Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[Na].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([CH3:28])[N:22]=1>CS(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:11][CH:12]=2)[CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(Oc2ccc(NC(=O)N(C)C)cc2)nc(Cl)n1

Procedure:
4-Hydroxyphenyl-N,n-dimethylurea (14.4 grams; 0.08 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.84 grams) in 50 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloro-6-methylpyrimidine (13.04 grams; 0.08 mole) in 70 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 52°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 80 minutes. Following the reaction period, the reaction mixture was poured into about 400 ml. of cold water and the resulting tan product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in boiling benzene and the resulting solution treated with activated charcoal. Approximately one-half of the solvent was removed by evaporation and the remaining portion was cooled to crystallize the product. As a result of these operations, the desired title product was obtained as a light tan crystalline solid having a melting point of 176°-178°C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27](=[O:29])[NH2:28])[CH:20]=1)[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1SCCCS1)(=[O:3])[CH3:2].C(#N)C.[OH2:33]>>[C:1]([O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27](=[O:29])[NH2:28])[CH:20]=1)[C:6](=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(c1cccc(OCC(N)=O)c1)C(c1ccccc1)C1SCCCS1
Reactant: O
Solvent: CC#N
Product: CC(=O)OC(C(=O)c1ccccc1)c1cccc(OCC(N)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-acetoxy-1-(3-carbamylmethoxyphenyl)-2-phenyl-2-(1,3-dithian-2-yl)-ethane (110 mg, 0.26 mmol) in 5 mL 9:1 (v/v) acetonitrile/water was added mercuric perchiorate (148 mg, 0.33 mmol). The solution was stirred for 15 min, filtered through a 0.45 mm PTFE syringe filter (Gelman) into a 5% sodium bicarbonate solution (10 mL), and extracted with 50 mL dichloromethane. The organic phase was dried and evaporated under reduced pressure to yield a colorless oil. Samples for analysis were evaporated from methanol, dissolved in warm water and lyophilized. Yield: 65 mg (76%). IR: 3445, 1743, 1694, 1462, 1236, 1075, 720 cm-1. 1H NMR (CDCl3, TMS) d 7.936 (d, J=7.82 Hz, 2 H), 7.529 (t, J=7.56 Hz, 1 H), 7.412 (t, J=7.57 Hz, 2 H), 7.319 (t, J=7.86 Hz, 1 H), 7.139 (d, J=7.51 Hz, 1 H), 7.051 (s, 1 H), 6.884 (dd, J=8.21, 2.75 Hz, 1 H) 6.835 (s, 1 H), 6.558 (s, 1 H), 6.148 (s, 1 H), 4.462 (s, 2 H), 2.207 (s, 3 H). 13C NMR (CDCl3, TMS) d 193.577, 170.825, 170.348, 157.593, 135.473, 134.494, 133.637, 130.516, 128.768, 128.711, 122.371, 115.205, 115.140, 77.144, 67.115, 20.715. Anal. Calcd. for C18H17NO5.H2O: C, 62.59; H, 5.54; N, 4.05. Found: C, 62.53; H, 5.12; N, 3.90.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) in pyridine (3 mL) was added 1-isocyanato-4-(trifluoromethyl)benzene (50 μL, 0.348 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=5/95→10/90). The obtained solution was concentrated under reduced pressure to give the title compound (58 mg, 37%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].[OH-].[Na+]>ClCCl.O>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:12]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of ethyl 2-aminoacetate hydrochloride (1.568 g, 11.24 mmol) in dichloromethane (9 mL) and water (2 mL) at 0° C. was added a solution of 2,4-dibromobutanoyl chloride (3.0 g, 10.21 mmol) in dichloromethane (2 mL). A solution of sodium hydroxide in water (11.5 M, 2 mL) was then added slowly. The reaction was stirred 1 hour at 0° C. and then 15 minutes at room temperature. The reaction was then treated with dichloromethane (40 mL) and water (25 mL). The layers were separated, and the organic layer was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried under vacuum to afford the crude title racemic compound (3.165 g in 90% purity, 84% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 6.81 (br s, 1H), 4.58 (dd, J=8.84, 4.80 Hz, 1H), 4.21-4.31 (m, 2H), 4.07 (d, J=5.56 Hz, 2H), 3.51-3.63 (m, 2H), 2.62-2.75 (m, 1H), 2.44-2.57 (m, 1H), 1.28-1.36 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[C:33]([Cl:39])=[N:34][C:35](Cl)=[CH:36][CH:37]=1)=[O:31].C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:34][C:33]=1[Cl:39]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1Cl
Reaction time: 0.17 h
Yield: 87 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (157 mg, obtained in Example 172) was added to a solution of methyl-2,6-dichloropyridine-3-carboxylate (81 mg, [CAS Reg. No. 65515-28-8]) in DMF (3 mL) followed by the addition of triethylamine (0.071 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (7 mg) was added. The mixture was stirred over night at r.t. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the desired compound as a colorless foam (195 mg, 87%). MS (neg. ion, m/e)=569.2 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1ncc2ccccc2c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(CBr)ncc2ccccc12
Temperature: 25 °C

Procedure:
39 mg azo-isobutyronitrile are added to a boiling mixture of 400 mg 3-methyl-4-cyano-isoquinoline and 440 mg N-bromosuccinimide in 30 ml carbon tetrachloride. The reaction mixture is refluxed for two hours. After cooling to ambient temperature the precipitate formed is suction filtered and washed with carbon tetrachloride. The filtrate is evaporated down and chromatographed through a silica gel column with methylene chloride as eluant.
Reaction SMILES: [Br:1][C:2]([Br:29])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][N:16]3C(=O)C4[C:18](=CC=CC=4)[C:17]3=[O:26])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28].O.NN>C1COCC1.C(O)C>[Br:29][C:2]([Br:1])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:26])[CH3:18])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of Example 1D (2.45 g) in 1:1 THF/ethanol (36 mL) was heated to 70° C., treated with hydrazine monohydrate (3×227 μL) at 1 hour intervals, cooled to 25 ° C., and filtered. The filtrate was concentrated, dissolved in a mixture of pyridine (10 mL) and dichloromethane (25 mL), cooled to −5° C., treated with acetic anhydride (880 μL), warmed to room temperature, stirred for 5 minutes, and concentrated to provide the desired product. mp 177-179° C.; MS (ESI(+)) m/e 437 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.81 (t, 1H), 7.50 (s, 1H), 7.47 (dd, 1H), 7.20 (dd, 1H), 5.92 (br t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.77 (dd, 1H), 3.75-3.55 (m, 2H), 2.02 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl.Cl[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1)=[O:9]>>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH2:7][C:8](=[O:9])[NH:10]2)=[CH:15][C:14]=1[F:17]
Reactant: O=C(CCl)Nc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(F)c(Cl)cc2N1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A 26.63 g. sample of the N-(2-chloro)-2-chloro-4-fluoroaniline was thoroughly mixed with 64 g. of anhydrous aluminum chloride, and the mixture was heated at 210°-230° C. for 8.5 hours. The reaction mixture was then poured onto a mixture of ice an 1N hydrochloric acid, with stirring. Stirring was continued for 30 minutes, and then the solid was collected by filtration (22.0 g.). The solid was dissolved in 1:1 ethyl acetate-hexane and chromatographed on 800 g. of silica gel. Elution of the column, followed by evaporation of the fractions, produced 11.7 g. of the N-(2-chloroacetyl)-3-chloro-4-fluoroaniline, followed by 3.0 g. of 6-chloro-5-fluorine-2-oxindole. The latter material was recrystallized from toluene to give 1.70 g. (7% yield) of the title compound, m.p. 196°-206° C. Analysis by NMR spectroscopy indicated that the product was contaminated by some 4-chloro-5-fluorooxindole. A second crop weighing 0.8 g. was obtained.
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][CH2:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][CH2:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCNC3)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCNC3)n(C)c1=O
Yield: 90 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrazino[2,1-f]purine-2,4(1H,3H)-dione (80 mg, 0.22 mmol) and a 1.0 M solution of hydrogen chloride in diethyl ether (1.0 ml, 1.0 mmol) in methanol (20 ml) was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate-2.0 M methanolic ammonia (3:1) to provide (R)-3-(5-hydroxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrazino[2,1-f]purine-2,4(1H,3H)-dione (CT-30099) (60 mg, 90% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]([C:21]#[N:22])([CH3:20])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:14][C:15]([C:18]#[N:19])([CH3:17])[CH3:16])[CH:10]=2)[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:16][C:15]([CH3:17])([CH2:18][NH2:19])[CH2:14][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:20])[CH2:21][NH2:22])[CH:5]=2)[CH:10]=1
Reactant: CC(C)(C#N)Cc1ccc2cc(CC(C)(C)C#N)ccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CN)Cc1ccc2cc(CC(C)(C)CN)ccc2c1
Temperature: 25 °C

Procedure:
In a 1-liter flask, equipped as described in Example 2(b), was put 9.06 g of 2,6-bis(2-methyl-2-cyanopropyl)naphthalene and 300 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 107 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 55 minutes. The mixture was then refluxed for 20 hrs. After the mixture had been cooled in an ice-water bath, a solution of 6 ml of water in 30 ml of methanol was added with stirring during 55 minutes. This was followed by the addition of a solution of 30 ml of water in 60 ml of methanol during 1 hr 35 min. The mixture was stirred for 1 hr while being cooled in the ice-water bath and then at room temperature overnight. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. The resulting solid residue, after being dried in vacuo for about 2 hrs, weighed 8.0 g and melted at 97° to 98.25°. Sublimation of this material at 145° to 165°/0.6 mm gave 2,6-bis(2,2-dimethyl-3-aminopropyl)naphthalene as a colorless, crystalline solid melting at 96.75° to 98.50°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19]C(=O)C(F)(F)F)=[CH:14][C:13]=2[F:26])[N:4](COCC[Si](C)(C)C)[CH:3]=1.Cl.[OH-].[Li+]>O1CCOCC1.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[CH:14][C:13]=2[F:26])[NH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3c(F)cc(NC(=O)C(F)(F)F)cc3F)ccnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 201 mg of N-{4-[(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-2,2,2-trifluoroacetamide (280 μmol) in 4.00 ml of a mixture of hydrogen chloride in dioxane (4N) is stirred at RT overnight, and the precipitated crystals are filtered off and washed with diethyl ether. The solid residue (131 mg) is dissolved in 20 ml of THF. 2.7 ml of a 5% strength solution of lithium hydroxide in water (5.62 mmol) are then added, and the mixture is stirred at RT for 60 h. The reaction mixture is diluted with water and extracted twice with ethyl acetate. After drying over magnesium sulfate, the combined organic phases are concentrated and the residue is purified by preparative HPLC.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36]N>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:31]=1[NH:36][CH:2]=[C:6]2[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Agent: Cl
Product: COc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c[nH]c12

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 420.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:12][C@@H:13]1[CH2:20][N:19]([CH2:21][CH2:22][CH2:23][C@@H:24]2[N:28]3[C:29](=[O:34])[C@H:30]([CH3:33])[NH:31][CH2:32][C:27]3([CH3:35])[O:26][CH2:25]2)[CH2:18][CH2:17][C:14]21[CH2:16][CH2:15]2>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:31]2[C@@H:30]([CH3:33])[C:29](=[O:34])[N:28]3[C@@H:24]([CH2:23][CH2:22][CH2:21][N:19]4[CH2:18][CH2:17][C:14]5([CH2:15][CH2:16]5)[C@H:13]([OH:12])[CH2:20]4)[CH2:25][O:26][C:27]3([CH3:35])[CH2:32]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1NCC2(C)OC[C@H](CCCN3CCC4(CC4)[C@H](O)C3)N2C1=O
Product: C[C@H]1C(=O)N2[C@@H](CCCN3CCC4(CC4)[C@H](O)C3)COC2(C)CN1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenyl isocyanate (28 mg, 0.15 mmol) was added at 0° C. to a solution of (3S,6S)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-6,8a-dimethyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (50 mg, 0.15 mmol), then the ice bath was removed. After 30 min the reaction mixture was evaporated and the residue chromatographed (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) to pruduce the title compound (57 mg, 73%). Colourless gum, MS: 525.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]([NH2:30])[C:28]#[CH:29]>>[CH2:27]([NH:30][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)[C:28]#[CH:29]
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: C#CCN
Product: C#CCNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (400 mg) and propargylamine (80 mg) were reacted in the same manner as described in Preparation Example 25 to give the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])NC1C=C(C=CN=1)C(O)=O)([CH3:3])[CH3:2].NC1C=C(C=CN=1)C(OCC)=O.[NH:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([O:40]C)=[O:39])[C:32]=2[CH:31]=[CH:30]1>>[CH:1]([NH:4][C:5]([N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([OH:40])=[O:39])[C:32]=2[CH:31]=[CH:30]1)=[O:16])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Agent: CCOC(=O)c1ccnc(N)c1
Product: CC(C)NC(=O)n1ccc2c(C(=O)O)cccc21

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl indol-4-carboxylate; [M+H]+ 247
Reaction SMILES: N1CCCCC1.BrC1OC(C=O)=CC=1.[N:15]1([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[O:25][C:21]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: O=Cc1ccc(N2CCCCC2)o1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)o1
Solvent: C1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCCCC3)o2)cc1OC
Yield: 29.6 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from piperidine (1.28 g) was introduced into 5-bromo-2-furaldehyde (875 mg), to thereby yield 5-piperidin-1-yl-furan-2-carbaldehyde (yield: 650 mg, 73%). The produced 5-piperidin-1-yl-furan-2-carbaldehyde (179 mg) was condensed with 3,4-dimethoxybenzyl cyanide (177 mg) through Method A (production step 2), to thereby yield the target product (yield: 100 mg, 30%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[C@@H:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:32][C:24]1[CH:23]=[C:22]([C@@H:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]([OH:34])=[O:5])[N:9]=2)=[O:33])[CH:27]=[CH:26][C:25]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
{3-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (95 mg, 0.19 mmol) was dissolved in 20% trifluoroacetic acid/methylene chloride (2 mL) and allowed to stir at 25° C. for 4 h, after which time the solvent was removed by blowing nitrogen into the reaction vessel. The crude material was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% ethyl acetate/hexanes to 75% ethyl acetate/hexanes), afforded {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (67 mg, 79%) as a white powder: ESI-LRMS m/e calcd for C20H24ClN3O5S [M+] 453.1, found 454.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.24 (m, 2H, CH2), 1.37-1.97 (m, 8H, 4×CH2), 2.12-2.26 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.62 (t, J=7.5 Hz, 1H, CH), 4.72 (AB, Jgem=17.4 Hz, 2H, NCH2), 6.82 (d, J=1.2, 1H, Ar), 7.39 (d, J=1.2, 1H, Ar), 7.43 (d, Jo=8.2 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 9.82 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH3:17])[CH2:10]3)[C:6]=2[CH:5]=[C:4](Cl)[C:3]=1[NH2:19]>CO.C(OCC)(=O)C.[OH-].[Na+].[OH-].[OH-].[Pd+2]>[CH2:15]([N:9]1[CH2:8][CH:7]2[CH:11]([CH2:12][CH2:13][C:14]3[CH:2]=[C:3]([NH2:19])[CH:4]=[CH:5][C:6]=32)[CH2:10]1)[CH2:16][CH3:17]
Reactant: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CC2CCc3cc(N)ccc3C2C1
Yield: 86.2 %

Procedure:
A mixture of 6,8-dichloro-2-propyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-yl-amine (800 mg, 2.67 mmol) and 20% palladiumhydroxide on carbon in methanol (50 ml) was hydrogenated over night at room temperature. The catalyst was filtered, and the solvent was removed under vacuum to yield the crude product. The residue was dissolved in ethyl acetate and 1 M NaOH solution. The aqueous phase was once more extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the pure product (530 mg, 86%).
Reaction SMILES: B(O)O.C([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.Br[C:20]1[N:21]=[C:22]([O:25][CH3:26])[S:23][CH:24]=1>>[CH3:26][O:25][C:22]1[SH:23]=[CH:24][CH:20]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[CH:13][C:14]=2[CH3:18])[N:21]=1
Reactant: COc1nc(Br)cs1
Reactant: Cc1cccc(S(=O)(=O)NC(C)(C)C)c1
Agent: OBO
Product: COC1=NC(c2ccc(S(N)(=O)=O)cc2C)C=[SH]1
Yield: 24.6 %

Procedure:
This compound was prepared analogously to Example 52, starting from N-tert-butyl-3-methyl-benzenesulfonamide boronic acid (1.0 g, 3.69 mmol) and 4-bromo-2-methoxy-thiazole (0.78 g, 4.05 mmol, 1.1 equiv.) After purification on silica-gel with n-heptane/tert.butylmethyl ether 510 mg of the t-butyl protected sulfonamide were obtained. Deprotection analogous to Example 98 yielded 260 mg of the title compound as a light yellow solid. MS (ES): m/e 270 (M−H)