Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1ccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)nc1
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)nc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. Obtained as a yellow solid (140 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH2:15]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:22][CH2:15][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OCc1cccc(OCCCCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1cccc(OCCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
m-(4-Phenylbutoxy)benzyl alcohol (510 mg) was dissolved in 5 ml of benzene, 1.4 g of thionyl chloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 520 mg of m-chloromethyl-(4-phenylbutoxy)benzene. This compound was then treated by the procedure of Reference Example 4 to give 470 mg of m-(4-phenylbutoxy)benzylamine.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (10.34 g, 23.17 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (9.51 g, 95.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.18 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:8][CH:7]([O:9][CH3:10])[O:6][CH:5]1[O:11][CH3:12].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>CCOCC>[CH3:12][O:11][CH:5]1[CH:4]([C:3]#[C:2][Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:8][CH:7]([O:9][CH3:10])[O:6]1
Reactant: COC1CC(C=C(Br)Br)C(OC)O1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To solution of crude 3-(2,2-dibromoethenyl)-2,5-dimethoxy-tetrahydrofuran (1.78 g, 5.64 mmol) in ether (30 mL) at -78° C. was added n-butyllithium (9.02 mL of 1.25 M in hex). After 1 hour at -78° C., tributyltin chloride (1.68 mL, 6.20 mmol) was added, and the mixture was allowed to warm to ambient temperature. After 16 hours, ether (35 mL) and saturated aqueous NH4Cl (30 mL) were added. The organic layer was separated, washed with saturated aqueous NH4Cl (30 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL), dried over K2CO3, and evaporated to give an orange oil, which was purified via flash column chromatography with 2% MTBE/hex to furnish 1.92 g (77%) of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran as a colorless oil. A mixture of diastereomers was evident in the 1H NMR spectrum, which was used immediately without further purification. IR: 2923, 1456, 1374, 1215, 1105, 1017, 967 cm-1. Anal. Calculated for C20H38O3Sn: C, 53.96; H, 8.60. Found: C, 54.21; H, 8.66.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)c(O)c[nH]1
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of 5-benzyloxy-2-methyl-1H-pyridin-4-one (2 g, 9.29 mmol) in methanol (30 ml) and water (8 ml) was placed in a Parr bottle. 10% Pd/C was added and the mixture was hydrogenated at 50 psi for 3 hours. A bed of CELITE™ was placed on a sintered glass, and washed with 0.1N HCl and then water. The content in the Parr bottle was removed from the Parr hydrogenator and flushed with nitrogen. The solution was filtered under suction. The filtrate was evaporated to give a white solid (820 mg, 70% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:10]1[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2cccc3c(O)cc(C)nc23)c(C)c1
Product: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-ol(335 mg, 1.21 mmol) and POCl3(2.5 ml) was heated in 130° C. oil bath for 3 hours. The mixture was cooled and poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 350 mg of crude material as a brown oil. The oil residue was purified through silica gel column chromatography using chloroform as eluent to give 316 mg (87%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 8.20(d,1H), 7.60(m,1H), 7.47(d,1H), 7.35(s,1H), 6.97(s,2H), 2.54(s,3H), 2.36(s,3H), 1.86(s,6H)ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[C:12](OCC)(=O)[CH2:13][C:14]([O:16]CC)=[O:15]>>[N+:1]([C:4]1[C:5]2[N:11]=[C:12]([CH2:13][C:14]([OH:16])=[O:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc([N+](=O)[O-])c1N
Product: O=C(O)Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 160 °C

Procedure:
3-Nitro-benzene-1,2-diamine (5.0 g) was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 48 h. After cooling to rt, flash chromatography of the crude reaction gave (4-nitro-1H-benzoimidazol-2-yl)-acetic acid (4.50 g). MS found: (M+H)+=250.0 (2b) A portion (500 mg) of the above derivative (20a) was dissolved in THF (6 ml) prior to the addition of a solution of LiOH.H2O (100 mg) in water (0.3 ml). A couple drops of MeOH were added until the solution became clear. After 3 h at rt, the reaction was concentrated and freeze-dried to provide (4-nitro-1H-benzoimidazol-2-yl)-acetic acid lithium salt (482 mg). 1H NMR (DMSO, δ ppm, 300 mHz) 3.57 (s, 2H), 7.15 (t, 1H), 7.81 (d, 1H), 7.9 (d, 1H). (2c) Derivative (2b) (50 mg) was incorporated into example (1e) to give the title compound (63 mg). MS found: (M+H)+=468.3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=O)[CH2:13][NH2:14])=[CH:6][CH:5]=1.[S-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:18][C:17]([SH:16])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: N#C[S-]
Reactant: COc1ccc(CCC(=O)CN)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CCc2cnc(S)[nH]2)cc1
Yield: 19.2 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-oxo-1-aminobutane, hydrochloride (8.6 g, 37.7 mmole) and potassium thiocyanate (3.6 g, 37.7 mmole) in acetic acid (100 ml) was heated under reflux for 20 minutes. The reaction was cooled, diluted with water and the product was filtered and recrystallized from ethyl alcohol and dried to give the product as a solid (1.7 g, 19%).
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][NH:68][C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][N:68]([C:12](=[O:14])[C@@H:11]([NH:10][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:9])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3cc(Cl)ccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
(S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (186 mg, 0.723 mmol), DIEA (0.303 mL, 1.735 mmol) and HATU (242 mg, 0.636 mmol) were added to a solution of (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (215 mg, 0.578 mmol) in DCM (7 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-50% EtOAc:Hex) to give (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (13 mg, 0.201 mmol, 35% yield) as a colorless oil. LCMS: rt=2.58 min. [M+H]+=612; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:33])[CH:32]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:33])[CH:32]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[O:22])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)oc23)CC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCNCC5)cc4)oc23)CC1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
4-[4-({1-[8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Example 29) (160 mg, 0.3 mmol) was dissolved ethyl acetate (20 mL) and cooled to 0° C. HCl gas was bubbled in slowly for 2 minutes. A solid began to precipitate. Methanol (3-4 mL) was added to dissolve this solid and HCl gas was bubbled in for another 2 minutes. The mixture was concentrated under reduced pressure and triturated with ether and dried under vacuum to yield a tan solid (100 mg, 76%). LCMS/m/z=448.6
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[ClH:38].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:38].[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:29])=[O:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(C3CCNCC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-(1-tert-Butoxycarbonyl-piperidin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (362 mg, 0.687 mmol) was dissolved in a mixture solution of ethyl acetate (4 ml) and 4 M hydrochloric acid/ethyl acetate (8 ml). This was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Thus, 5-piperidin-4-yl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester hydrochloride was obtained as a colorless amorphous material (332 mg).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Yield: 65.13 %

Procedure:
Cyclopentylamine (5.17 ml) and N,N-diisopropylethylamine (12.4 ml) were dissolved into 125 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (9.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 80 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (7.9 g) in a yield of 65.13%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.38 (s, 1H), 4.59 (m, 1H), 2.13-2.21 (m, 2H), 1.72-1.85 (m, 4H), 1.53-1.71 (m, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:22]([OH:24])=O)=[C:10]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:3]1=[O:29].[OH:30][C@@H:31]1[CH2:35][O:34][NH:33][CH2:32]1>>[OH:30][CH:31]1[CH2:35][O:34][N:33]([C:22]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:24])[CH2:32]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3c[nH]c4ncccc34)sc21
Reactant: O[C@H]1CNOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3c[nH]c4ncccc34)sc21

Procedure:
The title compound (55 mg) was prepared from the product of step b, (150 mg) by the method of example 1, step g), and (S)-4-hydroxyisoxazolidine, example 1 part b). MS (APCI) 484 [M+H]+. δ 1HDMSO 0.82-0.85 (6H,m), 2.03-2.13 (1H,m), 3.20-3.21 (3H,m), 3.53-3.68 (3H,m), 3.75-3.90 (2H,m), 4.00-4.18 (3H,m), 4.60-4.80 (1H,m), 5.50-5.55 (1H,m), 6.99-7.02 (1H,m), 7.41-7.44 (1H,m), 7.90-7.97 (1H,m), 8.18-8.20 (1H,m), 11.53 (1H,s,br)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].[CH2:29]([N:33]=[C:34]=[O:35])[CH2:30][CH2:31][CH3:32]>O1CCCC1.C(OCC)C>[CH2:29]([NH:33][C:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:35])[CH2:30][CH2:31][CH3:32]
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Reactant: CCCCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCNC(=O)OCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (11.1 mg) in anhydrous tetrahydrofuran (1 ml) was added sodium hydride (60% oil dispersion, 2.4 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and butyl isocyanate (4.5 mg) was added. After stirred for 2 hours at ambient temperature, the solvent was diluted with diethyl ether (2 ml) and washed with water, dried, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate) to afford 4-[3-(2-butylcarbamoyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (10.8 mg).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: Cc1cccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
A mixture of 1-(3-methylphenyl)piperazine dihydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(3-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][CH:36]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2CCN(C(C)=O)CC2)C3)cc1

Procedure:
Compound ef was synthesized according to the procedure described in Example 8 reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-acetylpiperidin-4-one. LC-MS: m/z=+522 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:10][CH:9]=1)[CH3:2].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([CH3:48])[CH:47]=1)[C:42](Cl)=[O:43]>O>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[C:42](=[O:43])[C:41]2[CH:45]=[C:46]([CH3:48])[CH:47]=[C:39]([CH3:38])[CH:40]=2)=[CH:12][CH:13]=1)[CH3:24]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 2.0 g. (6.2 mmol.) of the hydrochloride salt of 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran in 10 ml. of nitrobenzene was added a solution of 1.84 g. (13.9 mmol.) of aluminum chloride in 20 ml. of nitrobenzene. The solution was cooled to 0° and 1.24 g. (7.4 mmol.) of 3,5-dimethylbenzoyl chloride was added. The reaction mixture was stirred at 0° for 30 minutes then at 25° for 1.5 hours, after which time it was poured into water and the nitrobenzene was removed by steam distillation. The aqueous solution was extracted with ether, made alkaline with aqueous sodium carbonate solution and again extracted with ether. The etheral solution was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:12]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)OCC
Temperature: 25 °C
Yield: 80 %

Procedure:
16.0 g of diethyl malonate was added to 27.3 g of carbon tetrachloride. Into the resultant mixture was dropped 16.4 g of bromine under stirring at room temperature. After the completion of the dropping, the mixture was heated to 80° C. and refluxed for 1 hour to thereby remove hydrogen bromide formed by the reaction. The liquid reaction mixture thus obtained was washed with a 5% aqueous solution of sodium carbonate and carbon tetrachloride was distilled off. Then distillation was carried out to give 19.1 g (yield: 80.0%) of diethyl bromomalonate.
Reaction SMILES: [CH:1]1[C:6]([SH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:1]=1
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: Cc1cccc(S)c1
Product: CC(C)=CCCC(C)=CCSc1cccc(C)c1

Procedure:
thio-m-cresol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl m-tolyl sulphide (b.p.122° C/0.07 mmHg);