Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([CH3:3])[CH3:2].O.N.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O>[CH2:14]([O:10][C:9]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[NH:8][N:7]=1)=[O:11])[CH3:15]
Reactant: CCO
Reactant: CC(C)c1cc(C(=O)O)n[nH]1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(C(C)C)[nH]n1

Procedure:
5-Isopropyl-1H-pyrazole-3-carboxylic acid (WO 03/035065, page. 485, example 17b) (1.00 g, 6.49 mmol) was dissolved in a mixture of concentrated sulphuric acid (1.5 mL) and ethanol (25 mL) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was cooled, poured into water, basified with 0.88 ammonia then extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield the title product, 514 mg (43%).
Reaction SMILES: C[C:2]1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.N1C=CC=CC=1.[F:17][C:18]([F:24])([F:23])[CH2:19]C(Cl)=O>CN(C1C=CN=CC=1)C.ClCCl.CO>[CH3:2][O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:19][C:18]([F:24])([F:23])[F:17]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg, 1.41 mmol), pyridine (0.125 ml, 1.55 mmol) and DMAP (344 mg, 2.81 mmol) in dichloromethane (10 ml), was added 3,3,3-trifluoro-propionyl chloride (0.16 ml, 1.55 mmol) at 0° C. The resulting reaction mixture was stirred under nitrogen for 1 h at 0° C. and then allowed to warm to room temperature and stirred for 2 h. Volatiles were removed under reduced pressure, and the crude residue was diluted with diethyl ether and washed with 1 N HCl. The organic layer was dried and concentrated to get the intermediate, which was diluted with 10 ml of methanol and refluxed for 5 h. Volatiles were removed under reduced pressure to afford the crude 5,5,5-trifluoro-3-oxo-pentanoic acid methyl ester (120 mg, 46%) as brown liquid which was used in the following step without further purification. FIA-MS: 183 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-([(3,4-difluorophenyl)methyl]oxy)-N-4-pyridazinylbenzamide (may be prepared as described in Example 78; 200 mg, 0.48 mmol), 4-pyridinylboronic acid (88 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (33.0 mg, 0.03 mmol), sodium carbonate (0.95 ml, 0.95 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated to 120° C. for 1 hour under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 35 mg.
Reaction SMILES: COC.[O:4]1[CH2:9][CH2:8][O:7][CH2:6]C1.C(N([CH2:15][CH3:16])CC)C.[C:17](O)(=O)[CH3:18]>>[CH3:6][O:7][C:8]1[C:9](=[O:4])[CH2:17][CH2:18][C:15]=1[CH3:16]
Reactant: CC(=O)O
Reactant: C1COCCO1
Reactant: CCN(CC)CC
Agent: COC
Product: COC1=C(C)CCC1=O
Temperature: 100 °C

Procedure:
A 3.06 g quantity (0.0212 mol) of methyl ether of 2,5-diketohexanol-1 is added to 15 ml of dioxane containing 5% of triethylamine, and the mixture is heated at 100° C. for 2 hours. The reaction product is carefully neutralized with acetic acid and thereafter distilled at reduced pressure, giving 2-methoxy-3-methyl-cyclopentenone, the desired product, in a yield of 88%, b.p. 84°-85° C./18 mm Hg.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.B([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[N:3][C:4]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccc(C(=O)O)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 110 °C
Yield: 99 %

Procedure:
Tert-butyl N-[5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (184 mg, 0.3379 mmol), 4-boronobenzoic acid (56.07 mg, 0.3379 mmol) and Na2CO3 (71.63 mg, 0.6758 mmol) were suspended in MeCN (2.896 mL)/water (2.896 mL) and the mixture de-gassed (×5) and treated with Pd(PPh3)4 (39.05 mg, 0.03379 mmol). The reaction was de-gassed again and heated at 110° C. in the microwave for 30 minutes. The reaction mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH4 by (2M HCl) and resulting precipitate collected, washed with water and dried under vacuum (120 mg, 99% Yield). MS (ES+) 359.12
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.Cl.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)=[CH:34][CH:33]=1.[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69]([N:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=3)=[CH:43][N:42]=2)[CH2:49][CH2:48]1)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Clc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 80.9 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine dihydrochloride (0.228 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one(0.295 g), to yield the title compound as a yellow solid (0.325 g, 81%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl[C:10]([O:12]C1C=CC=CC=1)=[O:11].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+]>[C:10]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O:12][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
L-Proline (10 g, 86.6 mmol) was dissolved in 66 mL of 2N NaOH and cooled to 0° C. To this solution were slowly and simultaneously added 34.35 mL of a solution of phenyl chloroformate in toluene (104.2 mmol) and 33 mL of 4N NaOH, over a period of 1 hr, while maintaining the reaction temperature at 0° C. and the pH above 7. After all reactants were added, the reaction was stirred for 6 hr at room temperature. The solution was then extracted with ether. The remaining aqueous layer was neutralized to pH 6-7 with 1N HCl, then extracted with ethyl acetate. The extract was dried over Na2SO4 and concentrated to afford 21.19 g of the title product (98% yield). 1H NMR (CDCl3) δ 9.55 (d, 1H), 7.3 (s, 5H), 5.25 (d, 2H), 4.35 (t, 1H), 4.20 (t, 1H), 1.8-2.2 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH:23]=[N+]=[N-])([CH3:22])[CH3:21]>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:19]2[Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(/C=C/c2ccc(Cl)cc2)OC1(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC1(C)OB(C2C(c3ccc(Cl)cc3)C2[Si](C)(C)C)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((E)-2-(4-chlorophenyl)ethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg) and Pd(OAc)2 (127 mg) in Et2O (10 ml) was added trimethylsilyldiazomethane (2.83 ml), and the mixture was stirred at room temperature for 3 h. The mixture was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (260 mg) as an oil.
Reaction SMILES: [P:1](Cl)(Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-:12].[CH2:13]([O:20][C:21](=[O:25])[C@@H:22]([NH3+:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:12][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][P:1](=[N:24][C@@H:22]([CH3:23])[C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25])=[O:9]
Reactant: [Cl-]
Reactant: C[C@H]([NH3+])C(=O)OCc1ccccc1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](N=[P+]([O-])Oc1ccccc1Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Phenyl phosphorodichloridate (1.17 g, 2 N) was added to a solution of 43 (1 g, 5.58 mmol) in dichloromethane at −78° C. Triethylamine (1.13 g, 11.173 mmol) was then added drop-wise. Once complete, the reaction mixture was allowed to warm to room temperature and then evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (3:1)] provided 44 as an colorless oil (1.2 g, 60%). LC-MS (M+H)+=354
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Fc1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
The titled compound (178 mg) was prepared in 67% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-fluoro-benzene according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.74 (d, 2 H, J=8.0 Hz), 7.60 (d, 2 H, J=8.0 Hz), 7.28 (m, 3 H), 7.05 (m, 2 H), 6.67 (s, 1 H), 4.54 (AB2,2 H,Δv=17,Jab=57 Hz), 3.87 (m, 1 H), 2.76 (m, 1 H), 2.45 (m, 1 H), 1.47 (m, 6 H), 0.97 (m, 1 H); MS m/e 425.02 (M+H)+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CN(C)CCN(C)C.[CH3:24][C:25]1([CH3:43])[CH2:29][O:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)=[N:26]1.CON(C)[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CCCCCC>[CH3:24][C:25]1([CH3:43])[CH2:29][O:28][C:27]([C:30]2[C:31]([C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:54])=[CH:32][C:33]([N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)=[N:34][CH:35]=2)=[N:26]1
Reactant: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCN(c2cc(C(=O)c3ccccc3)c(C3=NC(C)(C)CO3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
2,2,6,6-Tetramethylpiperidine (0.932 g, 6.6 mmol) was placed in a three-necked flask. Under argon 10 ml of hexane were added, the solution was cooled to 0° C. and n-butyl lithium (1.6 M solution in hexane) was added slowly. After stirring the yellow suspension for 10 min at 0° C., N,N,N′,N′-tetramethylethylenediamine (767 mg, 6.6 mmol) was added. This mixture was added dropwise to a suspension of 1.65 g (6 mmol) of 1-[5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridin-2-yl]-4-methyl-piperazine in 20 ml of hexane at −78°. After stirring the yellow solution for 30 min at this temperature and for 45 min at 0° C., a solution of 1.19 g N-methoxy-N-methyl benzamide (7.2 mmol) in 2 ml hexane/2 ml tetrahydrofuran was added slowly at 0° C. After 30 min, the cooling bath was removed and stirring was continued at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 1.16 g (51%) of the product as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH3:33][CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:35])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[C:30]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:32]
Reactant: C1COCCN1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)N1CCOCC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and morpholine. LCMS (M+H)+: m/z=553.3
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OC)([O:21]C)[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O.C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:25]([N:4]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])=[CH:12][CH:13]=1)[CH2:1][CH2:2][CH3:3])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCN(CCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 61.8 %

Procedure:
N-Propyl-N-[2-[4-(4,4,4-trifluoro-3,3-dimethoxybut-1-yl)phenoxy]ethyl]dodecylamine (300 mg, 0.58 mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (169 mg, 62%) as a pale yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([C:3]2[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: COC(=O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.2 %

Procedure:
To a flask containing N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2.0 g, 8.9 mmol) and methyl acrylate (0.7 g, 8 mmol) in methylene chloride (100 mL) at 0° C. under an inert atmosphere was added TEA (0.90 g, 8.8 mmol). The reaction mixture was slowly warmed to ambient temperature, stirred for 20 h, quenched with water (30 mL), and extracted with methylene chloride (2×50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel, eluting with methylene chloride/methanol (100/1 to 95/5). The appropriate fractions were combined and concentrated in vacuo to give methyl 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 100%): LCMS: 274.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 8.03 (s, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.59 (dd, 1H), 5.28 (dd, 1H), 3.86 (s, 3H), 3.71 (dd, 2H).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[CH:1]1([NH:5][S:20]([C:16]2[CH:15]=[C:14]([S:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)NC2CCC2)c1

Procedure:
Using a procedure similar to that described in Preparation E, 4 ml of cyclobutylamine was added to 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride to give 813 mg of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][CH:14]1[N:7]2[C:8]3[C:4]([CH:5]4[CH2:18][NH:17][CH2:16][CH2:15][CH:6]42)=[CH:3][C:2]([NH2:1])=[CH:10][C:9]=3[CH2:11][O:12][CH2:13]1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1cc2c3c(c1)C1CNCCC1N3C(Cc1cccc(C(F)(F)F)c1F)COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR (CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB 14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[C:10]=2[F:12])[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:15]=[N:14][C:13]([C:9]2[C:10]([F:12])=[C:11]3[C:6]([CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=[C:2]3[F:1])=[CH:7][CH:8]=2)=[N:18][CH:17]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCOc1cc2ccc(-c3ncc(O)cn3)c(F)c2c(F)n1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc3cc(OCCCCCCCC)nc(F)c3c2F)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1,8-difluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxyisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1 -octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1,8-difluoro-3-octyloxyisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(Cl)CCl.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]([N:42]6[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]6)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CNCCN1
Reactant: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
A mixture of crude 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid (75 mg, 0.15 mmole), EDC (72 mg, 0.376 mmole), and DMAP (37 mg, 0.3 mmole) in dry DCM (1 mL) was stirred at RT for 0.5 hr. Piperazine (104 mg, 1.2 mmole) was added and, after 64 hr, the reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (11 mg, 13%). 1H NMR (CDCl3) δ 1.67-1.80 (m, 4H), 1.96-2.09 (m, 2H), 2.15-2.18 (m, 1H), 2.58-2.65 (m, 1H), 2.82-2.86 (m, 4H), 3.17-3.20 (m, 2H), 3.43-3.48 (m, 2H), 3.57-3.62 (m, 2H), 3.77 (s, 2H), 5.57 (s, 2H), 6.48 (d, 1H, J=2.5 Hz), 6.83-6.88 (m, 1H), 6.90-6.97 (m, 2H), 7.21-7.29 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 7.55-7.58 (m, 1H), 7.89 (s, 1H), 8.08 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 11.87 (br, 1H). MS: 568.67 (M+H+); HPLC Ret Time: 1.03 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).