Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=394.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:15]=[CH:16][C:3]=12.Cl.C([OH:26])C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:15]=[CH:16][C:3]=1[C:2]2=[O:26]
Reactant: Fc1cc2nc3c(cnn3-c3ccccn3)c(Cl)c2cc1F
Reactant: CCO
Agent: Cl
Product: O=c1c2cc(F)c(F)cc2[nH]c2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (3.17 g, 10.0 mmol) in ethanol (160 mL) was added 6 N hydrochloric acid (8 mL, 48.0 mmol), and the mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and subsequently recrystallized from ethanol to give the title compound (2.47 g, 83% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[N:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:16]1[CH:21]=[CH:20][C:19]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccncc2)CC1

Procedure:
At 0° C., to a mixture of tert-butyl (cis-4-hydroxycyclohexyl)carbamate (100 mg, 0.5 mmol), 4-pyridinol (106 mg, 1.11 mmol), and triphenylphosphine (292 mg, 1.11 mmol) in tetrahydrofuran (2 mL) was added diethyl azodicarboxylate (176 μL, 1.11 mmol) with stirring. The mixture was stirred at r.t. overnight, then quenched with sat'd NH4Cl solution, and extracted with ethyl acetate. The extract was washed with water twice, brine once. Then, the extracdt was dried over Na2SO4. After filtration, the filtrate was concentrated to yield tert-butyl [trans-4-(pyridin-4-yloxy)cyclohexyl]carbamate.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14]C([O-])(C)C.[K+].CI>C(Cl)Cl>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH3:14])([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC(C)CC1=CCC(C)(C=O)C(C)C1
Temperature: -3 °C
Yield: 99.4 %

Procedure:
4-Isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (8 g, 44 mmol) was dissolved in methylene chloride (400 ml) and cooled to −3° C. with stirring and under nitrogen. KOtBu (6.7 g, 58 mmol) and MeI (19 g, 130 mmol) were added sequentially and the suspension stirred for 30 min before being allowed to return to room temperature. After stirring for a further 3 h the reaction crude was poured onto brine (400 ml), stirred for 10 min and the phases allowed to separate. The upper aqueous phase was extracted with methylene chloride (150 ml) and the organic phases combined, dried (Na2SO4) and concentrated in vacuo to give 8.5 g of an orange oil (8.5 g). The oil was purified by flash chromatography (MTBE/hexane 1:9) and combination of pure fractions gave 3c as a 7:3 mixture of diastereomers (7 g, colorless oil, 80% yield). 1 g of the oil was distilled to give a sample for olfactory assessment. (0.52 g, colourless oil, >99% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([NH2:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:44][C:35]([CH3:37])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methoxybenzoic acid (1.00 g, 5.36 mmol) was dissolved in DMF (20 mL), and the solution was treated with EDCI (2.06 g, 10.7 mmol), HOBT monohydrate (724 mg, 5.36 mmol) and cumylamine (1.54 mL, 10.7 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-chloro-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (1.59 g, yield 97%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1
Yield: 69.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (142 mg, 70%). MS (ISP) 409.2 [(M+H)+]; mp 163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:18]=1)[CH:7]=[C:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]([CH3:16])([CH3:15])[C:9]1=[O:17].[OH:21]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:7]2[C:8]3([C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[O:11][C:12]3([CH3:13])[CH3:14])[O:21]2)[CH:18]=1
Reactant: OO
Reactant: CCc1ccc(Br)cc1C=C1C(=O)C(C)(C)OC1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Br)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Temperature: 35 °C
Yield: 87.2 %

Procedure:
To a solution of 4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one (32.07 g, 95.15 mmol) in methanol (1570 ml) at 35° C. is added 50% aqueous hydrogen peroxide (8.10 ml, 142.73 mmol), followed immediately by a solution of 2M aqueous lithium hydroxide (9.51 ml, 19.03 mmol). This reaction mixture is stirred at 35° C. for exactly 1 hour, then quenched with saturated sodium metabisulfite (340 ml) and distilled water (340 ml). After stirring at room temperature for 15 minutes solvents are then concentrated in vacuo (to approximately 500 ml), over which time the product precipitates as a yellow solid. To this suspension is added distilled water (500 ml), and the product is isolated by filtration. After additional washing with distilled water the solid is dried under vacuum overnight to afford 2-(5-bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (29.30 g) as a yellow solid which is used without purification in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].Br[CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]>CC(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: Sc1ccccc1Cl
Reactant: COC(=O)C(=O)c1sccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(=O)c1sccc1CSc1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 68281936 %

Procedure:
2.62 g (19 mmol) of potassium carbonate and 2.74 g (19 mmol) of 2-chlorothiophenol are added to a solution of 5 g (19 nmol) of methyl 3-bromomethylthien-2-ylglyoxylate in 50 ml of acetone, the mixture is stirred for 72 hours at room temperature and filtered and the filtrate is evaporated down. The residue is taken up in methylene chloride, and the solution is washed with Na2CO3 solution, dried and evaporated down. The crude product is recrystallized from methanol. 4.24 g (68%) of the abovementioned compound are obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[NH:12][C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([N:12]1[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:13]1=[O:14])[CH3:20]
Reactant: CCI
Reactant: O=C1Nc2ccccc2Sc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cccnc2Sc2ccccc21
Temperature: 50 °C

Procedure:
Sodium hydride (1.05 g of a 50% suspension in mineral oil) was added to a suspension of pyrido[2,3-b][1,5]benzothiazepin-5(6H)-one (4.0 g, 0.0175 mol) in 100 ml of dimethylformamide and the resulting mixture stirred until the evolution of gas stopped, at which time the mixture was heated to 50° C. for 30 min. After cooling to room temperature, ethyl iodide (5.46 g, 0.035 mol) was slowly added and the reaction mixture allowed to stir for 2 hours. Crushed ice was added to decompose unreacted sodium hydride. Water was then added and the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated in vacuo. After washing the solid residue with hexane, it was recrystallized from ethyl acetate/hexane to give 0.66 g (14% of theory) of product as yellow crystals, m.p. 148°-149° C.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3][CH2:4]C.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([O:42][CH3:43])[N:36]=2)=[O:34])=[CH:29][C:28]=1[Cl:44])(C(C)(C)C)(C)C.O>O1CCCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH:3]([CH3:4])[CH3:2])=[C:28]([Cl:44])[CH:29]=2)=[O:34])=[N:36][C:37]=1[O:42][CH3:43]
Reactant: COc1nc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1Cl
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C(=O)c2ccc(OC(C)C)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.39 mL) was added to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-chloro-6-methoxypyridin-2-yl)methanone (700 mg) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at room temperature for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 mL), and 2-iodopropane (333 μL) and potassium carbonate (464 mg) were sequentially added at room temperature, followed by stirring at 65° C. for three hours. The reaction solution was returned to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the title compound as a colorless oil (538 mg, 93%).
Reaction SMILES: O=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][N:6]2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:6]2[CH2:5][C@H:4]3[CH2:8][C@@H:7]2[C@@H:2]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:3]3)=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(N2C[C@H]3CC(=O)[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1C[C@@H]2C[C@H]1N(c1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a round bottom flask under argon was added 4-((1S,4R)-6-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (272 mg, 1.282 mmol), tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (330 mg, 1.538 mmol), CH2Cl2 (6.4 ml), solid anhydrous Na2SO4 (1 gm) and HOAc (1 drop). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (815 mg, 3.84 mmol) was added to the reaction which was then stirred at rt overnight. The reaction mixture was then diluted with CH2Cl2. The resulting solution was wash with saturated aqueous NaHCO3, water and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex. The fractions containing the desired product were concentrated to give tert-butyl (1R,2R)-2-((1R,4R,6S)-2-(4-cyanophenyl)-2-azabicyclo[2.2.1]heptan-6-ylamino)cyclohexylcarbamate (466 mg, 1.135 mmol, 89% yield). Anal. Calcd. for C24H34N4O2 m/z 410.5, found: 411.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2 H, d, J=8.8 Hz), 6.55 (2 H, d, J=8.8 Hz), 4.26 (1 H, s), 3.65 (1 H, br. s.), 3.47-3.41 (1 H, m), 3.30 (1 H, dt, J=8.8, 3.0 Hz), 3.15 (1 H, d, J=8.8 Hz), 2.98 (1 H, d, J=8.2 Hz), 2.64 (1 H, s), 2.29-2.19 (2 H, m), 2.10-2.02 (1 H, m), 2.01-1.93 (1 H, m), 1.74-1.59 (4 H, m), 1.45-1.37 (1 H, m), 1.35 (9 H, s), 1.30-1.18 (2 H, m), 1.09- -0.93 (2 H, m), 0.90 (1 H, ddd, J=12.9, 3.8, 3.6 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>CCCCCC.ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 90 %

Procedure:
To a mixture of 2.43 moles (324 g.) of aluminum chloride in 648 ml. of dichloromethane is added a solution 0.88 mole (274 g.) of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mole (92 ml.) of acetic anhydride in 880 ml. of dichloromethane over a 3 hour period while maintaining the temperature at above 0° C. The reaction mixture is then heated to its reflux temperature and stirred at reflux for 5 hours. The progress of the reaction is followed using thin-layer chromatography. The reaction mixture is placed in an ice bath and ice and 10 percent hydrochloric acid are added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 25° C. The organic phase is separated and washed once with 2 liters of 10 percent hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to provide a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. Upon drying, 250 g. of light yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained. The yield is 90 percent, the m.p is 84° to 86° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]1([NH:7][C:8](=[N:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:9][CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(=S)Nc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(=O)c1ccccc1)Nc1ccccc1

Procedure:
12.8 g (0.05 M) of N-phenyl-N'-benzoyl-thiourea, 5.3 g (0.038M) of potassium carbonate, 4.7 ml (0.075 M) of methyliodide and 200 ml of acetone are boiled in a reflux and constantly mixed for five hours. After cooling the sediment is filtered. The filtrate is washed with 150 ml of water. The separated sediment is ground and filtered. 12.4 g (93.3% of the theoretical yield) of N-phenyl-N'-benzoyl-S-methylisothiourea with a melting point of 78°-94° are obtained. After recrystallization twice from ethanol and ethylacetate 7.4 g (54.8 % of the raw one) of product with a melting temperature of 102°-104° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: Cc1cccc(C(=O)Nc2cccc(C(=O)C3CCN(C)CC3)c2)c1
Yield: 96.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-methylbenzoyl chloride (91 μl, 0.687 mmol), 74.0 mg (96%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)benzoic acid (15 g, 66.8 mmol) in methylene chloride (200 mL) was added oxalyl chloride (12.7 g, 100 mmol) drop wise followed by the addition of 5-6 drops of DMF. The reaction mixture was concentrated, the residue partitioned between methylene chloride and 5% aq. sodium carbonate. The organic layer was dried (MgSO4) and concentrated to give the title compound as a pale oil (16 g).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]=[C:6]1[C:11]2[CH:12]=[CH:13]O[C:10]=2[CH2:9][CH2:8][CH2:7]1.C(OC(C)C)(C)C>C(O)C>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[N:4]([CH2:3][CH2:1][OH:2])[CH:13]=[CH:12][C:11]1=2
Reactant: O=C1CCCc2occc21
Reactant: NCCO
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: O=C1CCCc2c1ccn2CCO
Temperature: 130 °C
Yield: 83.8 %

Procedure:
80 g of ethanolamine were added to a solution of 136 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran in 250 cm3 of ethanol. The solution was heated at 130° C. for 6 hours. After allowing the reaction mixture to return to room temperature with stirring, the mixture was poured over a mixture of 800 cm3 of isopropyl ether and 200 cm3 of petroleum ether. A product crystallized with stirring, and then it was drained, washed with petroleum ether and dried under vacuum over phosphorus pentoxide. 160 g of the expected product was recovered, which product was recrystallized from 240 cm3 of isopropanol. 150 g of the expected product was obtained whose melting point ranged from 96° to 97° C.
Reaction SMILES: Cl.[C:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]=1[Cl:10])([OH:4])=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH2:35])=[N:24][CH:25]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH:35][C:2]([C:5]2[S:6][CH:7]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]=2[Cl:10])=[O:4])=[N:24][CH:25]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CN1CCN(Cc2csc(C(=O)O)c2Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2csc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 78.5 %

Procedure:
A suspension of 2-carboxy-3-chloro-4-(4-methylpiperazin-1-yl)methylthiophene HCl salt (2.0 g, 5.8 mmol) in thionyl chloride (50 mL) was heated at reflux. After 90 hours, the mixture was cooled to ambient temperature and concentrated of all volatiles in vacuo. To a suspension of the resulting solid in pyridine (20 mL) at 0° C was added N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.5 g, 5.2 mmol) in pyridine (5 mL). The mixture was stirred and allowed to warm gradually to ambient temperature. After 16 hours, the mixture was concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (80% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan foam; NMR (DMSO-d6 /TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m, 7), 4.4 (s, 2), 3.04.0 (br m, 8), 2.9 (s, 3) ppm.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:36][CH:37]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:50])[C:38]([OH:40])=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:36][CH:37]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:50])[C:38]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Yield: 87.5 %

Procedure:
BOP coupling of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step D; 200 mg; 0.65 mmol) and 2-aminothiazole (70 mg; 0.70 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after flash chromatography (eluent: 30% ethyl acetate/hexanes) 226 mg (88%) of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C22H27N3O2S (M+) 397.1824, found 397.1825.