Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH2:6][CH2:5][C:4]1=2.C=O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:7]123[CH2:4][CH2:5][C:6]1=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:3][CH2:2][O:1][CH2:18]3
Reactant: OCC1CCCCCCCCC2=C1CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C1CCCCOCC23CCC2=C3CCCC1

Procedure:
A mixture of the alcohol obtained as indicated above (1 g), 0.2 g of paraformaldehyde, 0.1 g of p-toluenesulphonic acid and 10 ml of acetic acid in the presence of a few drops of acetic anhydride was heated for 41/2 hour at 95° while stirring. The usual treatments of extraction, separation, drying, and evaporation gave 0.7 g of a product which was distilled on a bulb apparatus. The purity of the thus obtained compound was of about 95 % as shown by gas chromatographic analysis. This compound was in all respects identical to that prepared in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:46]=1[CH2:47]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@H:9]1[CH2:33][N:34]([CH2:47][C:46]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:45]=1[F:44])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CNCc1cc(F)ccc1F
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN(Cc1cc(F)ccc1F)Cc1cc(F)ccc1F

Procedure:
Analogously, (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated with 2,5-difluoro-benzylbromide to give (2S,4R)-2-{[bis-(2,5-difluoro-benzyl)-amino]-methyl}-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester which was treated with TFA according to general method B (variation 0° C. to RT) to give (2S,4R)-bis-(2,5-difluoro-benzyl)-(4-tritylsulfanyl-pyrrolidin-2-ylmethyl)-amine yellow oil, MS: 627 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C(C)=CC=CC=1C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:18][CH2:17][C@@H:10]2[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]4[S:21][C:22]([C:25]5[O:26][CH:27]=[CH:28][CH:29]=5)=[CH:23][N:24]=4)[CH:4]=3)[O:9]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Yield: 76.3 %

Procedure:
The solution of alcohol 89 (1.0 g, 2.28 mmol) and p-toluenesulfonyl chloride (2.3 g, 11.8 mmol) in 2,6-lutidine (22.8 mL) was stirred at room temperature for 15 h. H2O (150 mL) was added to the reaction mixture and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided desired toluenesulfonate 90 (1.03 g, 78%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (120 mg, 0.264 mmol) and pyridine (41 mg, 0.528 mmol) in anhydrous CH2Cl2 (5 mL) was dropwise added acetic anhydride (30 mg, 0.291 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. under nitrogen. The above mixture was allowed to stir for overnight at ambient temperature. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over Na2SO4 and concentrate to give the crude product, which was purified by preparative TLC to give N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (60 mg, 46%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:13]3[CH2:12][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([C:2]([F:4])([F:1])[CH3:3])=[CH:10][CH:9]=4)[CH2:16][N:15]([C:17]([N:19]4[CH2:20][CH2:21][S:22][CH2:23][CH2:24]4)=[O:18])[CH2:14]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: NC(=NO)C1CC1
Reactant: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 150 mg (0.376 mmol) of the compound from Example 53A and 41.5 mg (0.414 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 77.9 mg (44% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[CH:20]=[C:19]([NH2:21])[C:18]([F:22])=[CH:17][C:16]=3[F:23])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([F:23])=[CH:17][C:18]([F:22])=[C:19]([NH:21][C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of 7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (500 mg, 1.58 mmol) and TEA (638 mg, 6.32 mmol) in DCM (5 mL) was treated drop-wise with phenyl isocyanate (503 mg, 4.8 mmol) and stirred at RT overnight. The mixture was concentrated to dryness and purified by silica gel chromatography (EtOAc/pet ether) to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (500 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.13 (m, 1H), 7.83 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.39-7.34 (m, 1H), 7.29-7.25 (m, 2H), 6.99-6.95 (m, 1H), 6.58 (s, 2H), 6.34 (s, 1H), 4.13-4.08 (q, J=0.8 Hz, 2H), 1.22 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:30]=[C:31]=[O:32])[CH:28]=[CH2:29]>N1C=CC=CC=1>[CH2:27]([NH:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:32])[CH:28]=[CH2:29]
Reactant: C=CCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: C=CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 mL) and allyl isocyanate (0.025 mL, 0.28 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.1 (dd), 158.0, 157.9 (dd), 151.2, 141.0, 138.8, 136.6, 136.1, 135.0, 132.7, 132.2, 128.9, 127.5 (dd), 126.0 (dd), 122.6, 121.0, 116.6, 115.7, 112.9, 112.7 (dd), 105.8 (dd), 43.2, 19.7
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:24][O:23][C:21]([CH2:20][CH2:19][C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:15]=[CH:14][C:13]=1[NH2:16])=[O:22]
Reactant: [H][H]
Reactant: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 116.1 %

Procedure:
A solution of methyl 3-(3-tert-butoxycarbonylaminomethyl-6-nitrophenyl)propionate (3.2 g, 9.5 mmol) in ethyl acetate (35 mL) in the presence of 10% Pd/C was hydrogenated under atmospheric pressure of hydrogen at room temperature. The catalyst was removed by filtration by using celite and the filtrate was concentrated to give 3.4 g of the title compound.
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH:28]4[CH:26]([CH:27]4[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:51][CH2:52]Cl>C(#N)C>[N:1]1([C@:2]23[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:35])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH2:29][CH:28]5[CH:26]([CH:27]5[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCCl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 130 °C

Procedure:
To a flame dried 75 mL thick-walled resealable vessel was placed ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (0.453 g, 0.809 mmol) and flame dried potassium phosphate (0.859 g, 4.05 mmol), followed by 1,2-dichloroethane (24 mL) and acetonitrile (12 mL). The reaction mixture was flushed with nitrogen, sealed, and warmed to 130° C. for 36 hours. The crude reaction mixture was cooled to room temperature and filtered through a short bed of silica gel, washed with ethyl acetate to obtain a very pale orange solution, it was evaporated to dryness. White solid was obtained (0.3 g, 0.512 mmole, 63.3%), and used as it is. MS: m/e 586.55 (M+H)+, 2.791 min.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[C:7]([O:11][C:12](=[O:15])[CH2:13][NH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:7]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:3](=[O:4])[CH2:2][Br:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CBr

Procedure:
77.8 g (385.5 mmol) of bromoacetic acid bromide is added in drops at 0° C. to 50 g (296.5 mmol) of glycine-tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ether/n-hexane.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]OC=C)[CH:2]1[O:4][CH2:3]1.[OH2:13]>>[CH2:1]([O:5][CH:6]([OH:13])[CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: O
Reactant: C=COCCCCOCC1CO1
Product: CCCC(O)OCC1CO1
Reaction time: 1 h
Yield: 99 %

Procedure:
5.0 g of paratoluenesulfonic acid and 140 g of pure water were charged in a 1 L four-necked separable flask, and a vacuum pump equipped with a stirrer, a thermometer, an air introduction tube and a cooling trap was installed. Under stirring, 500 g of the vinyloxybutyl glycidyl ether synthesized above was slowly added to the flask while the liquid temperature was adjusted so as to be kept at 40° C. After the addition was completed, the pressure was reduced to 20 kPa, and stirring was continued for 1 hour while dry air was introduced at 100 ml/min. The reaction solution was then analyzed by gas chromatography, and no peak of the vinyloxybutyl glycidyl ether was observed. However, since 5.2% of an acetal dimer was generated according to an analysis by liquid chromatography, 26 g of a 0.04% aqueous solution of paratoluenesulfonic acid was added, and an acetal decomposition reaction was conducted at a pressure of 5 kPa while the temperature was kept at 40° C. When the reactant was analyzed 1 hour after the reaction, the peak of the acetal dimer had almost disappeared, and thus the reaction was quenched. 2.1 g of sodium hydrogen carbonate was put into the solution in which the reaction had been completed to thereby neutralize the solution, and the water in the system was distilled off by concentration with a rotary evaporator, the water content in the system was confirmed to be 800 ppm or less, and the concentrated liquid was filtered to give the objective butanediol monoglycidyl ether with a purity of 92% and a yield of 99%. At this time, the butanediol contained in the obtained substance was 0.2%, and no acetal dimer was detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Yield: 59.5 %

Procedure:
A solution of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.0 g.) in ethanol (70 ml.) containing potassium hydroxide (7.0 g.) was heated under reflux for 30 minutes. The solution was then poured into water (250 ml.) and the aqueous solution was extracted with ether (2×150 ml.). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The solid which was thus precipitated was separated, washed with water, dried in vacuo and then recrystallised from a 6:2:3 v/v/v mixture of toluene, propan-2-ol and petrol (60-80) to give 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (3.9 g.), m.p. 186° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](Cl)=[O:14].[OH-].[NH4+:17]>>[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:14])[NH2:17]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1oc(-c2ccccc2)nc1C(N)=O
Reaction time: 8 h

Procedure:
9.4 Grams (0.0425 mole) of 5-methyl-2-phenyl-4-oxazolecarboxylic acid chloride is added in small portions to 200 ml. (3.33 mole) of concentrated ammonium hydroxide. The mixture is vigorously stirred and the temperature is maintained at about 0° during the addition step. After the addition, the temperature is allowed to rise to room temperature and the mixture is left standing overnight. The solid which forms is collected by filtration, washed with water, dried and recrystallized from methanol. 6.35 Grams of the title product is obtained; m.p. 154°-157° (from methanol).
Reaction SMILES: C[O-].[Na+].[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][C:26](=O)[CH3:27])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCC[CH2:33][OH:34].O>CO>[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][CH2:26][CH2:27][CH2:33][OH:34])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: OCCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CSCCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
5 ml of a methanolic solution containing 0.26 g of a 28% w/v sodium methoxide solution were added, whilst ice-cooling, to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(acetylthio)acetamide [prepared as described in step (b) above] in 5 ml of methanol, and the resulting solution was stirred for 20 minutes. At the end of this time, a solution of 0.11 ml of 3-chloro-1-propanol in 5 ml of methanol, was added, and the reaction mixture was heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.42 g (yield 81%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([N:4]2[CH2:8][CH2:7][NH:6][S:5]2(=[O:10])=[O:9])[CH2:3][CH2:2]1.F[C:12]1[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CN(C=O)C>[CH:1]1([N:4]2[S:5](=[O:10])(=[O:9])[N:6]([C:12]3[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=3)[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: O=S1(=O)NCCN1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CCN(C3CC3)S2(=O)=O)cc1C
Yield: 47.3 %

Procedure:
203 mg of 2-cyclopropyl-[1,2,5]thiadiazolidine 1,1-dioxide, 308 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 2.44 g of Cs2CO3 were stirred in 25 ml of anhydrous DMF at 80° C. for 5 hours. Standing at RT for 2 days was followed by dilution with 200 ml of EA and washing 3 times with 20 ml of water each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded 230 mg of an amorphous solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccccn1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: c1ccc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)nc1
Yield: 31 %

Procedure:
The title compound (25 mg, 31%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 2-bromopyridine similarly to the procedure used for example 152. 1H NMR (400 MHz, CDCl3) δ 1.68-1.72 (m, 2H), 1.84-1.94 (m, 6H), 2.00-2.16 (m, 8H), 2.63-2.67 (m, 2H), 2.74 (m, 1H), 3.49 (d, 2H), 3.56-3.62 (m, 2H), 3.80-3.85 (m, 2H), 4.02 (m, 1H), 4.31 (m, 1H), 6.22 (d, 1H), 6.51 (t, 1H), 6.91 (d, 2H), 7.24 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). HRMS ESI+ m/z 422.2792 [MH]+.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)N1CCN(c2ccccc2)CC1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 1-phenylpiperazine to give Compound 21 (0.21 g, 51%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][CH2:9][CH:10]([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[C:20]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:20]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:11](=[O:13])[CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(CSCC(C(=O)O)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CSCC(C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)C(F)(F)F)cc1

Procedure:
A solution of 3-(4-methoxybenzyl)thio-2-trifluoromethylpropanoic acid (6.5 g.) and proline tert-butyl ester (3.76 g.) in dichloromethane (500 ml.) is stirred at 0° and treated with dicyclohexylcarbodiimide (4.53 g.) After 30 minutes at 0° and overnight at room temperature, the mixture is filtered and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo. The TLC [silica gel methylene chloride/ethyl acetate (95:5)] shows two major spots Rf 0.46 and 0.51 corresponding to the two diastereoisomers.