Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:16]([CH3:18])[CH3:17])=[CH:15][CH:14]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)N(CCc1ccc(C(=O)O)cc1)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a DMF (10 ml) solution of 4-(2-diisopropylaminoethyl)benzoic acid (300 mg) was added 1,1-carbonyldiimidazole (215 mg), and the solution was stirred at room temperature for 15 minutes. To the solution was added 1-tert-butoxycarbonylpiperazine (247 mg), and the solution was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water and sodium chloride solution, dried and concentrated to give colorless oil of the title compound (483 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[CH2:60][CH2:61][CH2:62][NH2:63])=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:14](=[O:16])[NH:63][CH2:62][CH2:61][CH2:60][CH:59]([C:56]1[CH:55]=[CH:54][C:53]([F:52])=[CH:58][CH:57]=1)[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-tert-Butoxycarbonyl-N-methyl-L-leucine (0.42 g, 1.7 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.51 g, 1.7 mmol) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded the crude desired product which was used in the subsequent reaction without further purification.
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCOCC1.O>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: CCOC(=O)/C=C/c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(/C=C/C(=O)O)cc1

Procedure:
A solution of (E)-3-(4-(methylsulfonyl)phenyl)acrylic acid ethyl ester and lithium hydroxide in dioxane/water (100 ml/100 ml) was stirred for 16 h at room temp. It was washed with tert.-butyl methyl ether (200 ml). The aqueous phase was acidified with a 10% aqueous solution of sodium hydrogensulfate until pH 2. The precipitation was isolated by filtration and dried in vacuo. The residue was suspended in ethanol (100 ml). The solvent was removed. The latter procedure was repeated once to give 2.74 g of crude (E)-4-methylsulfonylcinnamic acid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.[Br:23]Br>C(O)(=O)C>[Br:23][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]([CH:11]([C:8]1[N:6]3[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)[CH3:12])=[CH:22][CH:21]=2
Reactant: Cc1ccc2nnc(C(C)c3ccc4ncccc4c3)n2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc2nnc(C(C)c3ccc4ncc(Br)cc4c3)n2n1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
2-Quinolin-6-yl-propionic acid hydrazide (intermediate 63) (500 mg, 2.32 mmol) was added to a stirred solution of 3-chloro-6-methylpyridazine (299 mg, 2.32 mmol) in n-butanol. The reaction mixture was heated at 120° C., overnight. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to obtain 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 53% yield). To 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 1.23 mmol) was added a dropwise solution of bromine (1.73 uL, 3.69 mmol) in acetic acid (3 mL). The reaction was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. A solution of 10% aq. NaSH (10 mL) was added and the product extracted with 10% methanol in dichloromethane. The organic phase was washed with 5% aqueous sodium sulfite. The filtrate was then concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (168 mg, 37% yield). Analytical data presented in Table 1.
Reaction SMILES: [CH2:1]=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].N>CO.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:1])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: C=O
Reactant: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(C2CCN(C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.042 ml) at 0° C. was added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (178 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Then sodium triacetoxyhydroborate (121 mg) was added and the mixture was stirred for 5 minutes at 25° C. A solution of ammonia in methanol 7N (2 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness, then the resulting solid was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (125 mg) as a solid; NMR Spectrum: (DMSOd6) 1.88-2.11 (m, 6H), 2.21 (s, 3H), 2.33 (s, 3H), 2.81-2.93 (m, 2H), 3.97-4.11 (m, 1H), 7.38-7.50 (m, 2H), 7.65 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+: 389
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:15]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:18]([C:31]([F:34])([F:33])[F:32])[CH:17]=3)[N:12]=[C:11]([C:35]#[N:36])[C:10]=2[N:9]=[CH:8]1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl.C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([N:28]1[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:12]=[C:11]([C:35]#[N:36])[C:10]4[N:9]=[CH:8][N:7]([CH3:6])[C:15]=4[CH:14]=3)=[CH:17][C:18]=2[C:31]([F:33])([F:32])[F:34])[CH2:26][CH2:27]1)=[O:4]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)CCl)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetylchloride (0.323 ml) in 1 ml DCM was added at 0° C. to the suspension of 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (free base) in THF/DCM (1:1, 40 ml) with DIPEA (1.7 ml). The mixture was stirred at rt for 2 hours, then 10 ml methanol added, followed by 200 ml ethyl acetate. The mixture was washed with water (100 ml), sodium bicarbonate (100 ml), dried, filtered, solvent removed, residue was columned on silica gel using 100:5 DCM/MeOH as eluant to give 0.7 g product as off white solid. 1H NMR (CD3OD) δ: 8.25 (d, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.10 (d, 1H), 4.58 (m, 1H), 4.21 (t, 2H), 4.09 (d, 1H), 4.08 (d, 1H), 3.99 (s, 3H), 3.90 (m, 1H), 3.12 (t, 1H), 2.65 (t, 1H), 2.2 (m, 1H), 1.8-2.0 (m, 4H), 1.1-1.4 (m, 2H).
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16](=[O:38])[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[C:11](OC)=[O:12])=[CH:6][CH:5]=1>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16](=[O:38])[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH2:11][OH:12])=[CH:6][CH:5]=1
Reactant: COC(=O)C(NC(=O)C=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)NC(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A solution of lithium borohydride (42.3 mg, 1.94 mmol) in THF (3 ml) was added at 0° C. to a solution of methyl 2-(4-fluorophenyl)-2-(2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ylidene)acetamido)acetate prepared in EXAMPLE 19 (350 mg, 0.647 mmol) in THF (7 ml) and the whole was stirred at room temperature for 18 hours. The reaction mixture was quenched with H2O and the resulting precipitation was collected and washed with H2O and n-hexane to give N-(1-(4-fluorophenyl)-2-hydroxyethyl)-2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ylidene)acetamide (298 mg, 92%) as a white solid: LCMS: 503 {M+1}+. 1H NMR (DMSO-d6)□ δ: 2.27 (m, 2H), 2.98-3.06 (m, 6H), 3.51 (m, 2H), 4.84 (m, 2H), 5.78 (s, 1H), 7.10 (m, 2H), 7.29 (m, 2H), 7.61 (d, 2H), 7.89 (d, 2H), 8.29 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:4]>CCCCCC>[CH3:5][C:13]1[CH:12]=[C:11]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[C:3]([N:2]([CH3:1])[CH3:15])[CH3:4])[C:6]2=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=C1C(=O)Nc2ccccc21)N(C)C
Solvent: CCCCCC
Product: CC(=C1C(=O)N(c2cccc(C)c2)c2ccccc21)N(C)C

Procedure:
Using a reaction time of 18 hours at reflux and crystallizing the product from hexane after chromatography, 3-(1-dimethylaminoethylidene)-2(1H,3H)-indolone (4.06 g, 20 mmoles) was converted to present title product, 0.45 g, m.p. 96°-99°.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:24][CH:25]([CH3:27])C)[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:8]>ClCCl>[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:24][CH2:25][C:27]3[CH:29]=[CH:28][C:10]([O:11][CH3:12])=[CH:9][CH:7]=3)[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:17][C:12]=2[O:11][C:10]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)=[O:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOCC3)c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOCC3)c(OCc3ccc(OC)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.1 %

Procedure:
Preparation of compound 30 (a) (2-(4-fluoro-phenyl)-5-hydroxy-6-morpholin-4-yl-benzofuran-3-carboxylic acid methylamide). Boron trichloride (1M solution in xylenes, 5.0 mL, 5.0 mmol) was added to a solution of 2-(4-fluoro-phenyl)-5-isopropoxy-6-morpholin-4-yl-benzofuran-3-carboxylic acid methylamide (0.71 g, 1.7 mmol, which can be prepared according to Example 24, above), dissolved in dichloromethane (30 mL). The reaction mixture was refluxed for 30 minutes, cooled to room temperature, quenched with 1M hydrochloric acid (10 mL) and stirred for 1 hour. The organics were removed by evaporation, and a saturated solution of sodium bicarbonate was added until pH=8-9. The product was extracted with ethyl acetate and purified via column chromatography (dry loading onto silica gel, ethyl acetate/hexanes gradient) to provide 0.53 g (84%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:28](=[O:30])[CH3:29])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 6.35 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 65 ml of acetic anhydride and 0.7 ml of pyridine is treated in the same manner as described in Example 2. The product is converted to its hydrochloride and recrystallized from acetone. 4.28 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[CH:30]=2)=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37]([NH:2][C:3]3([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]3)=[O:38])[CH:30]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). 3.07 ml of triethylamine were added dropwise at 20° C., the mixture was stirred for 5 min, and 2.61 g (10 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 3.6 g (73% of theory) of the title compound of melting point 186° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)nc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)n1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1cc(C)nc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)n1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 80) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light yellow solid as a mixture of diastereomers (0.68 g, 92%).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)cc2)C(=O)CCCCC)cc1

Procedure:
The title compound was prepared following the procedure G using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and hexanoyl chloride (purification by flash chromatography on SiO2, c-Hex/EtOAc 9:1) as a colorless oil (63%). M+ (ESI): 520.6. HPLC, Rt: 6.2 min (purity: 99.30%). 1H NMR (CDCl3) δ: 7.39 (d, J=8.3 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.16-7.05 (m, 4H), 6.91 (d, J=8.7 Hz. 1H), 6.85 (d, J=8.7 Hz, 1H), 4.65 (s, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 4.52 (s, 1H), 4.40 (s, 1H), 4.36 (s, 1H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 2.41 (m, 4H), 1.70 (m, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.31 (brs, 12H), 0.90 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[F:20][C:21]1[CH:22]=[C:23]([CH2:30][CH:31]=O)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:30][CH2:31][N:6]2[CH2:5][CH2:4][N:3]([CH:8]3[CH2:17][CH2:16][C:15]4[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=4[CH2:9]3)[C:2](=[O:1])[CH2:7]2)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]
Reactant: O=CCc1ccc([N+](=O)[O-])c(F)c1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])c(F)c3)CC1=O)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (3-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][C:18]2[C:26]3[C:25]([C:27]([OH:29])=O)=[CH:24][CH:23]=[N:22][C:21]=3[NH:20][CH:19]=2)([CH2:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:14]([C:11]1([N:16]2[CH2:17][C:18]3=[CH:19][NH:20][C:21]4[C:26]3=[C:25]([CH:24]=[CH:23][N:22]=4)[C:27]2=[O:29])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH3:15]
Reactant: CCC1(NCc2c[nH]c3nccc(C(=O)O)c23)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
3-((1-(tert-Butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (50 mg, 0.124 mmol), HATU (94 mg, 0.248 mmol), and 4-dimethylaminopyridine (46 mg, 0.373 mmol) were stirred in DMF (3 mL) at room temperature for 1 h. The solution was concentrated in vacuo to give the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Br[C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])N=1>>[CH3:19][C:15]1[S:14][C:13]2=[N:11][C:6]3[C:7]([C:8](=[O:9])[N:10]2[C:16]=1[CH3:18])=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=3
Reactant: Cc1nc(Br)sc1C
Reactant: Cc1cccc(N)c1C(N)=O
Product: Cc1sc2nc3cccc(C)c3c(=O)n2c1C
Yield: 76.2 %

Procedure:
9.6 g of 6-methylanthranilamide and 12.6 g of 2-bromo-4,5-dimethylthiazole were stirred for 12 hours at 150° C. After working up in the conventional manner there was obtained 11.9 g (81%) of the above compound; m.p. 278°-280° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][P:24]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4])([O:25][CH2:26][CH3:27])=[O:28])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: O=C1Nc2ccccc2N(C(=O)CBr)c2ccccc21
Product: CCOP(=O)(CC(=O)N1c2ccccc2NC(=O)c2ccccc21)OCC
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of 143 g (0.43 mol) of 5-bromoacetyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 400 ml of triethylphosphite was refluxed for 2 hours at 120° C., with stirring. In the course of the reaction, the 5-bromoacetyl compound went fully into solution and a grey precipitate began to settle out. After cooling, this was suction filtered and washed with ethyl acetate and 159 g (95% of theory) of 5-diethylphosphonoacetyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one were obtained; m.p. 195°-197° C.
Reaction SMILES: [F:1][C:2]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:3](OC)=[O:4].[NH3:27].[NH4+]>O1CCCC1>[F:1][C:2]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:3]([NH2:27])=[O:4]
Reactant: N
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A 3-1, four-necked, round-bottomed flask equipped with stirrer, thermometer, reflux condenser with bubble counter and inlet gas-tube, is charged with 745 g (1.74 mol) of methyl perfluorooctanoate and 1.5 l tetrahydrofurane. A stream of ammonia is passed from a pressure tank into the stirring solution. The ammonia feed rate is such that a negligible amount of gas is observed exiting the reactor as observed in the bubble counter. Temperature of the mixture increases to 40-50° C. Ammonium supply is continued until the temperature begins to decrease and an increasing volume of gas is observed exiting the reactor in the bubble counter . . . . After ending of ammonium supply, the mixture is left to stand for 12 hr. Solvent is removed under reduced pressure, yielding 712 g p perfluorooctanoic acid amide (99%), mp 136-137° C.