Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(#N)C.[S:29]1[C:33]([NH2:34])=[N:32][CH:31]=[N:30]1.[OH-].[Na+].O1CCOCC1.O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:34][C:33]4[S:29][N:30]=[CH:31][N:32]=4)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCC1(c2ccc(Cl)cc2)CC1)c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1ncns1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCC1(c2ccc(Cl)cc2)CC1)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A solution of 4-[({[1-(4-chlorophenyl)cyclopropyl]methyl}amino)carbonyl]-2-fluorobenzenesulfonyl chloride (Preparation 93, 205 mg, 0.510 mmol) in acetonitrile (1.0 mL, 19 mmol) was added dropwise to a solution of 1,2,4-thiadiazol-5-amine (155 mg, 1.53 mmol) and sodium hydroxide (61.1 mg, 1.53 mmol) in 1,4-dioxane (1.6 mL, 2.01 mmol) and water (0.32 mL, 18 mmol). After stirring 30 min at ambient temperature, the reaction mixture was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (37 mg, 15%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[Br:17])=[O:5])C.[NH2:19][CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=1)[N:8]=[C:7]([NH:19][CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(Br)cc(Br)c2nc1Cl
Reactant: NC(Cc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Br)cc(Br)c2nc1NC(Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 6,8-dibromo-2-chloro-quinoline-3-carboxylic acid ethyl ester is reacted with DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:27])=[O:26])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:10][C:9]=2[OH:8])=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of 2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetamide (0.38 g) in methanol (5 mL) was added 10% palladium-carbon powder (0.075 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1–20/1) to give 2-[4-(4-ethylbenzyl)-3-hydroxyphenyl]acetamide (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
A mixture of 66.0 gm. (0.235 mole) of 2,4-dichloro-3,5-dinitrobenzamide and 140 ml. of phosphorus oxychloride is heated at reflux for one hour. The solution is cooled to room temperature. The excess phosphorus oxychloride is distilled off in vacuo. The solid residue is triturated with ice-water and filtered. There is obtained 54.0 g. (88%) of a tan solid melting at 139°-141°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:23]2[CH2:25][CH2:24]2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[OH-].[K+]>C(O)C.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([CH:23]1[CH2:25][CH2:24]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C2CC2)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(C3CC3)nc12

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-2-cyclopropyl-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and KOH in a mixture of ethanol/water. White solid. MS (ESI): 338.2 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].BrC[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH:1]=[O:4])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(I)cc1[N+](=O)[O-]
Temperature: 86 °C
Reaction time: 19 h
Yield: 60.9 %

Procedure:
NaHCO3 (3.32 g, 39.48 mmol) was added to a solution of 1-bromomethyl-4-iodo-2-nitrobenzene (2.25 g, 6.58 mmol) in anhydrous DMSO (150 mL). The mixture was stirred at 86° C. for 19 hours under a nitrogen atmosphere, then cooled down to room temperature, diluted with water (300 mL), and extracted with methylene chloride four times (250 mL). The combined organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 4-iodo-2-nitrobenzaldehyde (1.11 g, 61%). 1HNMR (400 MHz, CDCl3): δ 10.38 (d, 1 H, J=1.6 Hz, CHO), 8.45 (d, 1 H, J=1.5 Hz, Ph-H), 8.15 (dd, 1 H, J=1.5 and 8.0 Hz, Ph-H), 7.67 (d, 1 H, J=8.1 Hz, Ph-H); 13C NMR (100 MHz, CDCl3): δ 187.28 (CH), 143.18 (CH), 133.29 (CH), 130.67 (CH), 130.28 (C), 109.60 (C), 99.78 (C).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1
Reactant: Cn1ncc2c1-c1cc(Cl)ccc1NC2
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cn1ncc2c1-c1cc(Cl)ccc1N(C(=O)C1CC1)C2
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.5 ml) was addded dropwise to a mixture of N,N-dimethylaniline (2.4 ml), 4-dimethylaminopyridine (5.0 mg) and 8-chloro-4,5-dihydro-1-methyl-1H -pyrazolo[4,3-c]quinoline (2.0 g) in chloroform (20 ml) at 0° C. and the mixture was allowed to stir at that temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was mixed with 5% hydrochloric acid and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent was evaported in vacuo to give light brown powder (2. 0 g), which was recrystallized from a mixture of n-hexane and ethyl acetate to afford 8-chloro-5-cyclopropylcarbonyl-4,5-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinoline as colourless prisms.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[S:18][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH2:1]([C:3]1[S:18][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]4[NH:21][N:20]=[N:19][N:17]=4)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Temperature: 100 °C

Procedure:
A mixture of 0.65 g (0.0026 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 28), 0.56 g (0.0086 mol) of sodium azide and 0.51 g (0.0095 mol) of ammonium chloride in 80 ml of dimethylformamide is heated at 100° C. for twenty-four hours. The reaction mixture is cooled, poured into 900 ml of ice water and acidified with concentrated hydrochloric acid. The resulting precipitate of 2-ethyl-7-(1-Htetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one, 0.2 g, is collected; mp 293°-295° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc2ncccc2c1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and rhodanine, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Yield: 84.7 %

Procedure:
3-Fluoro-4-nitro phenol (5 g, 0.032 moles), potassium carbonate (6.34 g, 0.047 moles) and tert-Butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (14 g, 0.04 moles) in dimethylformamide (50 mL) were stirred at 100° C. After completion of reaction, the mass was quenched on to water (100 mL) and extracted with ethyl acetate (2×100 mL). The resulting organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 0.5:9.5) to afford the title compound 9.23 g (Yield: 85%).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=1)[C:36]([OH:38])=O>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:5])[C:36](=[O:38])[C:35]2[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=[C:33]([O:32][CH3:31])[CH:34]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)n1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-methoxy-6-trifluoromethyl-isonicotinic acid after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2) as eluant. Colorless solid (33%). MS (ESI): m/z=436.13 [M+H]+.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CC(=O)Cl
Reactant: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)CC(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of 2-imino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (0.5 g) and triethylamine (0.6 g) in chloroform (30 ml), isovaleryl chloride (0.8 g) was dropwise added under stirring at room temperature, and stirring was continued for 2 hours. After removal of the solvent under reduced pressure, the concentrated residue was extracted with ethyl acetate (100 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.2 g of 2-isovalerylimino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (Compound No. 16).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([O:11]C)=[O:10])[C:6](=[O:13])[CH:5]=[C:4]([CH2:14][CH2:15][CH3:16])[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1>CO.[OH-].[Na+]>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([OH:11])=[O:10])[C:6](=[O:13])[CH:5]=[C:4]([CH2:14][CH2:15][CH3:16])[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1
Reactant: CCCc1cc(=O)n(CC(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(=O)n(CC(=O)O)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 78.4 %

Procedure:
A mixture of methyl 2,4-dioxo-6-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,2,3,4-tetrahydropyrimidine-3-acetate (0.25 g) in methanol (10 ml) and 1N sodium hydroxide (1.5 ml) was heated under reflux for 16 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was acidified with 1N hydrochloric acid to give a crystalline product (0.19 g, 79%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)[OH:22])C1C=CC=CC=1.[CH:29]([O-:31])=O.[NH4+]>CO.[Pd]>[CH2:11]([O:13][N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:10](=[C:29]=[O:31])[C@H:9]1[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)[OH:22])[CH:10]=[CH2:9]
Reactant: O=C[O-]
Reactant: Cn1cc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2Cc2ccccc2)cn1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: C=CCON1C[C@H](O[Si](C)(C)C(C)(C)C)C(=C=O)[C@H]1C(O)c1cnn(C)c1
Reaction time: 0.5 h
Yield: 193 %

Procedure:
To a solution of (2S,4R)-1-{1-benzyl-4-(t-butyl-dimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol (70 g) in methanol (700 ml) was added ammonium formate (44 g) and 10% Pd-C (wet, 20 g). The mixture was refluxed for 40 minutes, then cooled. After filtration of Pd-C, the solvent was evaporated. To the residue was added chloroform (500 ml) and precipitated excess ammonium formate was filtered off with celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran-water (1:1, 1 l) and a solution of allyl chloroformate (22.3 ml) in tetrahydrofuran (60 ml) was added thereto, while adjusting pH to 8.5~10 with 4N-sodium hydroxide solution at 0°~5° C. The mixture was stirred for 30 minutes at the same temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-{(2S,4R)-1-allyloxy-carbonyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methylpyrazol-4-yl) methanol (66.2 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)=S.[ClH:15].CNC(=NCCCCC1N=CNC=1)SC.[NH2:31][OH:32]>>[ClH:15].[ClH:15].[CH3:1][NH:2][C:3]([NH:31][OH:32])=[N:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1
Reactant: NO
Reactant: CNC(=S)NCCCCc1c[nH]cn1
Agent: CNC(=NCCCCc1c[nH]cn1)SC
Agent: Cl
Product: CNC(=NCCCCc1c[nH]cn1)NO

Procedure:
When N-methyl-N'-[4-(4-imidazolyl)butyl]thiourea is reacted with methanolic hydrogen chloride by the procedure of Example 1(i) the product is N,S-dimethyl-N'-[4-(4-imidazolyl)butyl]isothiourea which on treatment with hydroxylamine by the procedure of Example 1(ii) gives the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([NH:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:27])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: C#Cc1ccc(C2(NCCC)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-15% EtOAc-hexanes) afforded 40.0 mg (61%) of the title compound as an orange oil.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH:9]=1)(C)(C)C.N1C=CC=CC=1.F>C1COCC1>[C:20]1([C:17]2[S:16][C:15]([NH:14][C:10]3[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=[CH:12][N:11]=3)=[N:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: OCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-(5-phenyl-thiazol-2-yl)-amine (8-6), 0.805 g (2.03 mmol) was dissolved in 10 mL THF and the resulting solution was cooled to 0° C. Hydrogen fluoride-pyridine (Aldrich, HF ˜70%, pyridine ˜30%) 1.20 mL was added. After 1 h the reaction was allowed to arm to RT. The THF was removed in vacuo and the residue was diluted with sat Na2CO3 (aq). The resulting precipitate was filtered to provide the pure title compound. 1H NMR (DMSO-d6): δ11.35 (bs, 1H), 8.25 (d, 1H, J=5.2 Hz), 7.79 (s, 1H), 7.59 (d, 2H, J=7.4 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.25 (t, 1H, J=7.3 Hz), 7.08 (s, 1H), 6.86 (d, 1H, J=5.2 Hz), 5.42 (bs, 1H), 4.51 (s, 2H). Mp 236-237° C. M+1: 284.0.
Reaction SMILES: [CH:1]1([Si:4]([CH:11]2[CH2:13][CH2:12]2)([C:6]([OH:10])([CH3:9])[CH2:7][CH3:8])[CH3:5])[CH2:3][CH2:2]1.[CH:14]1([SiH](C2CC2)C(=O)CCC)CC1.C([Li])C>>[CH:11]1([Si:4]([CH:1]2[CH2:3][CH2:2]2)([C:6]([CH2:9][CH3:14])([OH:10])[CH2:7][CH3:8])[CH3:5])[CH2:12][CH2:13]1
Reactant: CCCC(=O)[SiH](C1CC1)C1CC1
Reactant: CCC(C)(O)[Si](C)(C1CC1)C1CC1
Agent: [Li]CC
Product: CCC(O)(CC)[Si](C)(C1CC1)C1CC1

Procedure:
Under an atmosphere of argon, a 1.9 M solution of tert-butyl lithium in pentane (10.0 ml, 19.0 mmol) was added in one portion with stirring at −78° C. to a solution of (E/Z)-1-ethoxyprop-1-ene (1.61 g, 18.7 mmol) in pentane (20 ml). The reaction mixture was then allowed to warm to 0° C. within 30 min. Subsequently, TMEDA (5.39 g, 46.4 mmol) was added, and the reaction mixture was allowed to warm to room temp. After stirring for 1 h at room temp., the mixture was cooled to −78° C. and chloro(dicyclopropyl)-methylsilane (3.00 g, 18.7 mmol, prepared according to Example 1) was added dropwise over a period of 30 min. After a further 16 h stirring at room temp., the mixture was poured into water (50 ml). After 10 min. of stirring, the organic layer was separated, and the aqueous one extracted with Et2O (2×50 ml). The combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to afford crude dicyclopropyl(1-ethoxypropionyl)methylsilane, which was taken up in acetone/1 N HCl (2:1, 48 ml). The reaction mixture was stirred for 45 min. at room temp. followed by the addition of water/Et2O (1:1, 100 ml). The organic layer was separated, and the aqueous one extracted with Et2O (2×30 ml). The combined ethereal extracts were dried (Na2SO4) and concentrated under reduced pressure. Silica-gel chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1, relevant fractions were determined by GC) followed by bulb-to-bulb distillation (0.08 mbar, 40° C.) of the resulting residue provided 437 mg (13% over 2 steps) of dicyclopropyl(methyl)propionylsilane. Following the procedure for the preparation of dicyclopropyl(1-hydroxy-1-methylpropyl)methylsilane (see Example 5), dicyclopropyl(methyl)propionylsilane (470 mg, 2.58 mmol) was then reacted with ethyl lithium (1.7 M in n-Bu2O, 12.1 ml, 20.6 mmol) to provide after purification by silica-gel flash chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1) 360 mg (66%) of the odoriferous title compound.