Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH3:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (0.59 g, 1.79 mmol) in Et2O (25 mL) under Ar at −70° C., was added methyl lithium (1.4 M in Et2O; 1.88 mL, 2.63 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm to RT over 15 min and stirred at this temperature for 1 h. The mixture was cooled to 0° C. to which was slowly added H2O (25 mL) and the solution was extracted between Et2O (100 mL) and H2O (100 mL). The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo to afford the title compounds as a light yellow oil (0.58 g, 94%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.42-0.57 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 0.97-1.15 (m, 5H, —NHCH(CH2CH3)CH(CH3)OH+—NHCH(CH2CH3)CH(CH3)OH), 2.01 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.26 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.39 (d, 1H, J=4.10 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.13-7.50 (m, 15H, 3×Bz).
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)C.[CH3:19][CH:20]([NH:28][NH2:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C(O)C>[CH3:8][C:6]1[NH:29][N:28]([CH:20]([CH3:19])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:4](=[O:18])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Reactant: Cc1ccc(C(C)NN)cc1
Solvent: CCO
Product: COc1ccc(Cc2c(C)[nH]n(C(C)c3ccc(C)cc3)c2=O)cc1
Reaction time: 8 h

Procedure:
31 g of α-(4-methoxybenzyl)-acetoacetic acid ethyl ester were added to a solution of 15 g of α-methyl-4-methylbenzylhydrazine in 30 ml of absolute ethanol in an inert gas atmosphere, during which the temperature of the reaction mixture rose to 60° C. After heating for 2 hours under reflux and standing overnight, the product crystallized out and was recrystallized from a mixture of ethanol and a little dimethylformamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:21](OC)=[O:22])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([O:43][CH:44]([O:49][CH2:50][CH3:51])[CH2:45][CH2:46][CH2:47][NH2:48])[CH3:42]>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[NH:19][CH:20]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[C:21](=[O:22])[NH:48][CH2:47][CH2:46][CH2:45][CH:44]([O:43][CH2:41][CH3:42])[O:49][CH2:50][CH3:51])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(CCCN)OCC
Reactant: COC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Product: CCOC(CCCNC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)OCC
Temperature: 38 °C
Reaction time: 51 h
Yield: 63.3 %

Procedure:
1.80 g (3.06 mmol) of methyl 7-[2,3-bis(t-butoxycarbonyl)-guanidino]heptanoyl-α-t-butyldimethylsilyloxyglycinate and 0.542 g (3.36 mmol) of 4-aminobutyraldehyde diethyl acetal were dissolved in 5.6 ml of benzene and stirred at 38° C. for 51 hours. Then the solvent was distilled off under reduced pressure and the oily substance thus obtained was subjected to column chromatography with the use of Silica gel 60 (mfd by Merck Co. & Inc.). By eluting with chloroform/ethyl acetate (3:2, v/v), 1.39 g of the aimed compound was obtained in the form of an oily product (yield 63.3%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([N:16]1[CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:14]
Reactant: O=C([C@@H]1CCCN1)N1CCSC1
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C([C@@H]1CCCN1C(=O)C[C@H]1CCc2ccccc2C1)N1CCSC1
Yield: 63 %

Procedure:
A colorless oil of 3-{1-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-prolyl}thiazolidine was prepared in the same manner as in Example 25, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 3-L-prolylthiazolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1([CH2:19][CH2:20][OH:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:15][CH2:14]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1

Procedure:
Using 4-nitro-benzoic acid (320 mg) instead of 3-nitro-benzoic acid, and 2-piperazin-1-yl-ethanol (282 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained as a crude product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][N:17]1[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]2[C:13]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)COCc1ccccc1
Yield: 80 %

Procedure:
Freshly distilled benzyl-glycidylether (60 g, 0.365 mmol), phthalimide (49.2 g, 0.304 mmol) and potassium carbonate (3.34 g, 24 mmol) were refluxed with stirring in ethanol (500 ml) for 27 hours. TLC indicated full conversion of the starting material. Ethanol was removed in vacuo. The residual oily material was transferred to a 2 l separation funnel and distributed between ethyl acetate (800 ml) and water (500 ml). The aqueous phase was extracted with ethyl acetate (200 ml), and the combined organic phases were washed with water (300 ml), dried over magnesium sulphate, filtered and concentrated in vacuo. The residual oily material (115 g) was diluted with an equal amount (w/v) of ether (115 ml) and allowed to stand for several days. Crystals were collected on a glass sinter and air dried with suction for 1 hour; then dried under vacuum to constant weight. Yield: 81.5 g (72%). The mother liquor was diluted with ether and seeded with crystals from the first crop. Total yield: 80%. TLC indicated one spot. Structure was confirmed by NMR and IR.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([NH:11][C:12]([NH2:14])=[O:13])[CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:11]([CH:7]2[CH2:10][CH2:9][CH2:8]2)[C:12](=[O:13])[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: NC(=O)NC1CCC1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 30 g (0.35 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 36.1 g (0.32 mol) of cyclobutylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling, white crystals were filtered off and washed with ethanol. Yield 36.4 g (63%) (VII). This was suspended in 100 ml of hot water and 50 ml of 2N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes. After cooling, white crystals were filtered off. Yield 3.6 g (20%) (VIII) NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:27])([CH2:22][C:23]#[C:24][CH2:25][CH3:26])[CH:20]=O>>[CH3:18][C:19]([CH3:27])([CH2:22][C:23]#[C:24][CH2:25][CH3:26])/[CH:20]=[CH:17]/[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: CCC#CCC(C)(C)C=O
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Product: CCC#CCC(C)(C)/C=C/S(=O)(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared, following procedure described in Example 1, step a), but starting from 1-(4-fluorophenyl)-4-(methylsulfonyl)piperazine (Intermediate B1, 855 mg; 3.31 mmol) and of 2,2-dimethyl-hept-4-ynal, 457 mg; 3.31 mmol), as a white powder (764 mg, 61% yield). HPLC, Rt: 4.75 min (purity: 97.7%). LC/MS, M+(ESI): 379.4, 1H NMR (DMSO-d6) δ: 6.97-6.82 (m, 4H), 6.74 (d, J=15.4 Hz, 1H), 6.07 (d, J=14.9 Hz, 3.26 (m, 4H), 3.15 (m, 4H), 2.21 (m, 2H), 2.01-2.16 (m, 2H), 1.15 (s, 6H), 1.06 (t, J=7.4 Hz, 3H).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](=O)[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([C:25]2[C:26]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(Cl)n1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 18.8 %

Procedure:
Add 1-aminopyridinium iodide (780 mg, 3.53 mmol), N,N-diisopropylethylamine (0.62 mL, 3.53 mmol), 1-(6-chloro-pyridin-2-yl)-2-quinolin-4-yl-ethanone (500 mg, 1.77 mmol), and ethanol (8 mL) to a sealed tube apparatus. The sealed vessel is heated at 110° C. for 5 hours. After cooling, the crude is concentrated in vacuo. Purification by flash column chromatography (Silica Gel, 25-40% acetone/hexanes) provides the title compound 119 mg (19%) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:26]2[C:27](=O)[NH:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[N:16]1([C:26]2[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[N:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (315.6 mg, 1.12 mmol) was added to a solution of methyl 3-(3, 4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200.0 mg, crude) and pyridine (176.8 mg, 2.24 mmol) in dichloromethane (50 ml). After stirring overnight at room temperature, the reaction was quenched with water (50 ml) and extracted with dichloromethane (3×80 ml). Then the organic layers were combined dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:17]=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:18].[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(-c2cc3n(n2)CCCC3)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-phenol (5.0 g) and N-chlorosuccinimide (2.65 g) in N,N-dimethylformamide (30 ml) was stirred at 65° C. for 2 hours. The resulting mixture was poured into water and the precipitate was collected by filtration and dried. 2-Chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (5.50 g) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][OH:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:49][S:50](Cl)(=[O:52])=[O:51]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48][S:50]([CH3:49])(=[O:52])=[O:51])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCO)CCC3)cc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 5(a)] was treated with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 739 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1(=[O:18])=[O:17].[CH2:19]([CH2:21][NH2:22])[OH:20]>C1COCC1>[OH:20][CH2:19][CH2:21][NH:22][C:8](=[O:9])[C:7]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:18])=[O:17]
Reactant: O=C1c2c([N+](=O)[O-])cccc2S(=O)(=O)N1CCO
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A solution of 2-(2-hydroxyethyl)-4-nitro-2H-1,2-benzisothiazol-3-one 1,1-dioxide (100 mg, 0.37 mmol) and ethanolamine (24 mg, 0.39 mmol) in THF (5 ml) was allowed to stand at 20°-25° for 3 days. After removal of THF under reduced pressure, the residue was recrystallized from MeOH-EtOAc-hexane to give 112 mg (91%) of product, m.p. 176.5°-177.5°.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[ClH:8].[CH3:9][O:10][C:11]1[CH:33]=[CH:32][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]3[CH2:24][O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:17][C:13]=2[CH:12]=1>C1COCC1>[ClH:8].[ClH:8].[CH3:9][O:10][C:11]1[CH:33]=[CH:32][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:1](=[O:3])[CH3:2])[CH2:20][CH:19]3[CH2:24][O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:17][C:13]=2[CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2nc(N3CCNCC3COc3cccnc3)sc2c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCN(C(C)=O)CC3COc3cccnc3)sc2c1
Temperature: 70 °C
Yield: 85 %

Procedure:
Acetic anhydride (0.100 mL) was added to a solution of 6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole hydrochloride (73.2 mg, 0.186 mmol) in THF (2 mL), and the mixture was heated to 70° C. for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 74.3 mg (85%) of the title compound as a white solid. LC-MS: RT=6.10 min, [M+H]+=399.0.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:26]1)=[O:24])[CH3:21].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:32][CH2:33][N:34]([C:15]([C:13]3[C:14]4[C:5]([CH:6]=[C:7]5[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]5)=[CH:4][CH:3]=[CH:2][CH:1]=4)=[O:16])[CH2:35][CH2:36]2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: CCOC(=O)C1CCCN(C2CCNCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anthracene-9-carbonyl chloride (62.2 mmol) was suspended in anhydrous dichloromethane (30 mL) and added slowly by pipette to a solution of [1,4′]bipiperidinyl-3-Carboxylic acid ethyl ester bishydrochloride (62.2 mmol) and triethylamine (4 eq., 35 mL) in anhydrous dichloromethane (50 mL) at such a rate that a gentle reflux was maintained. The resulting suspension was stirred overnight at ambient temperature then shaken with ice-cold water containing sodium hydroxide (0.19 mol, 7.6 g). The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane solution was washed with water, dried with anhydrous sodium sulfate, diluted with a little xylene and evaporated to dryness to give the title compound (containing a small amount of the corresponding isopropyl ester) as a pale yellow gummy foam (30.8 g).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[C:15]([CH2:17][CH2:18][C:19](OCC)=[O:20])=O)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[C:4]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[C:15]1[CH2:17][CH2:18][C:19](=[O:20])[NH:2][N:3]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC(O)CNC(C)(C)C
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NCC(O)COc1cc(Cl)ccc1C1=NNC(=O)CC1
Yield: 47.8 %

Procedure:
Hydrazine hydrate (1.57 ml, 0.0314 mole) was added to a stirred solution of ethyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorobenzoyl]propionate (2.4 g, 0.0065 mole) in glacial acetic acid (36 ml) and the solution was heated under reflux for 90 minutes. Evaporation under reduced pressure gave an oil which was dissolved in water, treated with an excess of aqueous sodium carbonate solution and the mixture was extracted with dichloromethane. Evaporation of the dried organic extracts gave an oil which ws purified on a silica column by elution with mixtures of chloroform and methanol to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone (1.1 g, 50%, m.p. 195°). The hemisulphate, crystallised from ethanol, had m.p. 250° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[O:2][CH3:1])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 125.2 %

Procedure:
2-(2-Methoxy-4-nitrophenoxy)ethanol (12.0 g) and triethylamine (8.9 g) were dissolved into chloroform (60 ml) and p-toluenesulfonyl chloride (12.3 g) was added into this solution. The solution was stirred for 9 hours at room temperature and allowed to stand for one night. The reaction mixture was washed with water (100 ml) two times and dehydrated with anhydrous sodium sulfate and then concentrated under vacuum to dryness to obtain 2-(2-methoxy-4-nitrophenoxy)ethyl p-toluenesulfonate (25.9 g) as yellowish solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N2CCNCC2)c(Cl)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
A solution of 4-(2-Chloro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.164 mmol) in MeCl2 (0.8 ml) was treated with trifluoroacetic acid (63 μl), heated up to 40° C. and stirred for 4 h. The solvent was removed in vacuo. The residue was dissolved in water and basified with NaOH 1N. The aqueous layer was extracted twice with MeCl2. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to provide the title compound (20 mg, 46%) as a yellow oil, MS (m/e): 265.0 (MH+, 100%).
Reaction SMILES: [K].[NH:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12]Br>CN(C)C=O>[Br:9][CH2:10][CH2:11][CH2:12][N:4]1[C:5](=[O:7])[CH2:6][NH:2][C:3]1=[O:8]
Reactant: BrCCCBr
Reactant: O=C1CNC(=O)N1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1CCCBr

Procedure:
The potassium salt of 2,4-imidazolinedione (hydantoin; 5.5 g, 0.04 mole; prepared as in Example 44) was reacted with 1,3-dibromopropane (14.3 ml, 0.14 mole) in 50 ml of dimethylformamide for 16 hours at room temperature and then for 2 hours at reflux. The reaction mixture was filtered, evaporated to dryness, and the residue recrystallized from isopropyl alcohol (950 mg, m.p. 103°-106° C., m/e 222/220).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:27]=1.[Cl-].[NH4+:30]>>[Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([NH2:30])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:27]=1
Reactant: [NH4+]
Reactant: Cc1nn(C)cc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 68 %

Procedure:
10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to the procedure in Example 2. 10-bromo-3((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 134 mg (68% yield) of the title compound.