Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14](=O)[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[NH2:24][OH:25]>CO>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14](=[N:24][OH:25])[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)C=Cc1ccc2c(c1)OCCCO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(C=Cc1ccc2c(c1)OCCCO2)=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
145 mg 1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methyl-1-penten-3-one was dissolved in methanol (20 ml), along with hydroxylamine hydrocholoride (244 mg) and sodium acetate (480 mg) and stirred in room temperature overnight. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (30 ml). After washing with 30 mL water and 30 mL Brine and drying with anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure to yield crude product (M+1=262.1), that was used for next reaction.
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]#[C:12]/[C:13](/[CH3:35])=[CH:14]\[CH2:15][P+:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37].O.[H][H]>CO>[Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7](/[CH:11]=[CH:12]\[C:13](\[CH3:35])=[CH:14]/[CH2:15][P+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37]
Reactant: [H][H]
Reactant: COc1cc(C)c(C#C/C(C)=C\C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Br-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(/C=C\C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Yield: 89 %

Procedure:
In a manner analogous to Example 2, a solution of 3.42 g of (Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium bromide in 240 ml of methanol was hydrogenated in the presence of 1.8 g of water-moist Raney-nickel. 188 ml of hydrogen were taken up within 28 hours. The crude product (3.4 g), which contained 89.4% of (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide (yield 89%), obtained after filtration and evaporation was dissolved in 20 ml of methylene chloride and crystallized by the dropwise addition of 50 ml of ethyl acetate while stirring. The suspension was left to stand at 0° C. overnight, filtered and the product, washed with a small amount of ethyl acetate/methylene chloride (volume ratio 5:1), was dried at 40°C./0.01 mbar. There were obtained 1.8 g of 99.6% (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide as white crystals of melting point 202°-204° C.; yield 52.5%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>ClCCCl>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C@:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)([C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[OH:23]
Reactant: OC(Cc1ccccc1Cl)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: O[C@@](Cc1ccccc1Cl)(c1cccc(F)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 1-(4-Benzyl-morpholine-2-yl)-2-(2-chloro-phenyl)-1-(3-fluoro-phenyl)-ethanol. (3.2 g, 1 equiv.) in dry 1,2-dichloroethane (40 mL) under nitrogen atmosphere was added ACE-Cl (20.33 g, 5 equiv.). The reaction mixture was stirred at room temperature overnight then refluxed until completion. All volatiles were evaporated under vacuum, and the resulting residue redissolved in acetonitrile. This solution was filtered through an ion exchange column and the filtrate taken-up with methanol (50 mL) and refluxed for 3 h. The solution was again filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was next purified via preparative HPLC followed by chiral HPLC. The purified active enantiomer was taken up in ethanol and hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture stirred. Then all the volatiles were evaporated in vacuo, to give 519 mg of the title compound as a white solid (18%). 1H NMR (300 MHz, DMSO D6) δ: 2.43-2.54 (m, 1H), 2.81-2.95 (m, 2H), 3.16-3.23 (m, 1H), 3.30-3.44 (m, 2H), 3.54 (bs, 1H), 3.92-4.00 (m, 1H), 4.15-4.23 (m, 2H), 6.96-7.29 (m, 8H), 9.32-9.45 (m, 2H). LCMS (12 minute method) [M+H]+=336.
Reaction SMILES: O(CC[Br:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=CC=CC=1.C1(O)C=CC=CC=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O>[Br-:10].[N:37]1([CH2:16][CH2:11][P+:17]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCNC1
Reactant: BrCCOc1ccccc1
Solvent: Oc1ccccc1
Solvent: CS(C)=O
Product: [Br-]
Product: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 110.5 °C
Reaction time: 24 h

Procedure:
A mixture of 2-phenoxyethyl bromide (90.6 g, 0.45 mol), triphenylphosphine (119.2 g, 0.45 mol), and phenol (854 g) was heated to a melt and then stirred over a hot oil bath (107-114° C.) for ˜24 h. The reaction mixture was extracted with 6:1 heptane/EtOAc (3×2 L), 9:1 heptane/EtOAc (3×0.5 L), and heptane (300 mL) to give an oil that solidified. After dissolving the reaction mixture in DMSO, the mixture was warmed, treated with pyrrolidine (150 mL), and stirred over a hot oil bath (50-55° C.) for 1.5 h. The reaction mixture was cooled to room temperature, seeded for crystallization, and treated slowly and intermittently with increasing amounts of t-butyl methyl ether (TBME) until it was evident that crystallization was complete. The solid was filtered, washed with TBME and then with heptane, and vacuum dried to give 90.27 g of the desired product. The structure was confirmed by 1H NMR.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:48][C:49]1[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=1.[NH:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl>[F:48][C:49]1[CH:54]=[CH:53][C:52]([O:27][CH2:26][C:22]2[CH:21]=[C:20]3[C:25]([C:16]([N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:17][C:18]([CH3:28])=[N:19]3)=[CH:24][CH:23]=2)=[CH:51][CH:50]=1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: Oc1ccc(F)cc1
Reactant: C1CCNC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2ccc(COc3ccc(F)cc3)cc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.9 %

Procedure:
Diisopropylazodicarboxylate (97 mg, 0.48 mmol) was added dropwise at r.t. to a solution of (4-chloro-2-methyl-quinolin-7-yl)-methanol (example 2c, 100 mg, 0.48 mmol), triphenylphosphine (126 mg, 0.48 mmol), and 4-fluorophenol (54 mg, 0.54 mmol) in dichloromethane (2.5 mL). After shaking 24 h at r.t., the solvent was evaporated, and the residue was taken up in pyrrolidine (1.37 g, 19.2 mmol) and shaken for 23 h at 80° C. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (66 mg, 41%). Off-white solid, ISP-MS: m/e=337. ([M+H]+).
Reaction SMILES: C([Cl:4])(=O)C.C(O[C:10](=O)[N:11]([C@H:13]([C:15](=[O:55])[NH:16][C@H:17]1[C@H:23]([CH3:24])[N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)[C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[N:19]([CH2:40][C:41]2[C:50]3[C:45](=[C:46]([Br:51])[CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][C:42]=2[O:52][CH3:53])[C:18]1=[O:54])[CH3:14])C)(C)(C)C>CO>[ClH:4].[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([N:22]2[C@@H:23]([CH3:24])[C@H:17]([NH:16][C:15](=[O:55])[C@@H:13]([NH:11][CH3:10])[CH3:14])[C:18](=[O:54])[N:19]([CH2:40][C:41]3[C:50]4[C:45](=[C:46]([Br:51])[CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][C:42]=3[O:52][CH3:53])[C:20]3[CH:39]=[CH:38][CH:37]=[CH:36][C:21]2=3)=[O:35])=[CH:31][CH:30]=1)(=[O:34])[CH3:33]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)c2ccc(C(C)=O)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccccc2N(C(=O)c2ccc(C(C)=O)cc2)[C@H]1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
Acetyl chloride (0.5 ml, 7.03 mmol) was added dropwise to a solution of {(S)-1-[(2S,3S)-1-(4-acetyl-benzoyl)-5-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (40 mg, 0.52 mmol) in methanol at 0° C. and the reaction was allowed to warm to ambient temperature and stir for 2 h. The reaction was concentrated in vacuo and the residue was triturated with diethyl ether, filtered and dried to give (S)-N-[(2S,3S)-1-(4-acetyl-benzoyl)-5-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride (30 mg, 82%). LR-MS [M+H+]672, 673
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]2[N:27]=[C:26]([O:28][C@@H:29]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:21][C:22]2[N:27]=[C:26]([O:28][C@@H:29]3[CH2:33][CH2:32][NH:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(O[C@@H]3CCNC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 1 h

Procedure:
tert-Butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate (80 mg, 0.14 mmol) was taken up in dichloromethane (1 mL). The mixture was treated with trifluoroacetic acid (0.2 mL, 2.6 mmol) and left to stir for 1 hour. The reaction was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash (methanol/dichloromethane) to provide 4-{5-[3-methyl-5-({4-[(3R)-pyrrolidin-3-yloxy]-pyrimidin-2-yl}amino)phenyl]-1,3-thiazol-2-yl}-1,4-diazepan-2-one. MS APCI: [M+H]+ m/z 466.1. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.22 (d, J=5.6, 1H), 7.63 (m, 2H), 7.49 (s, 1H), 7.38 (s, 1H), 6.96 (s, 1H), 6.25 (d, J=5.6, 1H), 5.56 (s, 1H), 4.16 (s, 2H), 4.10 (s, 1H), 3.80 (s, 2H), 3.44-3.05 (m, 5H), 2.27 (s, 3H), 2.21 (m, 1H), 2.06 (m, 1H), 1.77 (m, 2H). rhSyk=+++
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].C([O:9][CH:10](OCC)[CH2:11][NH2:12])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[CH2:43]([O:42][C:40](=[O:41])[N:12]([CH2:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:11][CH:10]=[O:9])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)C=O
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CN(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of pivaldehyde (1.00 mL, 0.00921 mol) in DCM (30 mL) was added 2,2-diethoxy-ethanamine, (1.35 mL, 0.00921 mol) followed by sodium triacetoxyborohydride (2.15 g, 0.0101 mol). The reaction mixture was stirred at room temperature for 1 h and then DIPEA (1.43 g, 0.0110) mol) was added. The reaction mixture was cooled to 0° C., and benzyl chloroformate (1.88 g, 0.0110 mol) was added dropwise. The reaction mixture was stirred for 1 h, concentrated, and 6 M TFA in water (20 mL) was added. The reaction mixture was stirred for 2 h and the TFA was removed under vacuum. The resulting aqueous solution was diluted with saturated NaCl (15 mL) The product was extracted with ethyl acetate (25 mL. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 10-20% ethyl acetate in hexanes to give an oil (2.2 g) which was further purified by flash column chromatography to give the title compound as a yellow oil (0.72 g).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.O1CCOCC1.C(N(CC)CC)C.[C:44](Cl)(Cl)=[O:45].[CH2:48]([CH2:50][NH2:51])[OH:49]>C1(C)C=CC=CC=1>[OH:49][CH2:48][CH2:50][NH:51][C:44]([NH:18][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=2)=[CH:20][CH:19]=1)=[O:45]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ccncn1)C2
Reactant: NCCO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CCN(c1ccncn1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0700 g, 0.000173 mol) in dry 1,4-Dioxane (1.50 mL, 0.0192 mol) was added Triethylamine (0.0266 mL, 0.000191 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.100 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added Ethanolamine (0.0628 mL, 0.00104 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.56 (s, 1H), 8.22 (dd, J=13.0, 7.3, 3H), 7.49 (d, J=8.8, 2H), 6.96 (d, J=5.4, 1H), 6.30 (t, J=5.6, 1H), 4.76 (d, J=18.6, 1H), 4.64 (d, J=18.3, 1H), 4.13 (d, J=6.9, 1H), 4.01 (d, J=12.8, 1H), 3.88 (d, J=11.5, 1H), 3.80-3.57 (m, 5H), 3.45 (m, 3H), 3.17 (m, 2H), 2.75 (s, 2H), 1.26 (d, J=6.7, 3H). LC/MS-m/z+491.2 (M+H)+
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].[ClH:46]>O>[ClH:46].[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)N1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added to 2-propanol (1.2 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.063 g), followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 6.5 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.025 g of 2-(2-hydroxy-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoic acid hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:38][C:39]([O:41][CH3:42])=[O:40]>ClCCCl>[ClH:38].[CH3:42][O:41][C:39](=[O:40])[NH:1][C@H:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][C:8]2([NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[C:9]2=[O:22])[CH2:23][CH2:24]1
Reactant: COC(=O)Cl
Reactant: N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 8-(3-(S)-amino-3-phenylpropyl)-3-(4-bromobenzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (60 μmol) in anhydrous DCE (1 mL) was added triethylamine (10 μL, 72 μmol) and a solution of methyl chloroformate (72 μmol) in anhydrous DCE. The reaction mixture was agitated overnight at room temperature and then concentrated in vacuo. The residue was purified by semi-preparative HPLC (Method D) and lyophilized to give Compound 82 as a colorless solid (14.1 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Solvent: CO
Solvent: COCCOC
Product: O=C(O)CCC(CC=Cc1cccc(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
Triton B (1.5 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4-phenyl-7-(m-chlorophenyl)-1,6-heptadien-3-one (22.8 g., 0.056 mole) in glyme (175 ml.), followed by addition of methyl acrylate (5.76 g., 0.067 mole) in glyme (25 ml.). After stirring for 20 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 48 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the sticky yellow solid which precipitates is collected and air-dried, yield 4.5 g., m.p. 65°-105°C. Recrystallization from benzene-petroleum ether (30°-60°C.) followed by several recrystallizations from n-butyl chloride gives material with m.p. 150°-151°C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH2:14])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl.O>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH2:3][CH2:2]1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of 2-cyclopropyl-4-fluoro-5-nitrobenzenamine (as described in WO2011068898) (1.98 g, 10.09 mmol, 1 equiv) in dichloromethane (50 mL) at room temperature, was added NaHCO3 (7.65 g, 90.84 mmol, 9 equiv), followed by 2-methylpropanoyl chloride (6.34 mL, 60.56 mmol, 6 equiv). The reaction mixture was stirred overnight. The reaction mixture was taken in water, and the layers were separated. The organic layer was washed with ice-cold 1N NaOH 2×, brine 1×, dried over Na2SO4, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with hex:EtOAc=100:0 to 50%-70% EtOAc using 10% EtOAc increments to afford N-(2-cyclopropyl-4-fluoro-5-nitrophenyl)isobutyramide (2.04 g, 84%) as a light-brown solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([N+:30]([O-])=O)=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2].C(OC([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:43](=[O:44])[CH2:42][CH2:41][NH2:40])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2]
Reactant: CC(C)Cn1cc(NC(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)cc1C(=O)NCCC(=N)N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCN)ccc3[nH]2)cc1C(=O)NCCC(=N)N

Procedure:
Compound 113 was reduced to its amine by hydrogenation according to the procedure for 36. The amine was then reacted with 3-tert-butoxycarbonylaminopropionic acid in the presence of HBTU, HOBt, and DIEA in dry DMF, followed by de-Boc protection according to the procedure for 109 to give 114 in quantitative yield. MS: 241.15 (M/2+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCC1CCCCN1Cc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CCCCN1Cc1ccccc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
(RS)-1-Benzyl-2-bromomethylpiperidine, D31 (4.2 g) was dissolved in dry dimethylsulphoxide (15 ml) and treated with sodium cyanide (5.0 g). The solution was then stirred at 85° C. under argon for 18 h. The reaction solution was then poured into water (300 ml) and extracted with dichloromethane (2×200 ml). The organic solution was dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, diethyl ether/petroleum ether mixtures) afforded the title compound (3.3 g).