Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:46])[CH:15]([C:20]1[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:52]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([F:35])[CH:31]=1)[CH2:27][O:26][C:24]1[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:46])=[O:52])[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=2)[CH:23]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (23.40 g, 36.73 mmol) in THF (180 mL) was added water (60 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (1.54 g, 36.73 mmol) and 30% H2O2 (16.65 mL, 146.92 mmol), drop-wise, maintaining the internal temperature below 5° C. The resulting cloudy solution was stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (97.9 mL, 146.92 mmol) and stirred at room temperature for 15 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×200 mL), dried over MgSO4, and concentrated in vacuo resulting in a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (12.25 g, 70%).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:32])=[O:22])[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1cccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2cccs2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(2-thienyl)-L-alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH3:20])[CH:17]=[CH:16]2)=[O:10])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:9]([OH:10])=[O:8])[CH:16]=[CH:17]1
Reactant: Cn1ccc2cccc(C(=O)OCc3ccccc3)c21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: Cn1ccc2cccc(C(=O)O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.65 g (0.25 mmol) of benzyl-1-methylindole-7-carboxylate (Step B) and 0.035 g of 10% Pd/C in 4 mL of a solution of 4.4% HCO2H in MeOH was stirred for 2 h at rt. The reaction mixture was filtered though a thin pad of celite and concentrated to give the title compound. 1H NMR (CDCl3) δ4.00 (s, 3H), 6.61 (d, 1H, J=3 Hz), 7.11 (d, 1H, J=3 Hz), 7.18 (t, 1H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 7.91 (d, 1H, J=8 Hz);
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][CH2:10][C:11]2[NH:26][CH2:25][CH2:24][N:12]=2)=[CH:8][C:2]=1[Cl:1]
Reactant: N#CCSc1ccc(N)c(Cl)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(SCC2=NCCN2)cc1Cl

Procedure:
The compound, 2-(((4-amino-3-chlorophenyl)-thio)methyl)-2-imidazoline p-toluenesulfonate was prepared by refluxing a mixture of 2-chloro-4-cyanomethylthioaniline (10 g), ethylenediamine p-toluenesulfonate (12 g) and 1,2-dichlorobenzene (150 ml). The reaction mixture was cooled and most of the 1,2-dichlorobenzene decanted off, leaving a viscous residue. Water and methylene chloride were added to the viscous residue and the mixture basified. The methylene chloride layer was separated and approximately 10 g of viscous residue obtained. The residue was dissolved in dimethoxyethane and 5 N hydrochloric acid in isopropanol added. Recrystallization from absolute ethanol containing HCl and then from dimethoxyethane gave 2-(((4-amino-3-chlorophenyl)thio)methyl)-2-imidazoline dihydrochloride, m.p. 195°-199° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.C(O)C.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1)=[O:18]>O>[OH:2][CH2:1][CH2:3][NH:4][CH2:16][C:17]([NH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: NCCO
Reactant: O=C(CCl)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: O=C(CNCCO)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
Ethanolamine (22 μl, 0.368 mmol) and triethylamine (128 μl) were added to an ethanol solution (2 ml) that contained the 2-chloro-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (70 mg, 0.184 mmol) obtained in step A. The obtained mixture was stirred at 70° C. for 18 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1), so as to obtain 2-(2-hydroxyethylamino)-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (19 mg, 26%).
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.O>CCOCC.CCCCCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 0.77 mL of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6M solution in hexanes, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and 25 mL of hexane added. 6-Methyl-6-phenylfulvene, 1.06 (6 mmol) in 5 mL of hexane was added dropwise at -78° C. The resulting yellow solution was stirred for 7 h at -78° C. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 0.8 g (79% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =2.0 ° (CHCl3), 5.8% ee.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:26]=2)[C:21]=1OB(O)O>CCOCC>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:26]=2)[C:21]=1[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc(NS(=O)(=O)c2cccc(Br)c2)s1
Reactant: COc1cccc(-c2ccc3c(OB(O)O)c(OC)ccc3c2)c1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(-c4cccc(S(=O)(=O)Nc5nnc(C)s5)c4)c(OC)ccc3c2)c1

Procedure:
The compound is prepared by the reaction of 3-bromo-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (92.4 mg, 0.28 mmol, 1 eq) with 2-methoxy-6-(3-methoxyphenyl)naphthalene-1-ylboric acid (100 mg, 0.36 mmol, 1.3 eq) according to method C. The raw product was not characterized, but directly subjected to ether cleavage.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:24]=[CH:23][C:11]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[CH:21][O:22][C:16]=3[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:7].[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[CH:24][CH:23]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH3:27]
Reactant: CNC
Reactant: C=O
Reactant: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1ccco1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccco3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.323 g (1.005 mmol) of 6-[4-(2-furoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.14 g (1.5 mmol) of 50% aqueous dimethylamine and 0.12 g (1.5 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH2:3].[C:18]([C:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1)#[CH:19].C(N(CC)CC)C.CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.O>[CH2:1]([C:4]1[CH:16]=[C:15]([C:19]#[C:18][C:20]2([OH:28])[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH2:3]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: C=CCc1cc(Br)ccc1OCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCc1cc(C#CC2(O)CN3CCC2CC3)ccc1OCC(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of ethyl 2-allyl-4-bromophenoxyacetate (912 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis (triphenylphosphine)-palladium (II) chloride (106 mg), copper (I) iodide (53 mg), triethylamine (3 ml) and dimethylformamide (6 ml) was stirred at 80° C. under an atmosphere of argon for 8 hours. The reaction mixture was cooled to ambient temperature and water (100 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined and filtered. The filtrate was washed with saturated brine solution (3×50 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on Alumina (Fluka 507C) using ethyl acetate containing 2.5% methanol as eluent to give 3-[2-(3-allyl-4-ethoxycarbonylmethyloxyphenyl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, mp 95.9° C.; microanalysis, found: C, 70.7; H, 7.30; N, 3.50%; C22H27NO4.0.25 H2O requires: C, 70.6; H, 7.35; H, 3.72%; NMR (CDCl3): 1.28 (3H, t), 1.34-1.47 (1H, m), 1.52-1.72 (1H, m), 1.90-2.25 (3H, m), 2.25-2.60 (1H, m), 2.62-2.92 (4H, m), 2.97-3.09 (IH, d), 3.25-3.35 (1H, d of d), 3.42 (2H, d), 4.26 (2H, q), 4.62 (2H, s), 5.02-5.15 (2H, m), 5.88-6.08 (1H, m), 6.60-6.68 (1H, m) and 7.17-7.27 (2H, m); m/z 370 (M+H).
Reaction SMILES: Cl.[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32]CC2C=CC=CC=2)=[C:26]([NH:28][C:29]([NH2:31])=[O:30])[CH:27]=1)[OH:21].CO.C(Cl)(Cl)[Cl:43]>CO.[Pd]>[ClH:43].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([NH:28][C:29]([NH2:31])=[O:30])[CH:27]=1)[OH:21]
Reactant: ClC(Cl)Cl
Reactant: NC(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 20 (in a solution of 40 mg of the compound in 5.3 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (25 mg), whereby the above-identified compound (29.8 mg) was obtained. Rf=0.08 (methanol/chloroform of 1/10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:20]=1.[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].CS[C:28](=[NH:30])[NH2:29]>CN(C)C=O.O>[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCNCC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)N1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 5-chloro-3-[(1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (3.0 g) in a mixture of N,N-dimethylformamide (30 ml) and water (5 ml) was added S-methylisothiourea sulfate (4.0 g). The mixture was stirred for 8 hours at 80° C. and then cooled. The precipitates formed were filtered and recrystallized from water (100 ml) to give 5-chloro-3-[(4-amidino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hemisulfate (2.63 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 100.5 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and morpholine (231 ul, 2.66 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (57 mg, 100%, HPLC 0.525 min 100%), MS (ISP) m/e=427.1 [(M+H)+].
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:12]1([C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.4 %

Procedure:
Monomethyl adipate (3.20 g) is dissolved in chloroform (70 ml), and thereto are added morpholine (2.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.75 g) and triethylamine (3.04 g) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure to give methyl 6-morpholin-4-yl-6-oxohexanoate (4.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=1)=[O:9]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1cc(Br)ccc1O
Yield: 32.2 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: O1C=CC=C1[CH2:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=[N:15][C:16]=2Cl)[N:11]=1)=[O:9].[CH3:26][NH2:27].C[OH:29]>>[CH3:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:21]3[S:22][C:23]([C:26]([NH2:27])=[O:29])=[CH:24][CH:25]=3)[CH:14]=[N:15][CH:16]=2)[N:11]=1)=[O:9]
Reactant: CN
Reactant: O=C(NCc1ccco1)c1ccc2c(Cl)ncc(-c3cccs3)c2n1
Reactant: CO
Product: CNC(=O)c1ccc2cncc(-c3ccc(C(N)=O)s3)c2n1

Procedure:
5-Chloro-8-thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid (furan-2-ylmethyl)-amide (1.0 equiv.) was combined with methylamine (10 equiv., 2.0 M in methanol) and irradiated in a microwave at 100° C. for 600 seconds. The reaction mixture was diluted with methanol (5 mL) and sonicated. The insolubles were filtered and the filtrate was evaporated to dryness to yield the expected product as an orange oil. LC/MS (M+H) 365.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:25][CH3:26])=[CH:13][C:14]2[O:19][C:18](=[O:20])[C:17]3[CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:24]=1)(=O)=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.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][O:25][C:12]1[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:24][C:15]2[C:16]3[CH2:23][CH2:22][CH2:21][C:17]=3[C:18](=[O:20])[O:19][C:14]=2[CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCOS(C)(=O)=O)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 55 %

Procedure:
Method B (16 h at 80° C.); starting materials: 2,3-dihydro-8-[4-(methanesulfonyloxy)butyloxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 84) and 1-phenylpiperazine; yield 55%; fusion point 162°-165° C. (from ethanol). Fumarate: method E; yield 95%; fusion point 179°-183° C. (from acetone).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([F:37])[C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([F:37])[C:31]=1[O:32][C:33]([F:35])([F:34])[F:36])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1OC(F)(F)F
Product: O=C(CN1CCC(Oc2cc(F)c(OC(F)(F)F)c(F)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 33.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3,5-difluoro-4-(trifluoromethoxy)phenoxy)piperidine (297 mg, 1.0 mmol) as crude materials, 87 mg title compound was generated and yield was 33%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH:28][CH2:29][CH2:30][CH2:31][OH:32].Cl.[C:34]1([C:40](=N)OCC)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:45](O)(=[O:47])[CH3:46]>>[C:22]1([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6]3[CH:5]=[CH:4][C:3]4[N:28]([CH2:29][CH2:30][CH2:31][O:32][C:45](=[O:47])[CH3:46])[C:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:1][C:2]=4[CH:7]=3)[CH2:14][CH2:13]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: CC(=O)O
Reactant: Nc1cc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)ccc1NCCCO
Agent: Cl
Product: CC(=O)OCCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
A mixture of 5.6 parts of 3-[{2-amino-4-[4-(diphenylmethyl)-1-piperazinylmethyl]phenyl}amino]-1-propanol, 2.8 parts of ethyl benzenecarboximidate hydrochloride and 50 parts of acetic acid is stirred first overnight at room temperature and further for 1 hour at reflux. The solvent is evaporated in vacuo and the residue is stirred in water. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98.2 by volume) as eluent. The fractions with the highest Rf-value are collected and the eluent is evaporated. The residue is crystallized from 35 parts of 2,2'-oxybispropane. The product is filtered off and dried, yielding 1.8 parts (24.8%) of [3-{5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazol-1-yl}propyl]acetate; mp. 111.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:25][C:26]([NH2:28])=[O:27]>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:28][C:26](=[O:27])[NH:25]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(O)cc2)N1

Procedure:
Followed the procedure described in Example 86, starting from 4-hydroxybenzaldehyde, 1,2-diphenylethanone and urea, and acetic acid was used instead of HCl.