Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(CCN(C)C)C.C([Li])CCC.CCCCCC.[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]=[O:37]>C1COCC1>[CH3:34][C:35]([CH3:41])([CH2:38][CH:39]=[CH2:40])[CH:36]([OH:37])[CH:6]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[C:5]1[CH:12]=[CH:13][CH:14]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Cn2ccnc2)c1
Reactant: C=CCC(C)(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC(C)(C)C(O)C(c1cccc(OC)c1)n1ccnc1
Yield: 6.4 %

Procedure:
7.52 g (40 mmol) of 1-(3-methoxybenzyl)-imidazole and 4.65 g (40 mmol) of TMEDA in 80 ml of absolute THF were metallized using 53.5 ml of 1.5 molar n-butyllithium/hexane solution according to the procedure described in Example 19, and the product was reacted with 5.00 g of 90% purity (≅40 mmol) 2,2-dimethyl-4-pentenaldehyde. Work-up was effected analogously to that in Example 19. The extract residue (12.2 g) was chromatographed as described in Example 19 on a silica gel S/CH2Cl2 column (φ 3.5 cm, height 40 cm), and the combined fractions which contained the compound desired (amount 6.3 g) were subsequently chromatographed a second time on a silica gel S/CH2Cl2 column (φ 2.4 cm, height 88 cm). A group of fractions (2.5 g) from the second chromatography crystallized from a hexane/diisopropyl ether 3:1 solution. After isolation of the substance, 0.77 g (≅6.3% yield) of pure 3,3-dimethyl-1-(1-imidazolyl)-1-(3-methoxyphenyl)5-hexen-2-ol of melting point 83° C. were obtained. C18H24N2O2 (300.41) calculated: C 71.97 H 8.05 N 9.33% found: C 68.9 H 8.0 N 8.6%.
Reaction SMILES: OS(O)(=O)=O.[I:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[CH3:14])N.N([O-])=[O:16].[Na+].C(Cl)Cl>O.CCOC(C)=O>[I:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccc(N)cc1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(O)cc1I
Temperature: 0 °C

Procedure:
A mixture of 8 mL of concentrated H2SO4, 12 mL of water, 3-iodo-4-methylaniline (5.00 g, 21.5 mmol) and 20 g of ice was stirred under ice-bath cooling until a paste resulted. To this paste was added slowly an ice-cold solution of NaNO2 (1.55 g, 22.4 mmol) in 3.5 mL of water and the resulting mixture stirred for 20 minutes while maintaining the temperature at <5° C. The resulting suspension was slowly added to a mixture of 26 mL of concentrated H2SO4 and 24 mL of water preheated to 80° C. This mixture was stirred at 80° C. for 15 min, then chilled in an ice-bath and poured onto 200 g of ice. The resulting mixture was extracted with 100 mL of EtOAc, and the organic extract washed with water, brine, dried (MgSO4) and evaporated to give a residue. The residue was adsorbed onto 15 g of SiO2 from CH2Cl2, loaded into a precolumn and subjected to MPLC through a 120 g column of SiO2 eluting with 5% EtOAc in hexanes (10 min) and then 10% EtOAc (20 min) to provide 3-iodo-4-methylphenol 1-1 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 2.25 (s, 3H), 6.71 (dd, 1H, J=8, 2 Hz), 7.11 (d, 1H, J=8 Hz), 7.23 (d, 1H, J=2 Hz), 9.51 (s, 1H); LC-MS: calculated for C7H7IO 234.0, observed m/e 234.6 (M+H)+.
Reaction SMILES: [Na].[CH:2]([C:13](OCC)=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:18](Br)[C:19]#C.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:13]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]#[CH:19]
Reactant: C#CCBr
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCC(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 180.3 %

Procedure:
To a mixed solution of triethyl methanetricarboxylate sodium salt (25.0 g) in toluene/DMF (120 mL/120 mL) was added propargyl bromide (25.0 g), and the mixture was stirred at 80° C. for 1.5 hr. After allowing to cool, dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was dissolved in THF (30 mL), sodium ethoxide (7.60 g) was added, and the mixture was stirred at room temperature for 1 hr. 1 mol/L Hydrochloric acid (150 mL) was added, and the mixed solution was extracted with chloroform (100 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (35.0 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:20]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33].N.C(#N)CC>[N+]([O-])(O)=O.O>[C:1]([C:3]1[C:4]([N+:32]([O-:34])=[O:33])=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:20]=1)[O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:13][CH2:14]1)#[N:2]
Reactant: CNC(=O)CN1CCC(Oc2cc(C#N)ccc2OC)CC1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCC#N
Product: CNC(=O)CN1CCC(Oc2cc(C#N)c([N+](=O)[O-])cc2OC)CC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
2-[4-(5-Cyano-2-methoxyphenoxy)piperidin-1-yl]-N-methylacetamide (4, 8.78 g, 26.11 mmoles) was suspended in acetic acid (22.82 g, 364.87 mmoles) and the resulting reaction mixture cooled to 5° C. To this was added sulfuric acid (23.64 g, 234.95 mmoles) maintaining the reaction temperature below 30° C. To the resulting solution was added nitric acid (2.40 g, 26.63 mmoles). The reaction mixture was then heated to 35° C. and held for 3 hours. Additional nitric acid (117 mg, 1.31 mmoles) and sulphuric acid (1.31 g 13.1 mmoles) were charged and the reaction mixture was heated at 35° C. for 30 minutes. The solution was cooled to 20° C. and quenched with aqueous ammonia (92.45 g 1.36 moles), resulting in an increase in temperature to 50° C. To the resulting slurry was added, propionitrile (61.58 g 1.12 moles) and water (19 g). The reaction mixture was heated to 80° C. resulting in a clear solution, which upon settling gave two layers. The bottom layer was removed. The reaction mixture was cooled to 20° C. resulting in a thick slurry. The solid was isolated by filtration, washed with propionitrile (6.16 g 112.0 mmoles) and dried to afford the title compound (7.44 g, 82% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 2H) 1.97 (m, 2H) 2.35 (m, 2H) 2.61 (d, J=4.7 Hz, 3H) 2.66 (m, 2H) 2.90 (s, 2 H) 3.96 (s, 3H) 4.73 (tt, J=8.4, 4.0 Hz, 1H) 7.71 (q, J=4.7 Hz, 1H) 7.82 (s, 1H) 7.86 (s, 1 H). Mass Spectrum: m/z (M+H)+ 349.2
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[C:15](=[O:32])[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[N:17]=[CH:18][C:19]=1[NH2:20]>O1CCCC1>[SH:7][C:6]1[NH:13][C:14]2[C:15](=[O:32])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:17]=[CH:18][C:19]=2[N:20]=1
Reactant: Nc1cnn(Cc2cccc3ccccc23)c(=O)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1c2[nH]c(S)nc2cnn1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.99 g (28.0 mmol) of N,N′-thiocarbonyldiimidazole were added to a solution of 4.4 g (16.5 mmol) of 4,5-diamino-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one in 100 ml of tetrahydrofuran and stirred overnight at ambient temperature. Then the mixture was concentrated by evaporation in vacuo, the residue was combined with approx. 30 ml of water, made weakly acidic with hydrochloric acid, the product precipitated was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:4]
Reactant: ClCCN1CCN(c2ccccc2)CC1
Reactant: CNC(=O)N1CCSC1c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
A mixture of 2.38 g of N-methyl-2-(2-hydroxyphenyl)thiazolidine-3-carboxamide, 1.38 g of potassium carbonate, 0.7 g of sodium iodide, 3.36 g of 1-(2-chloroethyl)-4-phenylpiperazine and 25 ml of dimethylformamide is stirred at 90° C. for 24 hours. The mixture is concentrated under reduced pressure to remove dimethylformamide. Water is added to the residue, and the aqueous mixture is extacted with ethyl acetate. The extract is washed with dilute sodium hydroxide solution and water, successively. The ethyl acetate solution is dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (sovent, benzene:ethyl acetate-1:5). 1.89 g of N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([O:30][CH3:31])[CH2:26][CH2:25]4)[C:20]3=[O:32])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:33][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C@H:24]2[CH2:25][CH2:26][C@H:27]([O:30][CH3:31])[CH2:28][CH2:29]2)[C:20]1=[O:32]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](OC)CC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Combine 3′,5′-dichloro-4′-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (1.60 g, 3.3 mmol), MeOH (15 mL) and 1N NaOH solution (15 mL). Stir for 3 hours at 70° C. Concentrate under vacuum and quench with 1N HCl. Filter the white precipitate and rinse the solid with water. Dry under vacuum to recover 1.32 g (86%) of the title compound: MS (m/z): 476 (M+).
Reaction SMILES: C([O:4][C:5](=[O:66])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:65])[NH:24][CH2:25][CH2:26][CH:27]([N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:57])[C:28]([NH:30][C@@H:31]([CH2:35][S:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]([NH2:34])=[O:33])=[O:29])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[NH2:34][C:32](=[O:33])[C@@H:31]([NH:30][C:28](=[O:29])[CH:27]([N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:57])[CH2:26][CH2:25][NH:24][C:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@@H:6]([C:5]([OH:66])=[O:4])[NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[CH:17][CH:18]=1)=[O:65])[CH2:35][S:36][C:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(CCNC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Temperature: 25 °C

Procedure:
2.2 g (2.38 mmol) of the compound from example 8A was dissolved in 48 ml tetrahydrofuran. 1.66 ml (11.9 mmol) triethylamine, 0.45 ml (11.9 mmol) formic acid and 0.275 g (0.238 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 50 ml water and twice extracted with approx. 50 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 100 g silica gel. Solvents used were dichloromethane, dichloromethane/methanol 50/1 and dichloromethane/methanol 4/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.44 g (1.61 mmol, 68% of theory) product as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:20])[C:13]3[C:14](=[CH:16][N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([N+:21]([O-:23])=[O:22])=[CH:6][N:5]=1)[CH3:2].[Br:24]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:24][C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:20])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[CH:8]=3)=[N:15][C:14]=12
Reactant: BrBr
Reactant: CCOc1ncc([N+](=O)[O-])cc1-c1nc2cn(C)nc2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ncc([N+](=O)[O-])cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the title compound of Example 52 (6.9 g, 21.8 mmol), bromine (1.35 mL, 26.2 mmol), and sodium acetate (2.7 g, 32.7 mmol) in acetic acid (100 mL) was heated under reflux for 7 h, then allowed to cool. Additional bromine (0.35 mL, 6.8 mmol) was added and the reaction stirred at room temperature for a further 18 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was partitioned between dichloromethane and water and the resulting precipitate filtered off, washed with dichloromethane, water, then diethyl ether and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:32]O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:32])=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(c2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 46 of Example 1 by reaction with thionyl chloride and methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccccc1Cl
Temperature: 83 °C
Yield: 101.6 %

Procedure:
To a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser capped with a nitrogen inlet, and a heating mantle were added o-chloroacetophenone (305.8 g, 1.98 mol), N,N-dimethylformamide dimethyl acetal (707.0 g, 5.93 mol), and acetonitrile (dried over molecular sieves, 3.0 L) at room temperature, giving an orange solution. The mixture was heated gradually to reflux (83° C.) over 1.5 hours, then maintained at reflux for 18 hours. After the dark red solution was cooled to room temperature, the acetonitrile was evaporated, leaving a heavy red oil. The oil was redissolved in toluene (1 L). The toluene was evaporated to afford the crude enamine which was further dried under high vacuum overnight to afford 2'-chloro-3-dimethylaminopropenophenone (422 g, quantitative) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[CH3:22][O:23][C:24]1[C:29]([NH2:30])=[CH:28][N:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[N:27]=[CH:28][C:29]=1[NH:30][C:19]([C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:20]
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: COc1cc(N2CCCC2)ncc1N
Product: COc1cc(N2CCCC2)ncc1NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 73.3 %

Procedure:
The process is carried out according to the method described in example 2, using 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.424 g (2.09 mmol) of 4-methoxy-2-(pyrrolidin-1-yl)-5-aminopyridine, obtained in step 6.1 (Compound Vb). 0.59 g of the expected product is thus isolated.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([CH3:13])([CH:11]=[CH2:12])[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:6][C:7]([CH3:13])([CH:11]=[CH2:12])[CH2:8][CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: C=CC(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(C)(C)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In a tetrahydrofuran (30 ml) solution of 3,3-dimethyl-4-penten-1-ol (3.6 g), triethylamine (4.1 g) and methanesulfonyl chloride (4.3 g) were added at 0° C., followed by raising the temperature to room temperature and further stirring for 30 minutes. Water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product (5.7 g) of methanesulfonic acid 3,3-dimethyl-4-pentenyl ester. This crude product was subjected to a subsequent reaction without being purified.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C[O:18][C:19]([C:21]1C(N[C:25](=[O:27])[CH:26]=1)=O)=O.S(=O)(=O)(O)O>O>[C:25]1(=[O:27])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:19](=[O:18])[CH:21]=[CH:26]1
Reactant: COC(=O)C1=CC(=O)NC1=O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)C=CC2=O)cc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A 3.02 g (20 mmols) portion of 4-aminomethylbenzoic acid was admixed with 100 ml of saturated aqueous solution of NaHCO3, and 3.1 g (20 mmols) of methoxycarbonylmaleimide was added to the mixture at 0° C. After stirring the mixture at 0° for 10 minutes, 200 ml of water was added thereto. The mixture was then stirred at 30° C. for 1 hour and thereafter adjusted to a pH of 2 with concentrated sulfuric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over Na2SO4 and concentrated, affording 3.18 g (yield 87%) of crude 4-maleimidomethylbenzoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:9]=[C:8]([C:24]([F:27])([F:26])[F:25])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]([C:24]([F:25])([F:26])[F:27])=[N:9]2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2nc(C(F)(F)F)cc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 93 (500 mg, 1.278 mmol) in ethanol (4.3 mL) was added a solution of NaOH (1.916 mL, 2N, 3.83 mmol) and the mixture was stirred at room temperature for 1 h, then it was concentrated and 1N HCl was added till the solution reached PH-1. Extraction with EtOAc and normal work-up gave crude 101 as colorless oil. LRMS (ESI): calc. 363.3; found 386.2 (MNa)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>>[C:1]([O:5][C:6](=[O:18])[N:7]([CH3:8])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]2[CH:14]([O:27]2)[CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(CCCC1CC=CCC1)C(=O)OC(C)(C)C
Product: CN(CCCC1CCC2OC2C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
(3-Cyclohex-3-enyl-propyl)-methyl-carbamic acid tert-butyl ester (14.24 g, 56.2 mmol) was treated with 3-chloroperbenzoic acid (70% purity, 14.8 g, 60 mmol, corrected) according to the method of Example 7 Step B and stirred for 3 hours at room temperature. After work up the title compound (14.6 g, 96% yield, uncorrected) was obtained as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[H-].[Na+]>CN(C)C=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To an N,N-dimethylformamide solution (100 mL) of 4-hydroxybenzaldehyde (10 g, 82 mmol) and 2-fluoropyridine (8.0 g, 82 mmol) was added sodium hydride (3.3 g, 82 mmol, 60% in oil), which was stirred for 30 minutes at 120° C., then for 45 minutes at 140° C., and then for 2 hours at 160° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water (three times), and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (9.3 g, 57%).
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:3]=1[CH2:4][O:5][NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@:8]1([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](=[S:16])[NH:14][CH3:15]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:3]=1[CH2:4][O:5][NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@:8]1([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](=[S:16])[NH:14][CH3:15]
Reactant: CNC(=S)[C@]1(c2cccnc2)CCCCC1NOCc1c(F)c(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[C@H]1NOCc1c(F)c(F)c(F)c(F)c1F

Procedure:
Prepared from (-)-(S)-2-(2,3,4,5, 6-pentafluorobenzyloxyamino)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (0.49 g) as described in Example 1. The crude product was subjected to flash chromatography on silica gel eluting with chloroform/methanol: 98.5/1.5 to give (1S,2R)-2-(2,3,4,5,6-pentafluoro-benzyloxyamino)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, a yellow solid (0.34 g, 69%), m.p. 57°-60°. Found: C, 53.7; H, 4.37; N, 9.5%; C20H20F5N3OS requires C, 53.9; H, 4.53; N, 9.43%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.O1CC[CH2:19]OO1.C(O)C>C(N(CC)CC)C>[CH2:19]=[N:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C1COOOC1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C

Procedure:
A mixture of 8.40 g. 9-amino-1,2,3,4-tetrahydroacridine and 4.71 g. Trioxan in 200 ml. ethanol in which 1 g. triethylamine had previously been dissolved was heated to reflux for 12 hours under vigorous stirring. The mixture was cooled to room temperature, then filtered. The filtrate was concentrated under reduced pressure and the dry residue was taken up in hot acetonitrile (25 ml.). The solution was filtered when hot and then cooled. The methylenic derivative started to crystallize as yellowish crystals.