Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH2:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)[CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1.C([O-])(O)=O.[Na+].[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([O-:42])=[O:41]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:33][S:49]([C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=1)(=[O:50])=[O:51])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)[CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
(S)-2-Amino-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro benzo[1,4]dioxin-6-yl}-propionic acid methyl ester hydrochloride (0.35 g) was taken in 2 mL of EtOAc and cooled to 0° C., NaHCO3 solution (1 mL) and 4-nitrobenzenesulfonyl chloride (178 mg) were added and stirred for 10 minutes. Reaction was stirred at room temperature for 4 hours. EtOAc layer was separated and washed with water and brine, and then dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel column (10% EtOAc in hexanes to 50% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g). 1H NMR (400 MHz, acetone-d6): 8.33 (m, 2H), 7.89 (m, 2H), 7.73 (d, 1H), 7.62 (d, 1H), 7.37-7.53 (m, 3H), 7.04-7.21 (m, 3H), 6.64-6.72 (m, 3H), 5.22 (s, 2H), 5.09 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 3.97 (m, 1H), 3.61 (s, 3H), 3.03 (m, 1H), 2.76 (m, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C(F)(F)F)=[CH:16][C:15]=2[F:27])[NH:6][CH:5]=1>O1CCCC1>[Cl:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:27])[NH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reaction time: 8 h

Procedure:
8 ml of 1N aqueous sodium hydroxide solution are added to a solution of 637 mg (1.70 mmol) of N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluorophenyl}-2,2,2-trifluoroacetamide in tetrahydrofuran (10 ml). The reaction is stirred overnight. The solution is extracted with ethyl acetate (two times 20 ml). The combined organic phases are washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. This gives a solid which is not purified any further.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][NH:10][C:11]2=[O:14])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:17][CH2:16]1)([O-:3])=[O:2].Br[CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])[C:11]2=[O:14])=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:20]1)([O-:3])=[O:2]
Reactant: Cc1ccccc1N1CCN(c2cc3cc[nH]c(=O)c3cc2[N+](=O)[O-])CC1
Reactant: O=C1OCCN1CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc3ccn(CCCN4CCOC4=O)c(=O)c3cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 7-nitro-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one (0.25 g, 0.68 mmol) in anhydrous DMF (10 mL), 3-(3-bromo-propyl)-oxazolidin-2-one (0.14 g, 0.68 mmol) was added followed by potassium bis(trimethylsilyl) amide (0.27 g, 1.37 mmol) at 0° C. under N2 atmosphere. The reaction mass allowed to stir at room temperature for 6 h. The progress of the reaction was monitored by LCMS analysis. Upon completion of the reaction, solvent was removed in vacuo. Residue obtained was quenched with water, and extracted in dichloromethane (3×75 mL). The combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) using 1.5-1.75% methanol in dichloromethane to afford the compound 7-nitro-2-[3-(2-oxo-oxazolidin-3-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one. Yield (0.25 g, 75%; and off-color solid).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OCC)(OCC)OCC)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4](/[C:8](=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(Cl)c1F
Temperature: 70 °C
Yield: 95.6 %

Procedure:
To a solution of 1-(3-chloro-2-fluorophenyl)ethanone (5.60 g, 31.5 mmol) and (R)-2-methylpropane-2-sulfinamide (5.72 g, 47.2 mmol) in THF (50.0 mL) was added tetraethoxytitanium (16.50 mL, 79 mmol) and the overall bright yellow solution was heated at 70° C. for overnight. The reaction was slightly cooled with ice-water bath, then was added EtOAc (50 mL), NaHCO3 (10 mL), and brine (10 mL). The slurry was filtered through a short path of Celite and the wet cake was washed with EtOAc. The resulted bright yellow solution was phase separated, and the organic layer was concentrated to afford the title compound (8.3 g, 30.1 mmol, 96% yield) as a light yellow oil. This material was used in the next step without purification. MS m/z=276.0 [M+H]+. Calculated for C12H15ClFNOS: 275.77.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][N:20]([S:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:19](=[O:35])[NH:18]2)=[O:16])[CH2:11][CH2:10]1.[CH2:36](I)[CH2:37][CH3:38].[I-].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][N:20]([S:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:19](=[O:35])[N:18]2[CH2:36][CH2:37][CH3:38])=[O:16])[CH2:11][CH2:10]1
Reactant: CCCI
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4cccc5ccccc45)C(=O)N3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2cccc3ccccc23)C[C@H]1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 66, step 4, (S)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(naphthalene-1-sulfonyl)-imidazolidin-2-one and propyl iodide were reacted in the presence of sodium iodide in a pressure tube to yield (S)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(naphthalene-1-sulfonyl)-3-propyl-imidazolidin-2-one as a white solid. MS: 535.0 ([M+H])
Reaction SMILES: ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.Br[CH2:21][C:22]([NH:24][NH:25][C:26]([N:28]1[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][C:30]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:29]1=2)=[O:27])=[O:23].[CH2:44]([O:46][P:47]([O:51]CC)[O:48][CH2:49][CH3:50])[CH3:45].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>O1CCCC1.[Na+].[I-]>[CH2:44]([O:46][P:47]([CH2:21][C:22]([NH:24][NH:25][C:26]([N:28]1[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][C:30]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:29]1=2)=[O:27])=[O:23])([O:48][CH2:49][CH3:50])=[O:51])[CH3:45]
Reactant: CCOP(OCC)OCC
Reactant: O=C(CBr)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [I-]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)OCC
Yield: 83 %

Procedure:
To a stirring solution of 2.57 g (6.3 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2bromoacetyl) hydrazide (19), prepared as described in Example 19 above, in 75 mL of tetrahydrofuran (THF) was added 1.25 g (7.5 mmol) of triethylphosphite and 0.15 g (1 mmol) of Nal. After 22 hours of refluxing, an additional 0.62 g (3.75 mmol) of triethylphosphite and 0.05 g (0.33 mmol) of NaI were added to the reaction, which was refluxed an additional 24 hours. The solvent was then removed under aspirator vacuum, and the reaction mixture was chromatographed to yield 2.46 g (83%) of 8-chlorodibenz-[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(diethoxyphosphinyl)acetyl]hydrazide (20), which was a beige foam. Analysis calculated for C20H23N23O6PCl (M.W. 467.85): C, 51.35; H, 4.96; N, 8.98; Cl, 7.58. Found: C, 51.02; H, 5.03; N, 8.83; Cl, 7.39.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1C(C)CCCN1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[NH:15]1
Reactant: Cc1cc(C)nc(N)c1
Agent: CC1CCCNC1=N
Solvent: CC(=O)O
Product: CC1CC(=N)NC(C)C1

Procedure:
The method of preparation of 2-Imino-3-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-4,6-dimethylpyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 163-166° C. MH+=127 ; 1H NMR (D2O): δ3.48-3.40 (m, 1H); 2.52-2.40 (m, 1H); 2.07-1.95 (m, 1H); 1.85-1.75 (m, 2H); 1.75 (s, 3H); 1.12 (d, J=6.3 Hz, 3H); 1.02-0.92 (m, 1H); 0.86 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][C:10]([C:14]([F:15])([F:16])[F:17])([OH:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(C(F)(F)F)C=C(c2cccnc2F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCC(c2cccnc2F)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A solution of 3-(2-fluoropyridin-3-yl)-1-(trifluoromethyl)cyclopent-2-enol (940 mg, 3.80 mmol) in tetrahydrofuran (35 mL) was treated with palladium, 10% wt. on activated carbon (202 mg, 0.190 mmol). The reaction mixture was purged through 3 vacuum-hydrogen cycles, and was stirred under hydrogen at 23° C. After 18 h, the reaction was filtered through celite and the filter cake was washed with tetrahydrofuran (50 mL). The combined filtrates were concentrated, affording the product as a yellow oil. MS (ESI, pos. ion) m/z: 250.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2]>[Pd].CO>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)OC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Charged methyl 4-ethyl-3-nitrobenzoate (5.0 g, 23.92 mmol), Pd/C (500 mg) and methanol (50 mL) to a flask, purged with hydrogen and stirred at r.t. overnight. It was then filtered and concentrated to give 4.0 g of the title compound (94%). 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.6 Hz), 2.54 (2H, q, J=7.6 Hz), 3.73 (2H, s), 3.87 (3H, s), 7.12 (1H, d, J=8.0 Hz), 7.35 (1H, s), 7.41 (1H, d, J=7.6 Hz). [M+H] Calc'd for C10H13NO2, 180. Found, 180.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) and 3-fluorobenzyl bromide according to General Procedure B. Yield 113 mg (15%), MP 134° C.; 1H-NMR (DMSO-d6): δ 3.75 (m, 4H), 3.95 (m, 4H), 5.51 (s, 2H), 6.66 (dd, J=1.6, 3.2, Hz, 1H), 7.06-7.10 (m, 4H), 7.33 (m, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.33 (dd, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H); EIMS: 492 (M+1). Anal. (C25H19ClFN5O3) C, H, N.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([NH:30][CH2:31][C@@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[N:24]=1.[OH-].[Na+]>>[Cl:22][C:23]1[N:24]=[C:25]([NH:30][CH2:31][C@@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[N:26]=[C:27]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([NH:10][CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)[N:28]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@H]2CC[C@@H](N)CC2)cc1
Reactant: C[C@@H](CNc1nc(Cl)nc(Cl)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(CNC(=O)[C@H]2CC[C@@H](Nc3nc(Cl)nc(NC[C@H](C)c4ccccc4)n3)CC2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-({[(cis-4-aminocyclohexyl)carbonyl]amino}methyl)benzoate (1.48 g, 3.67 mmol, 1.00 equiv) was added to the suspension prepared in step a. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 30 min and then used immediately in the next step without workup or purification. MS (ES+): m/e 537.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[S:4][C:3]=1[CH2:15][OH:16])[N:11]=[CH:10][CH:9]=[CH:8]3>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[S:4][C:3]=1[CH:15]=[O:16])[N:11]=[CH:10][CH:9]=[CH:8]3
Reactant: OCc1sc2ccc3ncccc3c2c1Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1sc2ccc3ncccc3c2c1Br
Reaction time: 7 h
Yield: 79.3 %

Procedure:
Under nitrogen atmosphere, manganese dioxide (318 mg, 3.65 mmol) was added to a solution of {1-bromothieno[3,2-f]quinolin-2-yl}methanol (16e) (215 mg, 0.731 mmol) in dichloromethane (31 mL) at room temperature. The mixture was vigorously stirred for 7 hours, then it was filtered and concentrated to give the desired aldehyde (16f) as a yellow solid (170 mg, 0.58 mmol, 58%)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reaction time: 3 h

Procedure:
To (1R,6S)-tert-butyl 8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (185 mg, 0.5 mmol) in DCM (3 mL) was added TFA (3 mL). After 3 h, the reaction was concentrated, neutralized with 5% Na2CO3 (aq) and extracted with DCM (3×). The combined organics were dried (Na2SO4) and concentrated to give the title compound that was used without further purification. MS (ESI) mass calcd. For C11H13F3N4, 258.2; m/z found 259.1 [M+H]+
Reaction SMILES: C(OC([N:11]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50]CC2C=CC=CC=2)=[CH:46][CH:45]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH:21]=2)[NH:16][C:15]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[Pd].O>[CH3:39][C:34]1[CH:33]=[C:32]([C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][CH2:12][NH:11][CH2:40][CH2:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[CH:21][C:20]([O:23][C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=3)[CH:37]=[C:36]([CH3:38])[CH:35]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(OC(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(OC(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of morpholine-4-carboxylic acid 3-(2-[benzyloxycarbonyl-[4-(4-benzyloxy-phenyl)butyl]amino]-ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl ester (20 mg in a mixture of 2 mL tetrahydrofuran and 0.5 mL methanol) was added 16.8 mg of 10% palladium on carbon catalyst followed by acetic acid (0.010 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (12 mg). m/e=542 (M+H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:20][C:19]4[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:18]=4[O:17][CH2:16][CH2:15]3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Br[C:29]1[CH:30]=[C:31]2[N:37](COCC[Si](C)(C)C)[C:36]([CH3:46])=[N:35][C:32]2=[N:33][CH:34]=1>>[CH3:46][C:36]1[NH:37][C:31]2[C:32]([N:35]=1)=[N:33][CH:34]=[C:29]([C:22]1[CH:23]=[CH:24][C:18]3[O:17][CH2:16][CH2:15][N:14]([C:8]4[C:7]5[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][N:9]=4)[CH2:20][C:19]=3[CH:21]=1)[CH:30]=2
Reactant: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Agent: Cl
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)ncnc2c1

Procedure:
Prepared as hydrochloride, according to the method of example 5 by using {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 35) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.84 (d, 1H), 8.78 (s, 1H), 8.39 (d, 1H), 8.24 (brd, 1H), 7.95 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 7.04 (d, 1H), 5.46 (s, 2H), 4.68 (m, 2H), 4.50 (m, 2H), 3.96 (s, 3H), 2.78 (s, 3H); MS (EI) for C25H22N6O2: 439 (MH+).
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[S:6][CH:7]=1.CCOCC>CC(O)=O>[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[S:6][CH:7]=1
Reactant: Cc1csc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1csc([C@H]2CCCN2)n1
Reaction time: 1 h

Procedure:
HBr in AcOH (60 mL) was added to (R)-benzyl 2-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (neat) at room temperature. After 1 h, ether (150 mL) was added slowly with vigorous string. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to PH˜8 with 1N LiOH and extracted with 5% MeoH/95% CHCl3 (3×100 mL) to yield 4.0 g of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:19])([C:13]1[N:17]=[C:16]([CH3:18])[O:15][N:14]=1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)(C)(C)C.[ClH:21]>CO>[ClH:21].[CH:10]1([CH2:9][C:8]([NH2:7])([CH3:19])[C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[CH2:12][CH2:11]1
Reactant: Cc1nc(C(C)(CC2CC2)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: CO
Product: Cc1nc(C(C)(N)CC2CC2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.4 g, 1.43 mmol) in methanol (10 mL) was added hydrochloric acid (4N in dioxane, 3.5 mL, 14.8 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to give the title product (0.25 g, 81%) as a light yellow solid. 1H-NMR (DMSO, 400 MHz): 0.010-0.02 (m, 2H); 0.38-0.42 (m, 2H); 0.61-0.63 (m, 1H); 1.67 (s, 3H); 1.78-1.91 (m, 2H); 2.66 (s, 3H); 8.89 (br s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][N:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][N:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1noc2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2noc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-benzisoxazolyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-benzisoxazolyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]([C:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]([CH3:28])[N:15]=1)([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:7][C:11]([C:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]([CH3:28])[N:15]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)O)nn1C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)F)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
At −10° C., 0.52 ml (3.9 mmol) of diethylaminosulphur trifluoride is added dropwise to a solution of 1.00 g (3.57 mmol) of ethyl 3-(2-hydroxypropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 20 ml of dichloromethane. The mixture is afterstirred for one hour at −10° C., sodium carbonate is added, and the mixture is stirred for 10 minutes at room temperature. After adding saturated sodium carbonate solution, extraction is carried out with dichloromethane, and the combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo on a rotary evaporator. Purification by flash chromatography on silica gel (cyclohexane/ethyl acetate) gives 700 mg of ethyl 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (67%).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:32])=O>>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([Cl:32])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
A mixture of 3,5-bis (4-nitrophenoxy) benzoic acid (51.9 g, 0.131 mol) and thionyl chloride (478 ml, 6.55 mol) are heated at reflux for 5 hours, with the excess thionyl chloride being removed by distillation. The residue is dried at 85° C. under vacuum overnight in the same reactor.