Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)[CH3:2].[Br:15]Br>ClCCl>[Br:15][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][NH:8][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(-c2ccccc2)n[nH]1
Reactant: BrBr
Solvent: ClCCl
Product: CCOc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 5-ethoxy-3-phenyl-1H-pyrazole (1.0 g, 5.31 mmol) in dichloromethane (20 mL), was added bromine (0.849 g, 5.31 mmol) dropwise at room temperature. The reaction was stirred for 2 h, washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was triturated with 10% ethyl acetate/hexane to give the title compound as a yellowish solid (1.20 g). LCMS m/z=268.07 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=4.2 Hz, 3H), 4.39 (q, J=4.2 Hz, 2H), 7.45-7.85 (m, 5H), 12.4 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17]([CH3:20])[CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17]([CH3:20])[CH2:18][O:19][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 66.3 %

Procedure:
198 mg (0,606 mmol) of (R)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol was dissolved in pyridine (3 ml) and cooled to 0° C. DMAP (18,5 mg; 0,152 mmol) was added followed by a slow addition of pivaloyl-chloride (97 ml; 0,79 mmol). The mixture was allowed to react for half an hour at 0° C. and half an hour at room temperature. The reaction mixture was poured in a cold aqueous HCl (25%) solution. Extraction with ether, washing with brine, drying over Na2 SO4 and solvent removal gave a dark oil which was purified by column chromatography on silica gel (eluent: n-hexane/ethyl-acetate 97:3) affording 215 mg (86,3%) of 2,2-Dimethyl-propionic acid (R)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl ester (J1) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])([CH3:11])[CH3:10]>>[CH3:8][Si:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:11])[CH3:10]
Reactant: C[C@H](N)C(=O)O[Si](C)(C)C
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](C)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-alanine or pyruvyl-glycine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting pyruvyl chloride with a suspension of alanine trimethylsilyl ester hydrochloride to yield a pyruvyl-alanine trimethylsilyl ester and then subjecting the pyruvyl-alanine trimethylsilyl ester to hydrolysis to yield pyruvyl-alanine. The pyruvyl-alanine synthesized via the method set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23](C([O-])=O)=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-:29].[Na+].[CH2:31]([OH:33])[CH3:32]>O1CCCC1>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23]([CH2:32][C:31]([OH:29])=[O:33])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Using General Procedure 1; a solution of ethyl [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:13][C:14]1[N:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:13][C:14]3[N:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Clc1cc(Br)c2ncccc2c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(c1ccc(Nc2cc(Cl)cc3cccnc23)nc1)N1CCOCC1
Temperature: 90 °C
Yield: 110.9 %

Procedure:
A mixture of 8-bromo-6-chlorquinoline (140 mg, 0.56 mmol), (6-aminopyrdin-3-yl)(morpholino)methanone (92 mg, 0.44 mmol), xantphos (38.5 mg, 0.067 mmol) and cesium carbonate was taken up in dry dioxane (6.5 ml). The reaction flask is evacuated and back-filled with argon (repeated 5 times). Tris(dibenzylidenacetone)palladium (0) (31 mg, 0.033 mmol) was added and the flask was evacuated and back-filled with argon (repeated 3 times). The material was heated to 90° C. (oil bath) under argon for 14 hours. The reaction mixture was cooled to ambient temperature and filtered through a short plug of celite, rinsing well with dioxane. The solvent was removed and the resulting residue loaded onto 2 preparative thin layer chromatography plates. The plates were eluted with 75% ethyl acetate/hexane and the product band collected. This provided the desired product as a light brown viscous oil (180 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1(=O)[O:35][C:33](=[O:34])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:33](=[O:34])[C:32]3[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:30]2=[O:35])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (177.9 mg) and triethylamine (98 μL) in THF (2.94 mL) was added phthalic anhydride (105 mg). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic anhydride (3 mL), and the mixture was stirred at 80° C. for 5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (252.7 mg).
Reaction SMILES: [Na+].[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O-:22])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CC(N(C)C)=O>[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O:22][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (402 mg, 0.90 mmol) (obtained as described in Example 3) in dimethylacetamide (5 ml) was added iodomethyl pivalate (261 mg, 1.08 mmol) at 0° C. under an atmosphere of nitrogen and the mixture was stirred for 1 hour. At the end of this time, to the reaction mixture was added ethyl acetate and the organic layer was washed sequentially with 10% aqueous sodium chloride solution 10% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added diethyl ether to afford pivaloyloxymethyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (450 mg, yield 93%) as a colorless powder.
Reaction SMILES: N.C(O)C.[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14]/[C:15](=[CH:17]\[C:18]#[N:19])/[C:16]=3[C:6]1=2.[H][H]>[Co].C(O)C>[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][C:15](=[CH:17][CH2:18][NH2:19])[C:16]=3[C:6]1=2
Reactant: N#C/C=C1\CCc2ccc3c(c21)CCO3
Reactant: [H][H]
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCC=C1CCc2ccc3c(c21)CCO3

Procedure:
A saturated ammonia/ethanol solution (150 ml) and Raney cobalt (8.4 g) were added to an ethanol (150 ml) solution of (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]-furan-8-ylidene)acetonitrile (2.6 g, 13.2 mmol), and the reaction mixture was stirred at room temperature in a hydrogen atmosphere (5 kgf/cm2) for 3 hours. The Raney cobalt was filtered off and the solvent was distilled off under reduced pressure to give 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine. To this residue was added a saturated hydrogen chloride/ethanol solution (100 ml), followed by 1 hour of heating under reflux. The reaction solution was concentrated and the residue obtained was recrystallized from ethanol to give 2.75 g (yield: 88%) of the target compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[CH2:40][C:39](=[O:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[C:40]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:39]([OH:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Agent: Cc1nc(CCl)n(C)n1
Solvent: O
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(OCC5CC5)c(Cl)c4)(C4CCCC4)OC3=O)cc(=O)n12
Yield: 1 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and using 6-{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from Step 4, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 1%. 1H NMR (300 MHz, DMSO-d6) □ 0.31 (m, 2H), 0.56 (m, 2H), 1.22 (m, 1H), 1.23-1.65 (m, 8H), 1.92 (m, 2H), 2.33 (m, 1H), 2.48-2.75 (s, m, 7H, overlap with DMSO-d5), 3.45 (m, 2H, overlap with H2O peak), 3.84 (d, J=7.8 Hz, 2H), 4.87 (s, 2H), 5.20 (s, 1H), 6.16 (s, 1H), 6.93 (d, J=9 Hz, 1H), 7.01 (dd, J=9, 1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H). LC-MS (APCI) calcd for C30H33ClN2O5S: 568.18; found (M+H+) 569.0 m/z.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].O.[S:25](=[O:29])(=O)([OH:27])[OH:26]>>[CH2:1]([O:2][C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:23]=[CH:22][C:21]([S:25]([OH:27])(=[O:29])=[O:26])=[CH:20][C:17]=4[CH2:18][O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)=[O:3])[CH2:4][CH2:9][CH3:8]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccccc1CO3
Solvent: O
Product: CCCCOC(=O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccc(S(=O)(=O)O)cc1CO3
Temperature: 0 °C

Procedure:
A solution of 7.0 gm (0.022 mol) of 2-chloro-6H-dibenzo-[b,d]-pyranyl-(3)-fumaric acid ether in concentrated sulfuric acid (see Example 9) was stirred for 2 hours at room temperature. The dark reaction mixture was then poured into ice water, and the resulting precipitate, consisting mainly of 2-carboxy-4-oxo-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f][1]-benzopyran, was filtered off. The aqueous phase was extracted with n-butanol, and the obtained solution was evaporated to dryness. After addition of ether, 2.5 gm (23.8% of theory) of the compound named in the heading, m.p. 95°-97° C, were obtained (contained 3 mols of water of crystallization).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (679 mg, 1.57 mmol) (from example 113, step 1) was dissolved in MeOH (10 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.463 mL, 1.57 mmol) dissolved in water (1.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.096 mL, 1.57 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8.11 mL, 48.63 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. Crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (603 mg, 96%) was isolated. MS m/z 401 (M+H)+
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>C(O)C.O>[I:13][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=[C:8]([NH2:3])[CH:12]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(I)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole (12.2 g) in ethanol/water (2/1, 180 ml) were sequentially added hydroxylammonium chloride (46.6 g) and triethylamine (9.3 ml), and the mixture was stirred at 95° C. for 72 hours. This reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added a 8M aqueous solution of sodium hydroxide (80 ml), and then the mixture was extracted with ethyl acetate (50 ml). This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give the titled compound (9.1 g).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(OCC)(=O)C>[CH2:24]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in THF (2 mL) was added benzyl bromide (0.036 mL) at 50° C., and the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:16]1([CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:26][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccccc3)CC2)CC1

Procedure:
A mixture of 3.081 g (11.075 mM) of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate, 1.96 g (12.2 mM) of 4-phenylpiperidine, and 3.06 g (22.2 mM) of potassium carbonate was stirred in 20 ml of N,N-dimethylformamide at 110° C. for 4 hours. This reaction mixture was poured in water and extracted with 2 portions of diethyl ether. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:3]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.38 g, 24.45 mmol) was dissolved in dry DMF (50 mL) under nitrogen and treated with 3-aminopropan-1-ol (5.51 g, 73.4 mmol) at RT. The mixture was stirred at room temperature for 3 h. TLC indicated no starting material remaining. The mixture was diluted with ethyl acetate and washed with water several times, then with brine once. It was dried (MgSO4), then filtered and evaporated to give a yellow oil which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([OH:28])=O)=[O:22])=[N:15]1.[NH3:36]>C(Cl)Cl.CN(C=O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([NH2:36])=[O:28])=[O:22])=[N:15]1
Reactant: COc1cc(C(=O)N[C@@H](CC(=O)O)c2ccccc2C)nn1-c1ccccc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@@H](CC(N)=O)c2ccccc2C)nn1-c1ccccc1F
Reaction time: 16 h
Yield: 34 %

Procedure:
DMF (1.8 mg, 25 μmol) and oxalyl chloride (160 mg, 1.26 mmol) were added to a solution of (S)-3-{[1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid (500 mg, 1.26 mmol) in DCM (5 ml) at room temperature. After 16 h at room temperature a 33% aqueous solution of ammonia (649 mg, 12.6 mmol) was added and the mixture was stirred for further 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 170 mg (34%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1.O>C1C=CC=CC=1>[C:2]([C:3](=[CH:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1

Procedure:
652 mg (3.00 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.340 ml (3.00 mmol) of 3-chlorobenzaldehyde and 0.030 ml (0.30 mmol) of piperidine were heated under reflux in 25 ml of benzene overnight while water was removed. Benzene was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15])([CH:10]([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.[Cl-].[Li+].O.C(OCC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([CH:10]([CH3:11])[CH3:12])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)C(C)(c1ccc(Cl)cc1)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)CC(C)(c1ccc(Cl)cc1)C(C)C

Procedure:
3.38 g (10.81 mmol) of dimethyl [2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate, 0.92 g (21.61 mmol) of lithium chloride and 0.2 ml of water in 10 ml of DMSO were heated under reflux for 4 h. After cooling, about 50 ml of diethyl ether were added to the reaction solution, and the phases were separated. The organic phase was washed twice with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.3 g (84% of theory) of the target compound.