Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].F[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>CS(C)=O>[N:1]1([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Under nitrogen atmosphere, a solution of pyrazole (2.43 g) in DMSO (90 mL) was cooled to 0° C., and thereto was added successively NaH (1.57 g, 60%), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added ethyl 4-fluorobenzoate (6.00 g) and the mixture was stirred at 110-120° C. for 20 hours. The mixture was cooled to room temperature, and thereto was added ice water (150 mL). The mixture was extracted twice with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=50/3→50/4) to give ethyl 4-(1H-pyrazol-1-yl)benzoate (6.12 g, 79%).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[NH:11][C:12](=[O:14])[N:13]=[C:6]2[CH:5]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[NH:11][C:12](=[O:14])[N:13]=[C:6]2[C:5]=1[Br:20])[CH2:2][CH3:3]
Reactant: CCCc1cc2nc(=O)[nH]n2c(C)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C)n2[nH]c(=O)nc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of 7-n-propyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, prepared in Example 193, in 120 ml of acetic acid containing 12 g of sodium acetate, and to which a solution of 2.6 ml of bromine in 50 ml of acetic acid has been added dropwise, is stirred at room temperature for 3 hours. The reaction mixture is then concentrated under vacuum and thereafter treated with water. The crystals formed are drained, washed with water and dried. 7 g of 7-n-propyl-5-methyl-8-bromo-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one are thereby obtained in the form of crystals of melting point 221° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([CH:27]2[CH2:29][CH2:28]2)[NH2:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:26][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:13][CH2:14]2)[CH:27]2[CH2:29][CH2:28]2)=[CH:23][CH:24]=1
Reactant: N[C@H](c1ccc(Br)cc1)C1CC1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC1(C)COC2(CCC(O)(CCN[C@H](c3ccc(Br)cc3)C3CC3)CC2)OC1
Yield: 71 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-(4-bromophenyl)(cyclopropyl)methanamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 71% of theory; LC (method 1): tR=1.64 min; Mass spectrum (ESI+): m/z=452/454 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: C#CCN
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A stirred mixture of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 15 ml of tetrahydrofuran was treated with 0.55 g (0.01 mole) of 2-propynylamine added dropwise from a needle and syringe. After 10 min, approximately 1 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly solidified. The precipitated solid was collected by filtration to yield 4.7 g of crude wet product. After air drying, the solid was recrystallized from benzene-ligroin to yield 1.78 g (72.9%) of fine white crystals, m.p. 140°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].COC1C=C(C=CC2C=CC(C(O)=O)=CC=2)C=C(OC)C=1C(C)C>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Agent: COc1cc(C=Cc2ccc(C(=O)O)cc2)cc(OC)c1C(C)C
Product: COc1cc(C=Cc2cccc(C(=O)O)c2)cc(OC)c1C(C)C
Yield: 77 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 3-bromobenzoic acid in 77% yield in the same way as described in preparation of 1B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J=17 Hz, 1H), 7.25 (d, J=17 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[CH3:20][CH2:19][CH:18]([C:7]([NH2:6])=[O:9])[CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2ccc(Br)cc2s1
Solvent: C1COCCO1
Product: CCCC(CC)C(N)=O

Procedure:
200 mg (0.869 mmol) of 6-bromo-3H-benzothiazol-2-one were reacted in analogy to Example 1 with 132.7 mg (1.04 mmol) of 1-isocyanatohexane in dioxane at 80° C. Yield: 185 mg (59%), M+H+: 357.1.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)\[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([C:24]3[CH:28]=[CH:27][O:26][N:25]=3)[CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+:38]>>[CH3:1][O:2]/[N:3]=[C:4](/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([C:24]3[CH:28]=[CH:27][O:26][N:25]=3)[CH2:20][C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)=[CH:29][CH:30]=1.[Na+:38]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)c3ccon3)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)[O-])c3ccon3)cc2)cc1)c1ccccc1
Yield: 71.2 %

Procedure:
Compound 29 was synthesized from 3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-3-(1,2-oxazol-3-yl)propanoic acid (0.07 g, 0.14 mmol) and sodium hydroxide (0.0057 g, 0.14 mmol) by following the procedure described in scheme 12 (0.052 g, yield: 71.2%); Purity: 99.00%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:20]=[C:19]([CH3:21])[C:14]([C:15]([O:17]C)=[O:16])=[C:13](/[CH:22]=[CH:23]/[CH3:24])[N:12]=1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:12]=[C:13]2[CH2:22][CH:23]([CH3:24])[O:17][C:15](=[O:16])[C:14]2=[C:19]([CH3:21])[CH:20]=1)[CH3:10]
Reactant: C/C=C/c1nc(-c2c(CC)cccc2CC)cc(C)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cccc(CC)c1-c1cc(C)c2c(n1)CC(C)OC2=O
Temperature: 160 °C
Reaction time: 0.75 h

Procedure:
A mixture of (E)-methyl 6-(2,6-diethylphenyl)-4-methyl-2-(prop-1-enyl)nicotinate (150 mg, 0.464 mmol), H2O (0.17 mL, 9.28 mmol) and TFA (2.9 mL, 37.1 mmol) was heated in a microwave reactor at 160° C. for 30 min. Starting materal was observed. Additional TFA (0.5 mL) and H2O (0.05 mL) were added and heating continued at 160° C. for 45 min and then at 140° C. for 2 h. The reaction was then poured into sat NaHCO3 and extracted with EtOAc. The organic layer was washed with brine and then dried over Na2SO4 and concentrated. The residue was then purified with FCC (0-50% EtOAc/heptane) to provide 2-(2,6-diethylphenyl)-4,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one. MS (ESI+) m/z 310.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7](Cl)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:11][C:12]1[C:21]([C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:37])[C:30]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1.CCN(CC)CC>CN(C=O)C>[NH2:11][C:12]1[C:21]([C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:37])[C:30]=2[N:31]2[CH2:36][CH2:35][N:34]([S:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])[CH2:33][CH2:32]2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCNCC1
Reactant: O=S(=O)(Cl)C1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCN(S(=O)(=O)C2CCOCC2)CC1

Procedure:
Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was added to a suspension of 2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.08014 mmol) (synthesized according to the procedure similar to Example 2) and Et3N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL). The crude mixture was purified by Fractionlynx HPLC. The clean aqueous fractions were combined and lyophilised, yielding 2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 523.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:11]Br)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:11][NH:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCCCC1
Product: OCCNCC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([C:3](=[O:2])[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C)CCN
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 76.1 %

Procedure:
Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (1.5 g, 3.97 mmol), triethylamine (1.1 mL, 7.92 mmol), N,N-dimethylethylenediamine (0.7 g, 7.94 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.65 g, 0.796 mmol) in N,N-dimethylformamide (30.0 mL). Reaction conditions, work up and silica gel chromatography (eluted with 46:4:25 dichloromethane:methanol:ethyl acetate) were also carried out in an analogous manner and afforded the title compound (1.25 g, 3.02 mmol) in 76% yield.
Reaction SMILES: [OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].C([O:9][Si:10]([O:17]CC)([O:14]CC)[O:11]CC)C>O>[Si:10]([O-:17])([O-:14])([O-:11])[O-:9].[OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
To a mixed aqueous solution of 20 g of commercially available 25% tetramethylammonium hydroxide and 165 g of pure water, 21 g of 95% tetraethoxysilane was added with stirring by disper to obtain tetramethylammonium hydroxide silicate aqueous solution being an alkaline silicate having pH of 12.8, conductivity of 8110 μm/S and SiO2 concentration of 2.9% by weight.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[C:19]12([CH2:29][NH2:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:30][CH2:29][C:19]34[CH2:28][CH:23]5[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]5)[CH2:26]3)[CH2:20]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Product: CP(C)(=O)c1ccc(Nc2cc(NCC34CC5CC(CC(C5)C3)C4)ncn2)cc1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 1-adamantanemethylamine.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)[C:15]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([Cl:34])[CH:27]=2)=[N:14][N:13]=1>>[ClH:11].[Cl:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH2:25][NH:24][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:12]([N:7]2[CH2:8][CH2:9][C:4]([OH:10])([CH2:3][OH:2])[CH2:5][CH2:6]2)=[N:13][N:14]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: OCC1(O)CCNCC1
Agent: Cl
Product: COc1ccc(CNc2nnc(N3CCC(O)(CO)CC3)c3ccc(C#N)cc23)cc1Cl

Procedure:
The resulting 4-(hydroxymethyl)-4-piperidinol hydrochloride was reacted with 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine in the same manner as in Example 4 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[CH:8]OCC)[C:6]#[N:7])[CH3:2].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([NH2:7])=[N:20][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=1)=[O:12])[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccccc2)nc1N
Yield: 80.5 %

Procedure:
2-(Ethoxymethylene)-2-cyanoacetic acid ethyl ester (78.2 g) and phenylhydrazine (50.0 g) were dissolved in ethanol (500 mL), and the mixture was refluxed for 3 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Hexane (500 mL) was added, to the residue, and the residue was washed by suspending and filtered. The obtained solid was vacuum dried to give the title compound (86.0 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(N(CC)CC)C.CN(C)C=O>O>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH3:26])[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNCC1
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.40 g), 1-acetylpiperazine (0.24 g), triethylamine (0.26 ml) and N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.33 g, yield 68%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 177-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].O.C(Cl)[Cl:15]>>[Cl:15][C:10]1[C:3]([O:2][CH3:1])=[C:4]([C:7]([O:11][CH3:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCCl
Reactant: COc1cccc(OC)c1C=O
Solvent: O
Product: COc1ccc(Cl)c(OC)c1C=O
Temperature: 50 °C

Procedure:
A solution of commercially available 2,6-dimethoxybenzaldehyde (3.000 g; 18.10 mmol) in DCM (12 ml) was treated dropwise with a solution of sulfuryl dichloride SO2Cl2 (2.437 g; 18.10 mmol) in DCM (9 ml), and the resulting mixture was heated to 50° C., under nitrogen, for 30 min. After cooling to rt, water was added and the separated aq. layer was further extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=3/1) afforded 3-chloro-2,6-dimethoxybenzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 201.03 g/mol.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C([OH:29])CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>CCCCCC>[C:2]([OH:9])(=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Nicotinoyl chloride hydrochloride (17.8 g, 0.1 mol) and oleyl alcohol (26.85 g, 0.1 mol) were added into hexane (250 ml). Pyridine (15.8 g, 0.2 mol) was added to the stirred mixture over a period of 10 min, and the reaction mixture was stirred at room temperature for 24 h. Pyridine hydrochloride was removed by filtration and washed with hexane. The combined filtrate was extracted with water, dried over MgSO4 and evaporated to dryness. The residue was digested twice with acetonitrile, and the sticky residue was dried to give a clear water-like liquid which turned soap-like upon cooling (21.1 g, 56.5 mmol, 56.5%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:24])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Yield: 100.7 %

Procedure:
In 100 ml of 1,2-dichloroethane, 57 g (0.19M) of 3,4,5-triacetoxybenzoic acid and 34 g (0.29M) of thionyl chloride were made to react with each other at 60° C. for 2 hours. Excess thionyl chloride and 1,2-dichloroethane were distilled away under reduced pressure. Thus, 61 g of the intended compound was obtained.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@H:53](C)[C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C.O1CCCC1>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (737 mg) in anhydrous acetonitrile (20 ml), N,N'-carbonyldiimidazole (281 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.75 ml) and a solution of the compound (1.157 g), which had been obtained in (2), in anhydrous tetrahydrofuran (10 ml) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (1.394 g) was obtained as an amorphous substance.
Reaction SMILES: S(Cl)([Cl:3])=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.Cl>C(O)C>[ClH:3].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[OH:2])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCO
Product: N=C(O)c1ccc(Br)cc1

Procedure:
Compound [H], 4-bromobenzoic acid is chlorinated with thionyl chloride to yield compound [I], 4-bromobenzoic acid chloride. Compound [I] is reacted with aqueous ammonia to yield compound [J] 4-bromobenzoic acid amide. Compound [J] is dehydrated with thionyl chloride to yield compound [K], a 4-bromobenzonitrile. Compound [K] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [L], 4-bromobenzimidate hydrogen chloride. In ethanol, compound [L] is reacted with gaseous ammonia to yield compound [M], 4-bromobenzamidine hydrogen chloride.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)C(=O)O
Yield: 56 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 56% yield as a pale yellow solid. MS: (M+H)+ 435.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][CH:18]2[CH2:19][CH2:20][CH2:21][C:22]3[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(Cl)c(Cl)c1)CCC2
Temperature: 25 °C
Reaction time: 41 h
Yield: 63.9 %

Procedure:
A mixture of 2-(3,4-dichlorophenyl)ethylamine (3.8 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (130 mg) was heated in refluxing toluene (50 ml), with azeotropic removal of water, for 41 hrs. An additional 1 g of the amine and 0.1 g of para-toluenesulfonic acid were added, and the mixture was heated for an additional 24 hrs. The solution was cooled and the precipitate was collected. Sodium borohydride (0.6 g) was added to a solution of the precipitate in ethyl alcohol (50 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in hot ethanol and treated with an equivalent amount of fumaric acid. The solid was collected and recrystallized from ethanol to provide 3.8 g (48%) of product, mp 172°-173° C.