Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CO
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 25 °C
Yield: 115.1 %

Procedure:
An anhydrous solution of piperazine (54 kg) in 150 l of methanol was stirred until a clear solution was obtained. 50 kg 4,7-dichloroquinoline were then slowly added to the solution. The latter was refluxed for 8 hours and cooled to RT. The resulting suspension was filtered and the solvent removed under reduced pressure. The oil obtained was washed with water (150 l) until solid precipitation occurred. The precipitate was filtered and washed with water to yield 72 kg of crystalline 7-chloro-4-(piperazin-1-yl)-quinoline Form B, containing 25% of water (w/w).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][C:15]([Cl:23])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])=[CH:5][CH:6]=1.C([O-:27])C.O>>[CH2:13]1[CH:12]2[CH:11]([NH:10][C:8]([C@H:7]([NH2:24])[C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:9])[C:18](=[O:19])[N:17]2[C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:23])[CH2:14]1.[OH2:27]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Reactant: CC[O-]
Solvent: O
Product: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Reaction time: 0.5 h

Procedure:
Loracarbef ethanolate, (4.0 g, 97.1% potency), was slurried in 56 ml of water (containing 0.004 eq sodium, ~0.02 g editate) at 50° C. for 2 hours. Within 30 minutes the slurry became very thick, indicating conversion to monohydrate. The product was vacuum filtered, washed with a minimum amount of water, and dried in a 40° C. vacuum oven. X-ray-confirmed as monohydrate.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:10])=[O:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a stirred solution of 5-formyl-2,4-dimethylbenzoic acid (compound 16.3, 950 mg, 5.33 mmol, 1.10 equiv) in DMF (15 mL) was added DIEA (2.48 g, 19.19 mmol, 4.00 equiv) followed by HBTU (3.67 g, 9.68 mmol, 2.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.00 equiv). After stirring overnight at ambient temperature, the reaction was quenched by the addition of 60 mL of water. The resulting mixture was extracted with 3×150 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:3) as eluent to yield 1.4 g (84%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([CH3:28])[O:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:23][C:24]([NH:26][CH3:27])=[O:25])[CH2:15]1.O>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][N:26]([CH3:27])[C:24](=[O:25])[O:23][C:20]2[C:21]3[O:22][C:14]([CH3:13])([CH3:28])[CH2:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: O
Solvent: c1ccncc1
Product: CN(Sc1ccc(C(C)(C)C)cc1)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 8 h

Procedure:
One-half (by volume) of the resultant solution of 4-(tert-butyl)benzenesulfenyl chloride was added to a solution of 10.9 g of carbofuran in 30 ml of pyridine. The mixture was allowed to stand overnight, then poured into water. The water-insoluble material was washed several times with water, then dissolved in ether. The ether solution was washed with water and dried. Removal of the ether under reduced pressure gave a solid which on recrystallization from hexane-ether gave 7.5 g of solid, m.p. 120°-3°. Four recrystallizations from hexane gave 2,3-dihydro-2,2-dimethyl-7-benzofuranyl [4-(tert-butyl)phenylthio] (methyl)carbamate, m.p. 122°-123°. The n.m.r. spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2.C(N(C(C)C)C(C)C)C>CC#N>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:27][C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[N:31]6)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3o2)cc1
Reactant: BrCc1ccc2nccnc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5ccc6nccnc6c5)CC4)c3o2)cc1
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a suspension of 2-(4-tert-butylphenyl)-7-piperazin-1-yl-1,3-benzooxazole 23.5 mg, 0.070 mmol) and 6-bromomethylquinoxaline (17.2 mg, 0.077 mmol) in CH3CN (anh., 10 mL) was added ethyldiisopropylamine (0.015 mL, 0.084 mmol). The mixture was heated in a 95° C. bath overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was adsorbed onto silica gel. Silica gel chromatography using a gradient of 25% EtOAc/hexane to 50% EtOAc/hexane then 100% EtOAc afforded the title compound (23.2 mg) as an ivory powder. MS (ESI) m/z 478 [M+H]+; HPLC Method C, r.t.=10.9 min (98.9% @210-370 nm; 97.4% @ 236 nm).
Reaction SMILES: [CH3:1][Si:2]([CH3:37])([O:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[O:3][Si:4]([CH3:31])([CH3:30])[O:5][Si:6]([CH3:29])([CH3:28])[O:7][Si:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([CH2:26][OH:27])[OH:25])([CH3:10])[CH3:9].C[SiH](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C>>[OH:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Si:8]([CH3:10])([CH3:9])[O:7][Si:6]([CH3:28])([CH3:29])[O:5][Si:4]([CH3:30])([CH2:31][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([OH:25])[CH2:26][OH:27])[O:3][Si:2]([CH3:1])([CH3:37])[O:32][Si:33]([CH3:34])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCCCCCCOCC(O)CO
Agent: C[SiH](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C
Product: C[Si](C)(C)O[Si](C)(C)O[Si](C)(CCCCCCCCCCCOCC(O)CO)O[Si](C)(C)O[Si](C)(C)CCCCCCCCCCCOCC(O)CO
Yield: 48 %

Procedure:
Undecamethylpentasiloxanylundecylglyceryl ether (F) was obtained in a 48% yield in the same manner as Example 4. At this time, since 1,5-dihydrodecamethylpentasiloxane was included in a raw material of undecamethylpentasiloxane, 1,5-bis[11-(2,3-dihydroxypropoxy)undecyl]decamethylpentasiloxane (C) was obtained at the same time. The obtained compound (G) was isolated and refined by a silica gel column. The structures of the obtained products were confirmed by an analysis using IR and NMR spectra. The result of the analysis of the compounds was as follows. ##STR25##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].[C:21]([O:27][CH2:28]I)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([O:27][CH2:28][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1=[O:12])=[O:26]
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.0 g of 6-bromo-3,4-dihydro-4,4-dimethylquinolin-2(1H)-one was dissolved in 10 ml of dry DMF, 3.85 g of cesium carbonate were added and 953 mg of iodomethyl pivalate were added dropwise while cooling with water, and the mixture was stirred at room temperature for 4 hours. The experiment was left to stand at room temperature overnight. Then a further 0.4 ml of iodomethyl pivalate was added at room temperature and the mixture was stirred at room temperature for a further 2 hours. (According to TLC and LC-MS, there is still reactant in the reaction solution). 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4, then concentrated under reduced pressure and purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 700 mg of 6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl 2,2-dimethylpropionate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](=[S:14])[NH2:13])[CH:9]=[N:8]2)[CH:2]=1.Br[C:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=1O.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[S:14][C:16]4[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: NC(=S)c1cnn(-c2cccnc2)c1
Reactant: O=C1CCCC(Br)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 25 °C

Procedure:
1-(3-pyridyl)pyrazole-4-carbothioamide (2.50 mmol, 0.510 g) and 3-bromo-2-hydroxy-cyclohex-2-en-1-one (2.50 mmol, 0.477 g, described in Tet. Lett. 2011, 52, 3633) were suspended in 10 ml acetic acid and the reaction mixture heated to reflux for 20 h. The reaction was cooled down to room temperature, diluted with water, slowly neutralised by dropwise addition in a saturated NaHCO3 solution, and the aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash to give a solid which was crystallized in diethylether to yield the title compound as a light yellow solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[C:10]([O:18][CH2:19][CH3:20])=[O:17])[CH3:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cnc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1F
Temperature: 110 °C
Yield: 85 %

Procedure:
To a stirred solution of 2,3,5-trifluoro-pyridine (2 g, 15.02 mmol) in dimethyl sulfoxide (20 mL) was added diethyl malonate (4.60 g, 28.72 mmol). Then cesium carbonate (9.35 g, 28.72 mmol) was added and the reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as oil in 85% yield, 3.5 g.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29]Br)[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1.C(OCC)(=O)C>C(O)C>[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29][NH:2][CH3:1])[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Temperature: 25 °C

Procedure:
Methylamine (2 ml of a 33% solution in ethanol) was added to a stirred suspension of N-(3-trifluoromethylphenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.5 g) in ethanol. Stirring was maintained at room temperature for 1 hour. The solution was diluted (ethyl acetate), washed (water), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with methanol/hexane to give N-(3-trifluoromethylphenyl)-2-(2,3-dihydro-6-methylaminomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 105, 0.21 g) as an orange gum, NMR (CDCl3)δ 1.6(s,6H), 2.25(s,3H), 3.25(s,2H), 5.3(s,2H), 7.1-7.3(m,8H), 7.55(m,1H), 7.75(s,1H), 8.45(s,1H);
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O: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.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCc1ccccc1
Solvent: CO
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccccc1

Procedure:
(1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.022 g, 0.082 mmol) was reacted with benzylamine (0.18 g, 1.64 mmol) in ethanol (Procedure E) to yield (2R, 4S, 5S)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol, (+)-29d 0.025 g (81%, [α]D=(+)53.7, c-=1, MeOH).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=O)=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:34][CH2:33][CH2:35][NH:36][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:30]
Reactant: NCCO
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCO)c(C)sc5c4)c3s2)C1
Yield: 28.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with ethanolamine (84 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (40 mg, 28%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.27 Hz), 8.33 (1H, t, J=5.56 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.86 (1H, d, J=8.85 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.75 (1H, d, J=5.46 Hz), 4.76 (1H, br s), 4.13-3.81 (3H, m), 3.67-3.50 (4H, m), 3.43-3.32 (2H, m), 3.27, 3.24 (3H, s), 2.61 (3H, s), 2.18-1.94 (2H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[N:27]([CH3:43])[C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: CN(C)C=O
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)N(C)C2=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a mixture of (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione (0.50 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, methyl iodide (0.16 g) was added, and the mixture was further stirred at room temperature for 30 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (0.47 g, yield 92%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 215-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:19][CH2:18][CH2:17][C:16]3[C:11]2=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)=[CH:5][C:4]=1[O:24][CH3:25].Cl.I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([S:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:34]#[N:35]>>[CH3:45][O:44][C:38]1[CH:37]=[C:36]([C:33]([S:46][C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:19]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[CH:10]2[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[CH:5]=2)[C:34]#[N:35])[CH:41]=[CH:40][C:39]=1[O:42][CH3:43]
Reactant: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CCCCCC(C#N)(Sc2ccc(C)cc2)c2ccc(OC)c(OC)c2)cc1OC
Yield: 61.1 %

Procedure:
The procedure of Example 49 is repeated using 0.345 g of tetrahydropapaverine hydrochloride and 0.30 g of α-(5-iodopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.263 g of the desired product as a yellow oil. MS(Hi res): m/z Calcd for C42H50N2SO6 711.34678 Found 711.3453
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25].S(Cl)(Cl)=O.[NH3:34]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:20])[NH2:34])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: N
Reactant: CCCCc1cc(C(=O)O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCc1cc(C(N)=O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 1 h

Procedure:
A mixture comprising 168 mg of 4-chloro-5-[3-(2-n-butyl-4-carboxyphenoxy)propylamino]-2-i-propyl-3(2H) pyridazinone (Compound No. 112), 119 mg of thionyl chloride and 10 ml of dried tetrahydrofuran, was refluxed under stirring for 1 hour. The reaction mixture was subjected to distillation under reduced pressure. To the residue, 20 ml of dried benzene was added. The mixture was again subjected to distillation under reduced pressure to remove excess thionyl chloride by azeotropic distillation. The residual oily substance thereby obtained, was dissolved in 10 ml of dried tetrahydrofuran, and ammonia gas was introduced thereinto for 5 minutes under cooling with ice. Then, the reaction solution was further stirred for 15 minutes. The reaction mixture was subjected to distillation under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed sequentially with a 5% sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off, and a pale yellow oily substance thereby obtained was crystallized from methanol-ethyl ether to obtain 143 mg of the above identified compound as colorless crystals having a melting point of 172° to 174° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[N:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1nc(C#N)cs1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nc(=O)c3ccccc3s2)cs1
Yield: 77.9 %

Procedure:
2-Methyl-1,3-thiazole-4-carbonitrile (0.46 g, 3.7 mmol) and methyl thiosalicylate (1.26 g, 7.4 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto. The mixture was refluxed for 15 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.75 g, 78%) as white crystals.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([O:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([O:24][C:19]2[CH:18]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[N:22]=[C:21]([CH3:23])[N:20]=2)[CH:34]=1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=C1Nc2ncccc2C12CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)C(=O)Nc2ncccc23)n1

Procedure:
36 mg (0.15 mmol) spiro[piperidin-4.3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 44 mg (0.15 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 91 μL (0.536 mmol) DIPEA in 2.0 mL DMF were stirred for 48 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.