Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][O:52][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 1 h
Yield: 60.2 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethylsilane 21 (2.4 g, 2.84 mmol) was dissolved in 20 mL methanol and stirred for 1 hour after addition of acetyl chloride (30 μL, 0.43 mmol). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-meth oxy-tetrahydropyran-2-yl]methanol 2j (1.25 g, yellow solid), with yield: 60.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[F:27])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.C[Si](C)(C)[C:35]#[C:36][C:37]1([CH3:41])[CH2:40][O:39][CH2:38]1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:27][C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:12]1[CH:13]=[C:14]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]#[C:36][C:37]4([CH3:41])[CH2:40][O:39][CH2:38]4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cnccc3F)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C#Cc2cnc3c(c2)[C@]2(CSC(N)=N2)c2cc(-c4cnccc4F)ccc2O3)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A vial was charged with (S)-3-bromo-7-(4-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (120 mg, 0.27 mmol), copper(I) iodide (20.62 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (31.3 mg, 0.027 mmol). The vial was flushed with Ar (g), then DMF (1 mL), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (137 mg, 0.81 mmol), DIPA (574 μL, 4.06 mmol) were added in sequence. The vial was flushed with Ar (g), sealed, and placed in a 90° C. oil bath. The mixture was stirred overnight. After cooling to rt, the crude was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-80% EtOAc in 90:10 CH2Cl2:CH3OH to provide a white solid, (S)-7-(4-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (35 mg, 0.076 mmol, 28% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1([C:13]#[N:14])[CH2:11][CH2:10][CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2].[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C.[Pt]=O>[C:1]([NH:4][C:5]1([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:11][CH2:10][CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(C#N)CCC2CCC1C2
Reactant: CC(=O)O
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1(NC(C)=O)CCC2CCC1C2

Procedure:
The procedure is as in Example 1, but starting from 2-acetylamino-2-cyano-bicyclo[3.2.1]octane (9 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in acetic acid (140 cc) and acetic anhydride (8.8 cc), in the presence of Adams platinum oxide (0.9 g); by chromatographing the residue from the evaporation on a column 5.5 cm in diameter containing silica gel (250 g), eluting with a mixture of ethyl acetate and ethanol (75/25 by volume) and collecting fractions of 100 cc. The fractions between 1400 and 3100 cc are concentrated to dryness. 2-Acetylamino-2-acetylaminomethyl-bicyclo[3.2.1]octane (9.75 g) is thus obtained in the form of fine white crystals which melt at 92°-3° C.
Reaction SMILES: [NH2:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:21][N:20]3[C:22]4[CH:23]=[C:24]([C:35](O)=[O:36])[CH:25]=[CH:26][C:27]=4[C:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:19]3[C:18]3[CH:38]=[CH:39][CH:40]=[CH:41][C:17]=3[O:16][CH2:15]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:29]1([C:28]2[C:27]3[CH:26]=[CH:25][C:24]4=[CH:23][C:22]=3[N:20]3[CH2:21][CH:14]([CH2:15][O:16][C:17]5[C:18]([C:19]=23)=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:13][CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[S:2](=[O:3])(=[O:4])[NH:1][C:35]4=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NS(=O)(=O)N1CCN(CCCC2COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)O)cc4n3C2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1NS(=O)(=O)N2CCN(CCCC3COc4ccccc4-c4c(C5CCCCC5)c5ccc1cc5n4C3)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 7-{3-[4-(aminosulfonyl)piperazin-1-yl]propyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.04 M) in DCM were added EDC (1.5 eq) and DMAP (3 eq). The mixture was stirred at 50° C. for 2 h before cooling to RT and evaporating all volatiles in vacuo. The residue was purified by RP-HPLC (Waters Sunfire column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (19%). 1H NMR (400 MHz, DMSO-d6+TFA, 335 K) 1.16-1.23 (m, 2H), 1.31-1.39 (m, 2H), 1.47-1.50 (m, 1H), 1.69-1.73 (m, 2H), 1.83-2.19 (m, 7H), 2.64-2.66 (m, 1H), 3.29-3.36 (m, 4H), 3.49-3.74 (m, 7H), 3.89-3.93 (m, 2H), 4.28-4.39 (m, 1H), 4.40-4.44 (m, 1H), 7.28-7.32 (m, 2H), 7.35-7.37 (m, 1H), 7.45-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.90-7.92 (m, 2H); (ES+) m/z 563 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=[O:23])[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:25]NO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:25][N:22]([OH:23])[C:15]1[CH:14]=[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20]
Reactant: CNO
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(O)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1,2-dinitrobenzene (2.50 g, 6.88 mmol), N-methylhydroxyamine (1.15 g), K2CO3 (1.14 g, 8.26 mmol) and THF (20 ml) is stirred at RT for 48 hours. The reaction mixture is filtered and the filtrate is concentrated. The resulting residue is taken up in CH2Cl2, washed, dried and evaporated to give N-methyl-N-[2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-hydroxyamine (IXB; R is H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1([CH3:22])[O:21][CH:18]([CH:19]=[CH2:20])[CH:12]([CH:13]([OH:17])[CH2:14][C:15]#[N:16])[O:11]1.N1C=CN=C1.C(Cl)Cl>C(OCC)C>[CH3:9][C:10]1([CH3:22])[O:21][CH:18]([CH:19]=[CH2:20])[CH:12]([CH:13]([O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][C:15]#[N:16])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC1OC(C)(C)OC1C(O)CC#N
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC1OC(C)(C)OC1C(CC#N)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
Two grams of tert-butyldimethylsilyl chloride were gradually added at 0° C. to a solution comprising 2.11 g of 4,5-(dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile, 2.0 g of imidazole and 50 ml of methylene chloride. After stirring was conducted at room temperature for 16 hours, the reaction mixture was diluted with 300 ml of diethyl ether, and washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 2.63 g of 4,5-(dimethylmethylenedioxy)-3-(tert-butyldimethylsilyloxy)6-heptenenitrile having the following properties (yield 79%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([CH3:13])[C:3]1=[O:14].[C:15]([OH:25])(=[O:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].NC1C2C=CC=CC=2CCN(C)C1=O.C(OC(C)C)(=O)C>C(OC(C)C)(=O)C.C(O)(C)C.[N+](C1C=C(C=O)C(O)=CC=1)([O-])=O>[C:15]([OH:25])(=[O:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].[NH2:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([CH3:13])[C:3]1=[O:14]
Reactant: CN1CCc2ccccc2C(N)C1=O
Agent: O=C(O)[C@H](O)c1ccccc1
Agent: O=Cc1cc([N+](=O)[O-])ccc1O
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Product: CN1CCc2ccccc2[C@H](N)C1=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
1-Amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (31.9 g, 168 mmol) was slurried in about 300 mL isopropyl acetate and heated to 45° C. In a separate flask, (R)-(−)-D-mandelic acid (25.0 g, 164 mmol) was heated in about 130 mL of isopropyl alcohol until a solution formed and was added to the 1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one/isopropyl acetate slurry obtained above to give a solution from which a precipitate quickly formed. The mixture was stirred at 45° C. for about 3 hours. 5-Nitrosalicylaldehyde (2-hydroxy-5-nitrobenzaldehyde) (1.40 g, 8.38 mmol, 5 mol %) was added to the warm solution and the mixture was stirred at 45° C. After about 14 hours, the slurry was cooled to ambient temperature and stirred for 2 hours before the solids were collected by filtration and rinsed with 70 mL of cold isopropyl acetate, and dried in the vacuum oven at 40° C. to obtain 46.62 g of (S)-1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (R)-mandelic acid salt (82.9% yield, 98.4% ee).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:14]1[CH2:18][CH2:17][C@@:16]([C:22]([N:24]2[CH2:29][C@@H:28]3[C@H:30](O)[C@H:25]2[CH2:26][N:27]3[C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)=[O:23])([CH:19]([CH3:21])[CH3:20])[CH2:15]1)[C@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[O:12][CH3:13])=O.CCN(S(F)(F)[F:50])CC>C(Cl)Cl>[F:50][CH:30]1[C@@H:28]2[N:27]([C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][N:33]=3)[CH2:26][C@H:25]1[N:24]([C:22]([C@@:16]1([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18][C@@H:14]([NH:5][C@H:6]3[CH2:11][CH2:10][O:9][CH2:8][C@H:7]3[O:12][CH3:13])[CH2:15]1)=[O:23])[CH2:29]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3[C@H](O)[C@H]2CN3c2cc(C(F)(F)F)ccn2)(C(C)C)C1
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C(F)[C@H]2CN3c2cc(C(F)(F)F)ccn2)(C(C)C)C1
Reaction time: 8 h
Yield: 53.1 %

Procedure:
2,2,2-trifluoro-N-((1R,3S)-3-((1R,4R,7S)-7-hydroxyl-2-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-5-carbonyl)-3-isopropylcyclopentyl)-N-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-yl)acetamide (30 mg, 0.057 mmol) in CH2Cl2 (2 ml) was cooled to 0° C. and DAST (0.025 ml, 0.086 mmol) was added to the solution. The reaction mixture was stirred overnight and purified by chromatography (10% EtOAc to 100% MeOH) to yield desired product (16 mg, 32%). LC/MS (M+H)=529.2802 exp, 529.3112 obs; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67-0.78 (m, 5H) 0.82 (d, J=6.59 Hz, 3H) 1.23 (br. s., 1H) 1.50 (d, J=3.66 Hz, 3H) 1.75 (d, J=4.39 Hz, 2H) 1.94-2.03 (m, 1H) 2.24-2.32 (m, 1H) 2.98 (s, 1H) 3.12 (br. s., 1H) 3.18-3.23 (m, 4H) 3.31-3.34 (m, 1H) 3.40 (d, J=10.98 Hz, 1H) 3.62 (d, J=12.08 Hz, 1H) 3.72 (d, J=10.62 Hz, 3H) 3.80-3.92 (m, 1H) 4.87 (br. s., 1H) 4.90-4.96 (m, 1H) 5.31 (d, J=1.83 Hz, 1H) 5.40-5.46 (m, 1H) 6.86-6.94 (m, 2H) 8.31 (d, J=5.49 Hz, 1H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7]>CN(C)C=O.O>[N:1]([CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(C)N=[N+]=[N-])nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 52.2 %

Procedure:
To a solution of sodium azide (20.16 mg, 0.310 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL) was added 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (100 mg, 0.207 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL). The reaction was heated to 65° C. for 2 hr, and then the solution was cooled to room temperature. The reaction contents were diluted with water, producing a precipitate. The suspension was filtered using a fritted funnel, providing 5-(1-azidoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (48 mg, 0.108 mmol, 52.1% yield) as a crude brown solid that was used directly in the next reaction. LC/MS m/z MH+=446 (theoretical), found=446.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67 (d, J=6.82 Hz, 4H) 2.47 (s, 3H) 3.48-3.66 (m, 5H) 3.68-3.87 (m, 5H) 3.97 (q, J=6.57 Hz, 1H) 5.42 (d, J=17.18 Hz, 1H) 5.76 (d, J=17.18 Hz, 1H) 6.41 (d, J=7.58 Hz, 1H) 7.07 (t, J=7.83 Hz, 1H) 7.35 (d, J=8.08 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[K+]>O.C(O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:3]=2)[OH:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(O)c2cccc(O)c2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(O)c2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A mixture of 3.7 g (0.016 mol) 1-(3-hydroxyphenyl)-1-(4-methoxyphenyl)methanol, 3.4 g (0.016 mol) 2-chloromethylquinoline hydrochloride and 2 g (0.036 mol) KOH in 5 ml water and 50 ml ethanol was heated over steam bath for a period of 4 hours. Reaction mixture was concentrated to dryness and slurried into water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure to obtain oily material. Repeated recrystallization from ethyl acetate, acetonitrite and isopropanol gave desired produce 1.1 g. m.p. 70°-80° C.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][C:24]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:24](=[O:25])[CH2:23][C:13]45[CH2:22][CH:17]6[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]6)[CH2:20]4)[CH2:14]5)[CH2:11][CH2:12][O:1][CH2:2][CH2:3]3)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: C1COCCNCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCN(C(=O)CC23CC4CC(CC(C4)C2)C3)CCOCC1

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and (1-adamantyl ) acetyl chloride.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O>[C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:29])=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12
Reactant: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phthalimido-3(4-propoxyphenyl)propionic acid (1.41 g, 4.0 mmol) in 25 mL of under nitrogen was added carbonyldiimidazole (0.68 g, 4.2 mmol) followed by a catalytic amount of dimethylaminopyridine. The mixture was stirred for 45 minutes at room temperature. To the reaction mixture was then added concentrated ammonium hydroxide (0.29 mL, 4.4 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then diluted with 10 mL of water and the tetrahydrofuran was removed in vacuo. The resulting slurry was filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 1.2 g of crude product. The crude product was purified by dissolving in 200 mL of ethyl acetate, stirring for 3 h and then concentrating to an 80 mL volume. The resulting slurry was filtered and the solid was washed with ethyl acetate (2×20 mL). The solid was air-dried to afford 0.513 g (36%) of 3-phthalimido-3-(4-propoxyphenyl)propionamide as a white powder: mp 109.5°-110.4° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.85 (br s, 4 H), 7.55 (br s, 1 H), 7.33 (d, 2 H, J=8 Hz), 6.75-7.00 (m, 3 H), 5.69 (t, 1 H, J=8 Hz), 3.88 (t, 2 H, J=6 Hz), 3.10-3.30 (m, 2 H), 1.60-1.80 (m, 2 H), 0.95 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 171.2, 167.7, 158.0, 134.5, 131.23, 131.19, 128.4, 123.1, 114.3, 68.9, 49.9, 36.9, 22.0, 20.4, 10.4; Anal. Calcd. for C20N2O4 0.37 H2O. Theoretical: C, 66.90; H, 5.61; N, 7.80. Found: C, 66.90; H, 5.52; N, 7.75.
Reaction SMILES: NC(=O)[C@@H](N1C(=O)CC(C(OC)=O)C1)C.[NH2:16][C:17]([C@@H:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]1)[CH2:20][CH2:21]C)=[O:18].CNC([C@@H](N1C(=O)CC(C(OC)=O)C1)CC)=O>>[NH2:16][C:17]([C@@H:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]1)[CH2:20][CH3:21])=[O:18]
Reactant: CCC[C@@H](C(N)=O)N1CC(C(=O)OC)CC1=O
Agent: CC[C@@H](C(=O)NC)N1CC(C(=O)OC)CC1=O
Agent: COC(=O)C1CC(=O)N([C@@H](C)C(N)=O)C1
Product: CC[C@@H](C(N)=O)N1CC(C(=O)OC)CC1=O

Procedure:
Alternatively, methyl 1-[(1S)-2-amino-1-methyl-2-oxoethyl]-5-oxo-3-pyrrolidinecarboxylate, methyl 1-[(1S)-1-(aminocarbonyl)butyl]-5-oxo-3-pyrrolidinecarboxylate, methyl 1-{(1S)-1-[(methylamino)carbonyl]propyl}-5-oxo-3-pyrrolidinecarboxylate, are prepared in similar ways.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])[OH:30]>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([O-:33])(=[O:32])[CH:29]([CH3:31])[OH:30]
Reactant: CC(O)C(=O)O
Agent: CN1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Product: CC(O)C(=O)[O-]

Procedure:
The pH value of the emulsion is 4.5, the molar ratio azelastine : lactic acid is 1:1.1.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH3:13])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nc2ccccc2c(=O)n1N
Solvent: ClCCCl
Product: Cc1nc2ccccc2c(=O)n1NC(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 3-amino-2-methyl-4-quinazolone (1.60 g, 9.10 mmol) and 4-chlorophenyl isocyanate (1.54 g, 10.0 mmol) in 1,2-dichloroethane is heated at reflux for 22 hours, concentrated in vacuo, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 2.45 g (82%), mp 228°-229.5° C.
Reaction SMILES: C1(C)C=CC(S(NC(CC)CO[S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.Br.Br.Br.[CH2:30]([CH:32]1[CH2:40][NH:39][CH2:38][CH:37]([CH2:41][CH3:42])NCCN1)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([CH2:42][CH2:41][CH2:37][CH2:38][NH:39][CH2:40][CH2:32][CH2:30][CH3:31])(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CCC(COS(=O)(=O)c1ccc(C)cc1)NS(=O)(=O)c1ccc(C)cc1
Reactant: CCC1CNCC(CC)NCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNCCCCS(=O)(=O)c1ccc(C)cc1

Procedure:
1.1.7 2,6-Diethyl-1,4,7-triazacyclononane trihydrobromide 2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy) butane (1.1.8) and ammonium hydroxide were reacted to form 2-(p-toluenesulfonamino)-1-aminobutane (1.1.9). This was reacted with 2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy)butane (1.1.8) and potassium carbonate. The 3,7 bis(p-toluenesulfonylamino)-5-azanonane (1.1.10) product was purified by chromatography and reacted with p-toluenesulfonyl chloride to obtain the corresponding tri-p-toluenesulfonyl compound 3,7 bis(p-toluenesulfonylamino)-5-(p-toluenesulfonyl-5-azanonane (1.1.11). This was purified by chromatography and reacted with 2.2 equivalents of sodium amide in DMF and then with 1,2-di(p-toluenesulfonyloxy)ethane (1.1.1 2). The 2,6-diethyl-1,4,7-tris(p-toluenesulfonyl) triazacyclononane (1.1.13) that was obtained following purification was heated in a solution of HBr in acetic acid to remove the p-toluenesulfonyl groups and form the titled compound (1.1.7)
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was added portionwise to the stirred cooled (4° C.) mixture. After 30 minutes, benzyl bromide (9.2 ml) was added dropwise and, after a further 1 hour at 4° C., stirring was continued overnight at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic extracts washed with water and brine, then dried (MgSO4) and evaporated. The crystalline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as off-white crystals: m.p. 70°-72° C.; NMR (CDCl3) δ 7.32(5H, m), 7.14(2H, d), 6.76(2H, d), 5.12(2H, s), 3.59(2H, s); m/e 242 (M°)+.