Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1)#[N:27]>O>[C:37]([O:36][C:35](=[O:41])[N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][CH:32]=1)[CH2:42][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1

Procedure:
Sodium hydride (60% in mineral oil, 895 mg, 22.4 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 4.52 g, 18.7 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (4-cyano-phenyl)(phenylsulfonyl)methylcarbamate (6.90 g, 18.5 mmol) is added, and mixture is stirred at room temperature for 30 min Water is added, and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 9.20 g; ESI mass spectrum [M+H]+=473; Retention time HPLC: 1.09 min (Z018_504).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([Cl:21])[CH3:20]>CC(=O)CC>[Cl:21][CH2:19][CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(OCCCl)ccc1Cl
Temperature: 25 °C

Procedure:
To a 500 mL 3-neck round-bottom flask was added 4-chloro-3-nitro-phenol (10 g, 0.058 mol), potassium carbonate (20 g, 0.14 mol), bromochloroethane (34.5 g, 0.24 mol) and 2-butanone (200 mL). The mixture was mechanically stirred and heated to reflux for 20 hours under nitrogen then allowed to cool to room temperature and the solids were filtered. The solvent was evaporated under vacuum and the oil dissolved in diethyl ether (300 mL) and washed with 10% sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The product was dissolved in 1:1 methylene chloride-hexanes and filtered through a short pad silica. Upon concentration and standing 12.9 g (94.8.% %) of light yellow crystalline solid was afforded: mp 46°-48° C.; MS EI m/e 235, 237, 239 (M+); 1H NMR (400 MHz, DMSO-d6) δ 3.95 (t, 2H, J=5.2 Hz), 4.36 (t, 2H, J=5.2 Hz), 7.32 (dd, 1H, J=3.2, J=8.9 Hz), 7.66, (d, 1H, J=9 Hz), 7.69, (d, 1H, J=3.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:50]([O:52][C:53]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:54])[CH3:51]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:50]([O:52][C:53](=[O:54])[NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[O:58])[CH3:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(Cl)OC(=O)NCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (215 mg, 0.349 mmol) in dimethylformamide (22 mL) was added cesium carbonate (2.15 g, 6.6 mmol). After stirring for 10 min, a solution of the freshly made benzyl 2-((1-chloroethoxy)carbonylamino)acetate (2.77 g crude, ˜5.55 mmol) in dimethylformamide (5 mL) was added. The reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was taken up in ethyl acetate, washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 1-(2-(benzyloxy)-2-oxoethylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (191 mg, 64% yield). LCMS (ES+) m/z calcd. for C43H43Cl2F2N4O8 [(M+H)+]: 851, found: 851.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].N1C=CC=CC=1>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:33]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:23])([F:24])[F:25])=[O:16])=[CH:12][CH:13]=3)[CH2:4][CH2:3]2)=[O:34])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride salt (2.0 g, 4.43 mmol) in methylene chloride (20 mL) at room temperature was added p-nitrophenyl chloroformate (1.11 g, 5.52 mmol) followed by pyridine (1.1 mL, 13.6 mmol). The mixture was stirred at room temperature overnight. The slurry was filtered and the filtrate was evaporated to give a crude material (2.4 g). The crude was triturated with methanol and filtration gave 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester (850 mg, crude) as a white solid, which was directly used in the next step without further purification. LCMS calcd for C29H23F3N4O6 (m/e) 580, obsd 581 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[OH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][C:19](C=O)=[CH:18][N:17]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:18]2[N:17]=[C:16]([CH:5]=[O:6])[CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Oc1cccnc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc(Oc2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of sodium hydride (407 mg, 8.48 mmol, 50% in oil) and N,N-dimethylformamide (45 mL) was added an N,N-dimethylformamide (5 mL) solution of 3-hydroxypyridine (806 mg, 8.48 mmol) at 0° C., which was stirred for 30 minutes. An N,N-dimethylformamide (5 mL) solution of 2-chloro-5-formylpyridine (1.0 g, 7.06 mmol) was added to this reaction mixture at the same temperature, which was stirred for 5 hours at 100° C. The reaction mixture was cooled to room temperature, and water was added thereto, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (505.1 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCN1CCOCC1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(Cl)nc1NCc1ccncc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(NCCN2CCOCC2)nc1NCc1ccncc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and 2-morpholin-4-ylethylamine (300 μL) was stirred at 80° C. for 20 h. The reaction mixture was purified on silica gel chromatography to yield N-(3,4-dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+):501 (M+H)+; (ES−):499 (M−H)−. Calc'd for C24H26Cl2N6O2—500.15.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CS([CH2:41][CH2:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)(=O)=O>O>[O:46]1[CH:47]=[CH:48][CH:49]=[C:45]1[CH2:44][O:43][CH2:42][CH2:41][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CS(=O)(=O)CCOCc1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCOCc2ccco2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (0.5 g, 1.6 mmol) and tetrahydrofuran (10 mL). Cool to -78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5M in toluene, 1.8 mmol). After 30 minutes, add fur-2-ylmethyl 2-methanesulfonylethyl ether (1.8 mmol). Warm to ambient temperature and heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give (1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: Rf =0.55 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [C:1]([NH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:14](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:8]([CH:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:11][CH:12]=[CH2:13])(=[O:10])[CH3:14]
Reactant: C=CCC(NC(=O)C(C)C)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=CCC(NC(=O)C(C)C)C(C)=O

Procedure:
7.77 g of the above synthesized 2-isobutyrylamino-pent-4-enoic acid (41.95 mmol) were dissolved in 36.5 ml of pyridine, treated with 19.83 ml of acetic anhydride (5 eq.), and heated to 100° for 1 h. After cooling, 28.3 ml of water were added and the mixture kept for 20 Min. at 90°. Careful pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=1/1) left finally 6.63 g of the title compound as yellowish oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])#[N:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Sulfur trioxide pyridine complex (480 mg, 3.0 mmol) was added to a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (315 mg, 0.9 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.5 mL, 3.9 mmol) and anhydrous dimethyl sulfoxide (0.2 mL, 2.8 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (30 mL). The mixture was extracted into dichloromethane (3×40 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (260 mg, 83%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 8.11 (m, 1H), 7.94 (m, 1H), 7.78-7.81 (m, 2H), 6.65 (s, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.24 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:20]2=[C:21]3[CH:16]([CH2:17][C:18]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=42)[CH2:15][N:14]([CH3:30])[CH2:13][C:12]3=[CH:11][C:10]=1[O:31][CH3:32].C1(C)C=CC=CC=1.[OH-].C1([N+](C)(C)C)C=CC=CC=1.[ClH:51]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:2][O:8][C:9]1[C:20]2=[C:21]3[CH:16]([CH2:17][C:18]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=42)[CH2:15][N:14]([CH3:30])[CH2:13][C:12]3=[CH:11][C:10]=1[O:31][CH3:32].[ClH:51]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(cc1OC)-c1c(O)c(OC)cc3c1C(C2)CN(C)C3
Agent: C[N+](C)(C)c1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)CN(C)C3

Procedure:
2.2 g. (±)-5,6,6a,7-Tetrahydro-1-hydroxy-2,9,10-trimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline trifluoro acetate (see Example 3) are dissolved in 10 ml. of a mixture of toluene and dimethylformamide (9:1 v/v) and methylated with phenyltrimethylammonium hydroxide in a manner analogous to that described in Example 7. When the reaction is finished, the reaction mixture is evaporated in a vacuum and the residue is partitioned between water and methylene chloride. The organic phase is worked up in the usual manner and the crude product obtained is converted, either directly or after previous chromatography on silica gel with chloroform as eluent, into the hydrochloride by treatment with ethanolic hydrochloric acid. Crystallisation from ethanol/diethyl ether gives (±)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of a yellow hydrochloride; m.p. 212°-225° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:38]5[CH2:39][CH2:40][C:35]6([O:34][CH2:33][CH2:32][O:31]6)[CH2:36][CH2:37]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCC5(CC4)OCCO5)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 1,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.1 (m, 20H), 2.05 (m, 4H); MS (DCI) m/z 478 (M+H)+;
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3C=C(N3CCCCC3)[C:6]3[CH:21]=[CH:22][CH:23]=[CH:24][C:5]2=3)[CH2:3][CH2:2]1.[BrH:26].[C:27]([OH:30])(=O)[CH3:28]>C(#N)C>[Br:26][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:28][C:27](=[O:30])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2
Reactant: CC(=O)O
Reactant: OC1(C2CC2)c2ccccc2C=C(N2CCCCC2)c2ccccc21
Reactant: Br
Solvent: CC#N
Product: O=C1Cc2ccccc2C(=CCCBr)c2ccccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Cyclopropyl-10-piperidin-1-yl-5H-dibenzo[a,d]cyclohepten-5-ol (5) (69 mmol, 1.00 equiv.) was dissolved in 100 mL acetic acid, then 48% aqueous HBr (100 mL) was added and the resulting mixture was heated in a 100° C. oil bath. LC/MS analysis after 18 hours showed that the starting material was consumed. The mixture was diluted with H2O (100 mL) then extracted in a separatory funnel with ethyl ether (3×100 mL). The aqueous phase was discarded, after which the combined organic phases were washed with saturated sodium bicarbonate (3×50 mL). The aqueous phase was discarded, and the organic phase was filtered through a silica gel plug and concentrated under vacuum to obtain a thick brown oil, which was dissolved in acetonitrile (200 mL) and dried under vacuum. The residue was then dissolved in toluene (200 mL) and again dried under vacuum. The resulting crude 5-(3-bromo-propylidene)-5,11-dihydro-dibenzo[a,d]cyclohepten-10-one (6) was used without further purification in the next step. ESI MS m/z 327.0 (M+H)+. 1H NMR (d6-DMSO, 250 MHz): 7.98 (1H, d), 7.67-7.25 (7H, m), 5.76 (1H, t), 4.46 (1H, d), 3.73 (1H, d), 3.64 (2H, m), 2.83-2.50 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:29][C:26]([C:24]1[O:23][N:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[CH:25]=1)([CH3:28])[CH3:27])(=[O:32])[CH3:31]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (97 mg, 0.234 mmol) and DMAP (2.89 mg, 0.023 mmol) were dissolved in pyridine under nitrogen atmosphere. The reaction mixture was cooled to 0° C., acetic anhydride (25.1 mg, 0.246 mmol) was added and the reaction mixture stirred for 2 h in RT. The mixture was again cooled to 0° C. and 10 μA of acetic anhydride was added. The reaction mixture was stirred in RT overnight after which the solvent was evaporated. Yield 99%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 1.80 (s, 6H), 2.05 (s, 3H), 4.25 (dd, 1H), 4.42 (dd, 1H), 4.58 (m, 1H), 6.58 (s, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.89 (d, 1H), 8.09 (d, 1H).
Reaction SMILES: ClC1C=C2C(CCN)=C([Si](CC)(CC)CC)NC2=[N:6]C=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30]([NH2:6])=[O:31])[CH:26]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:51]=[CH:52][CH:53]=2)[O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:24]([NH:50][CH2:49][CH2:48][CH2:47][O:46][C:45]2[CH:51]=[CH:52][CH:53]=[C:43]([CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:44]=2)=[O:25])[CH3:17])=[CH:6][CH:7]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.7 g (2.1 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.7 g (2.8 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=606 ([M+H]+, 4), 230 (100); IR (KBr): 1643 cm-1 (C≡O).