(=O)CC(=O)OCC
Temperature: 45 °C
Yield: 40.2 %

Procedure:
To a solution of (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane (5.0 g, 12.8 mmol) in tetrahydrofuran (THF, 50 ml) were added sodium hydride (60% dispersion in oil, 1.03 g, 25.6 mmol) and then pentanal (1.10 g, 12.8 mmol) followed by stirring. After addition of water (three drops), the mixture was heated at 45° C. for 1 hour. The reaction mixture was treated with dilute hydrochloric acid and extracted with ether. The organic layer was washed with aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, dried (MgSO4), and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The column was eluted with dichloromethane-hexane (1:1 to 3:2) to give 1.02 g (40.0%) of the title compound as an oil. The 1H-NMR spectrum indicates that the product is a mixture of keto/enol isomers.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.O1CCCC1>CN(C)C1C=CN=CC=1.CCCCCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:26]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCCCCCBr)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of benzoin (26.15 g), 8-bromooctanoic acid (25.0 g), 4-dimethylaminopyridine (1.35 g), 1,3-dicyclo-hexylcarbodiimide (25.4 g) and dry tetrahydrofuran (350 ml) was stirred under nitrogen at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (350 ml), washed with 5% aqueous hydrochloric acid (3×175 ml), saturated sodium hydrogen carbonate solution (2×200 ml), saturated sodium chloride solution (220 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chro-matography on silica gel eluted with a hexane: dichloromethane gradient gave a yellow oil. This oil was stirred in hexane to give 2-oxo-1,2- diphenyl-ethyl 8-bromooctanoate (27.1 g, 52.7%) as a pale yellow solid m.p. 60°-61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].Cl>C(O)C.C1C=CC=CC=1.CO>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=3)[C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=Cc1cc[nH]n1
Reactant: COc1ccc(Nc2ccc(CCO)cc2)c(N)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Pb+4]
Solvent: CO
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc2c(c1)nc(-c1cc[nH]n1)n2-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A mixture of 2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was 1.37 mmol) in methanol (4 ml) was added 10% HCl in methanol (2 ml) at room extracted with ethyl acetate (150 ml×4). The organic layer was washed with water (100 ml×5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16%) of the title compound as an amber solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][C:17]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)[CH:3]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccccc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 55 %

Procedure:
The product of Example 35A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 35A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (39 mg, 55%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.45 (d, J=5.88 Hz, 2 H) 6.83 (d, J=8.82 Hz, 2 H) 6.82-6.93 (m, 1 H) 7.16-7.44 (m, 7 H) 7.56-7.81 (m, 2 H) 7.90 (br s, 1 H) 8.61 (br s, 1 H) 8.79-9.22 (br m, 3 H) 9.94 (br s, 1 H) 10.28 (br s, 1 H); MS (ESI+) m/z 480 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][N:14]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCNC2
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCN(Cc1ccccc1)C2

Procedure:
React 10-(3-chlorophenyl)-6,7,8,9-tetrahydropyrido[2,3-b] [1,6]naphthyridin-5(10H)-one (5 mmol) with benzylbromide (5.8 mmol) in acetone (40 ml) at 25° C. for 3 hours. Evaporate the acetone solvent, and elute the product from silica gel with chloroform to provide the product, 10-(3-chlorophenyl)-6,7,8,9-tetrahydro-7-N-benzyl-pyrido[2,3-b] [1,6]naphthyridin-5(10H)-one, m.p. 157°-161° C. after crystallization from CH3CN.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:39]1[C:44](=O)[CH2:43][CH2:42][C:40]1=[O:41])=[N+](C)C)C.[CH:46]12[CH2:55]C3CC(C[CH:48]([CH2:49]3)[CH:47]1N)[CH2:53]2>CN(C)C=O.C(Cl)Cl>[OH:41][C:40]12[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:55][CH:43]([CH:44]3[NH:39][C:14]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9]=3[C:10]([F:11])([F:12])[F:13])=[O:16])[CH2:42]1)[CH2:53]2
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC2CC(O)(C4)C3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To a stirred solution of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2.334 g; 9.88 mmol) in N,N-dimethylformamide/methylene chloride (1:4 ratio, 15 mL) at room temperature was added diisopropylethylamine (9.00 mL; 51.13 mmol). TSTU (5.420 g; 18.0 mmol) was then added. The resulting mixture was allowed to stir at room temperature for 2 hr and then 2-adamantylamine (1.654 g; 9.89 mmol) was added. The mixture was allowed to stir over night at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with 0.5N HCl, saturated sodium bicarbonate then brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as a light brown solid. Purification by column chromatography (RediSep-120 g silica gel, 10%—100% ethyl acetate/hexanes) provided the desired trans-isomer of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (1.23 g, 32%) as a white solid. by resulting light yellow gum was triturated with diethyl ether to provide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (4.02 g, 80%) as a white powder. The cis-isomer was also isolated (1.58 g, 41%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36]([OH:38])=O)([O-:32])=[O:31]>>[N+:42]([C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=1)[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38])([O-:44])=[O:43]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dinitrobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dinitrobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 558 (M-H)-.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.N1C=CC=CC=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1)([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: C=C(C)n1c(OCCCCCO)nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Reaction time: 5 h
Yield: 69.1 %

Procedure:
A solution of 2 g of the compound obtained in Example 14a in 20 ml of dichloromethane was added with 5 ml of pyridine and 1.8 g of p-toluenesulfonyl chloride and stirred for 5 hours. The organic layer was washed with 10% aqueous citric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 2.2 g of the title compound (yield: 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:26][CH3:27])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:26]([N:13]([C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:27]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 105 °C

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:29]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CCC(CC)CC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 31 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as an off-white solid (50 mg, 31%); ES+-HRMS m/e calcd for C25H31N5O4F2 [M+H+] 504.2417 found 504.2417. 1H-NMR (400 MHz, CDCl3-d) δ ppm 0.86 (t, J=7.5 Hz, 3H) 0.87 (t, J=7.5 Hz, 3H) 1.08-1.14 (m, 1H) 1.15 (s, 3H) 1.16 (s, 3H) 1.21-1.50 (m, 4H) 2.01-2.19 (m, 1H) 2.19-2.37 (m, 1H) 3.93 (s, 2H) 5.67 (dd, J=9.6, 5.8 Hz, 1H) 6.01 (d, J=3.0 Hz, 1H) 6.72 (d, J=2.3 Hz, 1H) 7.08 (t, J=8.0 Hz, 2H) 7.27-7.33 (m, 2H) 8.01 (d, J=3.0 Hz, 1H) 8.59 (s, 1H).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH:5][C:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 13.3 g of Z-Asn-OH (50 mmol), 26 g of triphenylmethanol (100 mmol), 150 ml of acetic acid and 9.5 ml (100 mmol) of acetic anhydride is stirred at 50° for 15 minutes. Addition of 0.25 ml of conc. sulfuric acid produces, after 5 minutes, a clear yellow solution. After 11/2 hours, it is cooled and poured into 1.5 liters of ice-water. The precipitate is filtered off, thoroughly washed with water and dissolved in about 500 ml of ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to 250 g. Z-Asn(Trt)-OH is induced to crystallize by addition of 125 ml of hexane, m.p. 195°-196°.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 95 °C
Yield: 11.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 10 mg (11%) of the title compound as an orange crystalline solid. MS-EI m/z 449 [M+].
Reaction SMILES: [Br:1]Br.[C:3]1(=[O:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:11]([OH:14])[CH2:12]O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]1[O:14][C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[Br:1])[O:10][CH2:12]1
Reactant: BrBr
Reactant: OCCO
Reactant: O=C1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: BrC1CCCCCC12OCCO2
Reaction time: 5 h

Procedure:
Bromine (44.8 g, 0.28 mol) was added dropwise to a stirred solution of cycloheptanone (28.5 g, 0.25 mol) in a 1:1 solution (300 mL) of ethylene glycol and tetrahydrofuran at room temperature. The mixture was stirred for 5 hours, then poured into aqueous sodium bicarbonate and extracted 3X with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-bromocycloheptanone ethylene ketal(60 g). A mixture of this crude bromo ketal and a methanolic solution of sodium methoxide (250 mL, 25 wt. % solution) was heated at reflux overnight. The mixture was cooled to ambient temperature, poured into water, and extracted with hexanes. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-cycloheptenone ethylene ketal (39 g).