Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]O)=[O:35])([CH3:32])([CH3:31])[CH3:30].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH:38]=3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCc3cccc(NC(=O)OC(C)(C)C)c3)cc2)cc1
Yield: 83 %

Procedure:
2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24 (315 mg, 0.83 mmol) was dissolved in 20 ml of methylene chloride-THF mixture (1:1 v/v), added with 3-(tert-butoxycarbonylamino)benzyl alcohol (465 mg, 2.1 mmol), 1,1′-azobis(N,N′-dimethylformamide) (359 mg, 2.08 mmol) and tri-n-butyl phosphine (520 ml, 2.1 mmol) and the reaction mixture was stirred over a night. After completing the reaction, the solvent was removed under reduced pressure and the obtained crude residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate 75:25 v/v) to obtain the subject compound (404 mg, 0.693 mmol) in the form of a colorless gummy substance. The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:10]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-butanol (1.0 kg, 3.5 mol) in toluene (10 L) at 0° C. was added triethylamine (684 mL, 4.9 mol) and methanesulfonyl chloride (353 mL, 4.6 mol). After stirring for 5 min, the reaction mixture was filtered, and the precipitate was washed with toluene (8 L). The filtrate was washed with sodium bicarbonate (6 L, 50% saturated aqueous solution) and water (3 L), and concentrated to give the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(Cl)Cl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-chlorosuccinimide (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127-128° C. 1H-NMR ([D6 ] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hα,β --C(2')), 4.05 (s, OCH3), 4.17 (m, H--C(5')), 4.30 (m, H--C(4')), 5.56 (m, H--C(3')), 6.41 (m, H--C(1')), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21H26Cl2N4O7 (517.4): C, 48.75, H, 5.07, N, 10.83; found: C, 49.04, H, 5.09, N, 10.66.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([O:14]C)=O)[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([NH:2][NH2:3])=[O:14])[CH2:6][CH2:5]1
Reactant: COC(=O)c1snnc1C1CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1snnc1C1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.1 %

Procedure:
Hydrazine monohydrate (1.75 g; 35 mmols) was dissolved in ethanol (15 ml), and methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate (1.29 g; 7 mmols) was added thereto, followed by stirring at room temperature for 10 hours. Ethanol was evaporated under reduced pressure and, after adding thereto water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was washed with a mixed solvent of hexane-ethyl acetate to obtain 1.2 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carbohydrazide.
Reaction SMILES: FC(F)(F)C=CC(OCC)=O.[F:12][C:13]([F:28])([F:27])[CH:14]([C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][C:16](O)=[O:17].O.[NH2:30][NH2:31]>>[C:20]1([C:19]2[CH:14]([C:13]([F:28])([F:27])[F:12])[CH2:15][C:16](=[O:17])[NH:30][N:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CC(C(=O)c1ccccc1)C(F)(F)F
Reactant: NN
Agent: CCOC(=O)C=CC(F)(F)F
Solvent: O
Product: O=C1CC(C(F)(F)F)C(c2ccccc2)=NN1

Procedure:
In the same manner, reaction of α-phenyl-4-morpholinoacetonitrile with ethyl 3-trifluoromethylacrylate, followed by treatment of the resulting 3-trifluoromethyl-3-(benzoyl)propionic acid with hydrazine hydrate gives 6-phenyl-5-trifluoromethyl-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:27](=N)[CH2:28][Cl:29])C>C(O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:27]([CH2:28][Cl:29])=[N:22][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Yield: 59.9 %

Procedure:
A mixture of 3′,4′-diamino-biphenyl-2-sulfonic acid tert-butylamide (1.0 g, 3.13 mmol), 2-chloroacetimidic acid ethyl ester hydrochloride salt (591 mg, 3.76 mmol) (prepared according to the procedure described in J. Med. Chem., 1986, 29, 2280) in anhydrous ethanol (100%, 20 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to afford the title compound as an off-white solid (708 mg, 60% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.1 Hz, J=1.5 Hz), 7.79 (m, 1H), 7.74 (dd, 1H, J=8.5 Hz, J=1.1 Hz), 7.65 (td, 1H, J=7.5 Hz, J=1.6 Hz), 7.57 (td, 1H, J=7.8 Hz, J=1.6 Hz), 7.50 (dd, 1H, J=8.3 Hz, J=1.6 Hz), 7.39 (dd, 1H, J=7.3 Hz, J=1.2 Hz), 5.05 (s, 2H), 1.02 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C18H20ClN3O2S: 378.89 (M+H), Found 378.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2.60 g (14.6 mmol) of 4-morpholinoaniline in 20 ml of methylene chloride were added 14.07 ml (105 mmol) of triethylamine and 3.53 g (17.5 mmol) of 4-nitrophenyl chloroformate under ice-cooling, followed by stirring at room temperature for 7 hours. After the solvent was evaporated, water was added to the residue, and the precipitated crystals were collected by filtration, washed water, and dried to give 4-morpholino-N-(4-nitrophenoxycarbonyl)aniline.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[O:14][CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)c(I)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)=O)cc(C)c(C#N)c1I
Temperature: 60 °C
Yield: 89.4 %

Procedure:
The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (50.0 mL) and the potassium carbonate (4.6 g, 33 mmol) and ethyl iodide (2.1 mL, 33 mmol) were added. The reaction was heated to 60° C. and monitored by LC/MS. After heating for 2 hrs the reaction was complete. This was allowed to cool, diluted with ethyl acetate (300 mL) and filtered to remove the remaining solids. The organic layer was washed with water (3×), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark solid. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-ethoxy-2-iodo-6-methylbenzonitrile as a pale yellow crystalline solid (5.0 g, 96%). LCMS calculated for C12H13INO2 (M+H)+: m/z=329.9; found: 330.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:15]([CH:16]=[O:17])=[CH:14][N:13]=[CH:12]1.C(=O)C1C=CC=NC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]([C:15]2[N:11]([CH3:10])[CH:12]=[N:13][CH:14]=2)[OH:17])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Cn1cncc1C=O
Agent: O=Cc1cccnc1
Product: Cn1cncc1C(O)c1ccc(F)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 27: step a using (4-fluorophenyl)magnesium bromide and 1-methyl-1H-imidazole-5-carbaldehyde in place of (3,4-dimethoxyphenyl)magnesium bromide and nicotinaldehyde, respectively.
Reaction SMILES: COC1C=C(N2CCC(N3CCP(C)(=O)CC3)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][CH:50]([N:53]4[CH2:58][CH2:57][P:56]([CH3:60])(=[O:59])[CH2:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][C:42]=2[O:61][CH3:62])[C:37]([Cl:63])=[CH:36][N:35]=1.[CH:64]1([C:67]2[O:71][C:70]([NH2:72])=[N:69][CH:68]=2)[CH2:66][CH2:65]1>>[Cl:63][C:37]1[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:48][CH2:49][CH:50]([N:53]4[CH2:58][CH2:57][P:56]([CH3:60])(=[O:59])[CH2:55][CH2:54]4)[CH2:51][CH2:52]3)=[CH:43][C:42]=2[O:61][CH3:62])=[N:39][C:34]([NH:72][C:70]2[O:71][C:67]([CH:64]3[CH2:66][CH2:65]3)=[CH:68][N:69]=2)=[N:35][CH:36]=1
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ncc(C2CC2)o1
Agent: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nc(Nc2ncc(C3CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine. 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine is then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.[CH:9]1([C:12](=[O:31])[C:13](=[CH:27]OCC)[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:15])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]([C:13]2[CH:27]=[N:7][O:15][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:31])[CH2:11][CH2:10]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2oncc2C(=O)C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.4g) was added to a mixture of hydroxylamine hydrochloride (6.3 g) and 3-cyclopropyl-2-ethoxymethylene-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (29.0g) in ethanol. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (anhydrous magnesium sulphate) filtered and evaporated to dryness. The residue was triturated with ether and filtered. The resultant solid was recrystallized from methanol. The mother liquors from the recrystallization were combined and evaporated to dryness. The residue was purified by column chromatography on silica gel to give 4-cyclopropylcarbonyl-5-(2-fluoro-4-methylsulphonylphenyl)-isoxazole (compound 1) as a white solid, m.p. 129.5°-130.5° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([S:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([S:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A solution of rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid methyl ester (50 mg, 0.16 mmol) in ethanol (3 mL) at 25° C. was treated with a solution of potassium hydroxide (44 mg, 0.79 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water and evaporated under reduced pressure. The concentrate was acidified to pH 2 with art aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to afford rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid (43 mg, 90% yield) as a colorless oil: EI-HRMS m/e calcd for C13H14Cl2SO2 (M+) 304.0091, found 304.0101.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][NH:29][CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]>CN(C)C=O>[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][N:29]([CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Reactant: ClCCOC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCOC1CCCCO1)CC2
Temperature: 70 °C
Yield: 26.9 %

Procedure:
40 g of ethyldiisopropylamine and 52.5 g of 2-(2-chloroethoxy)tetrahydropyran (96% pure according to GC) were added to 54.5 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1.5 l of dimethylformamide, with stirring, and the mixture was heated for 30 h at 70° C. It was concentrated under vacuum, the residue was worked up by extraction with dichloromethane and water and the combined dichloromethane phases were dried and concentrated to give 25 g of 3-methyl-6-[2-(tetrahydropyran-2-yloxy) ethyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, which was purified by bulb-tube distillation at a bath temperature of 80° C. and 0.1 mbar and by column chromatography on aluminum oxide (activity grade III) and elution with dichloromethane/ethanol (volume ratio 95:5).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=1[NH2:18].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([NH:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[O:14])=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1cccc(I)c1N
Reactant: O=C(O)CC1=CCC2(CC1)OCCO2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(I)c1NC(=O)CC1=CCC2(CC1)OCCO2
Yield: 89.6 %

Procedure:
A solution of (1,4-dioxaspiro[4.5]dec-7-en-8-yl) acetic acid (567 mg; 2.86 mmol; 1 eq) (7) and 2-iodo-6-methoxyaniline (1 g; 2.86 mmol; 1 eq) in anhydrous dichloromethane (30 mL) is admixed with 2-chloro-1-methylpyridinium iodide (1.46 g; 5.73 mmol; 2 eq) and triethylamine (3.98 mL; 28.65 mmol; 10 eq). The reaction mixture is heated at reflux for 20 hours. After cooling and acidification with 1N HCl solution to pH=5-6, the mixture is extracted with dichloromethane. The organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4/6) gives 1.10 g of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxy-phenyl)acetamide (16) in the form of a yellow foam (yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][CH2:23]O>>[Br:20][CH2:21][CH2:22][CH2:23][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Reactant: OCCCBr
Product: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Yield: 61.2 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.49 g, 1.8 mmol) was reacted with 3-bromopropanol (0.31 mL, 3.6 mmol) to afford 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 63%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: NCCCO
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cl)cc1Oc1cccc(CNCCCO)c1
Yield: 100.4 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.21 g, 0.81 mmol), 3-aminopropan-1-ol (65 μL, 64 mg, 0.85 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(3-hydroxypropylamino)methyl]phenoxy}benzonitrile fumarate (352 mg, 99%) as a white solid.
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O)[NH2:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[N:24]=[C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[NH:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(Cl)cc3)n[nH]2)CC1
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A mixture of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (1.0 g), 4-chlorobenzonitrile (1.7 g), potassium carbonate (0.28 g), and butanol (8.0 mL) was heated at 150° C. for 2 hours using a microwave device. After leaving to be cooled, the solvent was evaporated under reduced pressure, and the residue was azeotroped with toluene. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10). To the purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-[3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate (0.62 g).
Reaction SMILES: N1C=C(CC[NH:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)N=C1.[CH3:19][C:20]1[C:21]([CH:27]=O)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][C:20]1[C:21]([CH2:27][NH:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: c1cnc2c(c1)CCCC2NCCc1c[nH]cn1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of [2-(1H-imidazol-4-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine and 3,5-dimethyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 380 as a yellow oil. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.90 (m, 2H), 2.05 (m, 2H), 2.11 (s, 3H), 2.18 (s, 3H), 2.47 (m, 1H), 2.75 (m, 2H), 2.90 (m, 2H), 3.77 (d, 1H, J=12.0 Hz), 4.04 (m, 2H), 6.65 (s, 1H), 7.04 (t, 2H, J=6.0 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.55 (s, 1H), 8.09 (s, 1H), 8.43 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.2, 18.4, 22.1, 23.2, 23.6, 29.7, 51.4, 55.1, 61.1, 122.1, 124.8, 130.4, 133.0, 134.9, 135.0, 137.1, 139.1, 146.4, 154.3, 158.3. ES-MS m/z 362 [M+H]+. Anal. Calcd. for C22H27N5.0.4H2O.0.3 CH2Cl2: C, 73.10; H, 7.53; N, 19.37. Found: C, 67.69; H, 7.28; N, 17.64.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[Br:22]>CO.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:18]([CH3:21])=[N:19][O:20][C:16]=1[NH:15][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)s1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccs3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5,2'-bithiophene (300 mg, 1.14 mmol) with 5-amino-4-bromo-3-methylisoxazole (183 mg, 1.03 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, 430 mg (94%) of a pale brown solid, m.p. 210° C.