Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=O)[CH2:5][CH2:6][C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3].[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[C:15]2[C:16]=1[CH:17]=[CH:18][CH2:19]2)([CH3:14])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C(=O)CCC(=O)C(C)(C)C
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(C)(C)C)c2c1C=CC2
Temperature: 25 °C
Reaction time: 30 h
Yield: 10.3 %

Procedure:
A mixture of 14.8 g (74.6 mmol) of 2,2,7,7-tetramethyl-3,6-octanedione and 6.7 ml (82.1 mmol) of cyclopentadiene was added to 34.3 ml of a 30 percent strength solution of sodium methanolate (186 mmol) in methanol at 0° C. in the course of 10 minutes. After the mixture had been stirred at room temperature for 30 hours, it was hydrolyzed and extracted with methylene chloride. After drying over MgSO4, the product was evaporated to dryness. Column chromatography on silica gel with hexane as the mobile phase gave 1.75 g (10 %) of the indene 10. For the NMR data, see Table 1.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8][N:7]=1>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8]1)=[O:4]
Reactant: CN=C=O
Reactant: Oc1nsc(OCc2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CNC(=O)n1sc(OCc2ccc(Cl)cc2)nc1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
5 ml of methyl isocyanate were added to a solution of 12.1 g of 3-hydroxy-5-(p-chlorobenzyloxy)-1,2,4-thiadiazole in 150 ml tetrahydrofuran and the mixture was stirred for 2 hours and 20° C and then concentrated to dryness. The residue was crystallized from ethyl acetate to obtain 7.3g of 2-(N-methylcarbamoyl)-5-(p-chlorobenzyloxy)-1,2,4-thiadiazole-3-one melting at 145° C.
Reaction SMILES: CS([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34]>CN(C)C(=O)C>[CH3:23][NH:22][C:20]([C:16]1[CH:15]=[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:7]3[N:8]=[C:4]([NH:24][C@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][C@H:26]4[OH:34])[O:5][C:6]=3[CH:12]=2)[CH:19]=[CH:18][N:17]=1)=[O:21]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4c5ccccc5C[C@H]4O)oc3c2)ccn1

Procedure:
A solution of 4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide (17 mg, 0.05 mmol, 1.0 eq) and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (30 mg, 0.2 mml, 4.0 eq) in 1 mL of N,N-dimethylacetamide was heated in the microwave at 90° C. for 600 seconds. The crude product was purified by reverse phase prep HPLC to give the title compound. MH==417.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1>>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:17]1[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:25]2
Reactant: COc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: COc1ccc(-c2nc3cccc(C(=O)NC4CC5CCCC(C4)N5C)c3o2)cc1
Yield: 36 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 36% yield as a off-white solid: mp 160-162° C.; 1H NMR (500 MHz, CD3OD) δ 8.22 (dt, J=9.7, 2.8 Hz, 2H), 7.82 (dd, J=7.9, 1.0 Hz, 1H), 7.72 (dd, J=7.7, 1.0 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz, 2H), 4.61 (m, 1H), 3.90 (s, 3H), 3.16 (m, 2H), 2.59 (m, 2H), 2.55 (s, 3H), 2.14 (m, 1H), 2.08 (m, 2H), 1.61 (m, 3H), 1.99 (m, 2H); MS (ESI) m/z 406 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH3:19])[CH2:4][NH:5][C:6]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=[C:8]([S:16][CH3:17])[N:7]=1)[CH3:2].C(O)C.[OH-].[Na+]>O>[CH2:18]([CH:3]([CH2:1][CH3:2])[CH2:4][NH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([S:16][CH3:17])[N:7]=1)[CH3:19]
Reactant: CCC(CC)CNc1nc(SC)ncc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(CC)CNc1nc(SC)ncc1C(=O)O
Yield: 90.6 %

Procedure:
The product of Example 108A (0.50 g, 1.68 mmol)) in water and ethanol (1:2) was reacted with sodium hydroxide (0.22 g, 5.50 mmol) at ambient temperature for 3 hours. The reaction was concentrated under vacuum to remove the ethanol and neutralized with aqueous hydrochloric acid (1 M). The resulting precipitate was collected by filtration and dried to yield the title compound (0.41 g, 91%). MS (DCI/NH3) m/z 270 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.88 (t, J=7.54 Hz, 6H), 1.31 (dt, J=14.25, 7.03 Hz, 4H), 1.53 (m, 1H), 2.47 (s, 3H), 3.46 (t, J=6.07 Hz, 2H), 8.50 (s, 1H), 13.22 (s, 1H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCCCc3ccccc32)cc1

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (1.05 g, 7.14 mmol) in dichloromethans (40 ml) were added 4-cyanobenzoic acid (1.26 g, 8.57 mmol), triethylamine (1.00 g, 7.14 mmol), 4-(dimethylamino)pyridine (0.87 g, 7.14 mmol) and WSCDI (2.86 g, 14.28 mmol). The mixture was stirred at reflux for 18 h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.50 g (76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:33])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([NH:25]C(=O)OC(C)(C)C)[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[NH:18][CH:17]=[C:16]2[CH2:15][C@H:14]([N:10]1[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][C:11]1=[O:13])[CH3:33]
Reactant: C[C@H](Cc1c[nH]c2c(NC(=O)OC(C)(C)C)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Agent: Cl
Solvent: CO
Product: C[C@H](Cc1c[nH]c2c(N)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl 3-((2R)-2-((5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl)propyl)-1H-indol-7-ylcarbamate (419.2 mg, 0.894 mmol) in methanol (2 mL) is added a 10% solution of hydrochloric acid in methanol (10 mL) under nitrogen atmosphere, and the mixture is stirred at room temperature for 21 hours. The solvent is evaporated, and the residue is separated into a saturated ammonia solution in chloroform and water, and the organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (a saturated ammonia solution in chloroform-methanol=1:0 20:1) to give the title compound (299 mg, 90%).
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[Br:16]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:16][C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CCCCCCCCCCC(=O)OC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCC#CBr
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.9 %

Procedure:
To a mechanically stirred solution of ester 4 (37 g, 176 mmol) in 700 mL of acetone under nitrogen was added N-bromosuccinimide (34.4 g, 194 mmol) followed by silver nitrate (2.7 g, 18 mmol). The reaction mixture was allowed to stir at room temperature in the absence of light for 21 h. The thick, pale yellow reaction mixture was filtered through a sintered glass funnel, concentrated in vacuo to one third volume, and diluted with 500 mL of water. This was extracted with 4×250 mL of hexanes, and the combined organic layers were washed with 100 mL of brine, dried over sodium sulfate, concentrated in vacuo, and vacuum dried to give bromoacetylene 5 (47.81 g, 94%) as a yellow oil:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:18][NH2:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
100 g piperidine-1,4-dicarboxylic acid 1-tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/MeOH=20/1)
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([B:35]4[O:39]C(C)(C)C(C)(C)[O:36]4)[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C1(B(O)O)C=CC=CC=1.Cl>O1CCCC1>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[C:31]([B:35]([OH:36])[OH:39])[CH:32]=[CH:33][CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(B4OC(C)(C)C(C)(C)O4)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(B(O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.3 %

Procedure:
A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide (269 mg, 0.45 mmol), polymer-supported benzeneboronic acid (770 mg, 2.23 mmol), aqueous 5N HCl (0.62 mL, 3.12 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 48 hours. The mixture was filtered, the filtrate was concentrated to dryness and purified by reverse phase HPLC to afford 3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic acid (41 mg, 0.078 mmol, 17% yield) as a white solid. 1H NMR (METHANOL-d4) δ 7.99-7.95 (m, 2H), 7.94 (s, 1H), 7.77-7.38 (m, 4H), 7.32-7.25 (m, 3H), 3.32 (s, 3H), 2.98 (s, 3H), 2.29-2.25 (m, 1H), 1.10-0.37 (m, 4H). LCMS (m/z, ES+)=523 (M+H+).
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([NH:33][CH3:34])=[O:32])[CH:25]=3)=[CH:11]2)=[N:6]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([NH:33][CH3:34])=[O:32])[CH:25]=3)=[CH:11]2)=[N:6]1
Reactant: CNC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2ccc3nn(CCOC)cc3c2)ccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2ccc3nn(CCO)cc3c2)ccn1
Yield: 53.4 %

Procedure:
50 mg (0.11 mmol) of N-[2-(2-methoxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide is introduced into 5 ml of methylene chloride and mixed drop by drop under argon and in a moisture-free environment at −78° C. with 0.56 ml of boron tribromide (1 molar in methylene chloride). It is stirred for 15 more minutes, the cold bath is removed, and it then is stirred for 2 more hours. Then, it is mixed with water, the methylene chloride is drawn off, made alkaline with sodium bicarbonate solution and extracted twice with 15 ml each of ethyl acetate. The collected organic phase is dried, filtered, and concentrated by evaporation. The residue is chromatographed on silica gel with a gradient of methylene chloride:ethanol=100:0 to 90:10 as an eluant, and 27 mg of N-[2-(2-hydroxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)OCC4C=CC=CC=4)=[C:21]([F:36])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:10])[CH2:5][CH2:4]1>O1CCCC1.[C].[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]([N:6]3[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:37])[CH2:8][CH2:7]3)=[O:10])[CH:17]=2)=[CH:20][C:21]=1[F:36]
Reactant: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After adding 10% palladium-carbon (21.2 mg) to a solution of benzyl (4-{2-[(4-dimethylaminopiperidine-1-carbonyl)amino]pyridin-4-yloxy}-2-fluorophenyl)carbamate (101 mg) in tetrahydrofuran (10 ml), the mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran (4 ml) to provide a solution of 4-dimethylaminopiperidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide in tetrahydrofuran (14 ml). A 7 ml portion thereof was concentrated to almost dryness. A solution of 2-phenylacetyl isothiocyanate (26.4 mg) in toluene (3.0 ml) was added to a solution of the residue in ethanol (3.0 ml) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (60 ml) and saturated aqueous sodium hydrogencarbonate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol 20:1). The obtained solid was suspended in hexane and filtered. It was then washed with hexane. It was subsequently purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and then the residue was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The organic layer was then concentrated to provide the title compound (8.4 mg) as white powder.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[Cl:6][CH2:7][CH:8]=O>Cl>[Cl:6][CH2:7][CH:8]1[NH:5][S:1](=[O:3])(=[O:2])[NH:4][CH:8]([CH2:7][Cl:6])[NH:5][S:1](=[O:3])(=[O:2])[NH:4]1
Reactant: O=CCCl
Reactant: NS(N)(=O)=O
Agent: Cl
Product: O=S1(=O)NC(CCl)NS(=O)(=O)NC(CCl)N1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid are added to 0.012 mole of chloroacetaldehyde, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and recrystallised from acetone/petroleum ether. 3,7-Di-(chloromethyl)-1,5-dithia-2,4,6,8-tetra-aza-cyclooctane-1,1,5,5-tetraoxide is obtained as colourless crystals of melting point 175° C (decomposition) in a yield of 70% of the theoretical yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.O.O.[Sn](Cl)Cl>[OH-].[Na+]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(N)ccc1F
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-fluoro-5-nitrobenzoate (1.96 g, 9.82 mmol) in ethyl is 5 acetate (40 ml) was added tin (II) chloride dihydrate (7.53 g, 33.38 mmol). The mixture was stirred overnight. Then aqueous NaOH solution (1 M, ca. 50 ml) was added to adjust the pH to 9. The layers were separated, the aqueous layer was extracted with ethyl acetate (4 times 20 ml) and the combined organic layers were washed with water and dried with Na2SO4. Filtration followed by evaporation of the solvent in vacuo afforded a yellowish solid, 1.48 g (90%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@H:13]([OH:25])[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2].CC1C2COC(=O)C=2C=CC=1[C@H]1CO1>>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@@H:13]([OH:25])[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@H](O)c1ccc2c(c1C)COC2=O
Agent: Cc1c([C@H]2CO2)ccc2c1COC2=O
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@@H](O)c1ccc2c(c1C)COC2=O

Procedure:
Synthesis is analogous to that for (S)-tert-butyl 3-(acetylthiomethyl)-4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate starting from 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one: LC/MS: [(M+1)]+=465.3;
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O>CC(N(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(O)c1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1-c1ccc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)s1
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
1-{3-[4-(5-Bromothiophen-2-yl)pyrimidin-2-ylamino]-phenyl}-ethanol (15 mg, 0.04 mmol), 2,6-dimethylphenylboronic acid (7.2 mg, 0.048 mmol) and PdCl2(dppf)2 (1.6 mg, 0.002 mmol) were combined in Smith microwave vial (0.2-5.0 mL) in degassed DMA (300 uL) and 2 M Na2CO3 (250 uL). The mixture was micro waved at 165° C. for 900 s. The mixture was diluted with 500 uL DMSO and purified directly by preparative HPLC to afford 1-(3-{4-[5-(2,6-dimethylphenyl)-thiophen-2-yl]-pyrimidin-2-ylamino}-phenylethanol (4.9 mg, 30% yield). 1H NMR (500 MHz, DMSO-d6) δ1.29 (d, J=6.5 Hz, 3H), 2.14 (s, 6H), 4.64 (m, 1H), 5.07 (d, J=3.5 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.02 (d, J=4 Hz, 1H), 7.16-7.25 (m, 4H), 7.35 (d, J=5 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.84 (br t, 1H), 8.03 (d, J=3.5 Hz, 1H), 8.48 (d, J=5 Hz, 1H), 9.58 (s, 1H). MS: m/z 402 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.Cl.[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)N)=[O:18])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]2[C:2]3[CH2:3][CH:4]([C:8]([OH:10])=[O:9])[CH2:5][CH2:6][C:7]=3[C:22]3[C:21]2=[CH:26][CH:25]=[C:24]([O:27][CH3:28])[CH:23]=3)=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(N(N)C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccc(Cl)cc2)CC(C(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
3-Oxocyclohexanecarboxylic acid (27.2 mg, 0.19 mmol) was added to a stirred solution of 4-chloro-N-(4-methoxyphenyl)benzohydrazide hydrochloride (50 mg, 0.16 mmol) in acetic acid (0.5 mL), the mixture was heated at 80° C. under nitrogen for 3 h, then it was allowed to cool to ambient temperature and stirred overnight. Ice-water (2 mL) was poured into the cold reaction mixture and the formed precipitate was collected by filtration, carefully washed with water and dried in vacuo to yield the title compound (50 mg, 82%) as an off-white solid. C21H18ClNO4, Mr=383.82; 1H NMR (400 MHz, DMSO-d6) d: 1.79-1.87 (m, 1H), 2.11-2.14 (m, 1H), 2.57-2.75 (m, 5H), 6.73 (dd, J=2.8/9.0 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 7.62-7.69 (m, 4H); LCMS (ESI) tR: 2.82 min (>99%, ELSD), m/z: 384.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([O:19]CC)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:23]>CO>[CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([NH2:23])=[O:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(CC(C)C)n(Cc2ccccc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1cc(C(N)=O)nn1Cc1ccccc1

Procedure:
A solution of ethyl 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxylate (30 g) in methanol (60 mL) was treated with ammonium hydroxide (60 mL) according to a modification of the method described in Part D of Examples 1-4. The reaction was heated for 14 hours. At the end of the reaction, the methanol was removed under reduced pressure, and the remaining solution was extracted with tert-butyl methyl ether (3×). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Toluene was added twice and removed under reduced pressure to remove residual water. Hexane was added to the residue; crystals formed and were isolated by filtration, washed with hexane, and air-dried overnight to provide 6.93 g of 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide as small, off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2cccc(Cl)c2)CC1

Procedure:
250 mg of the target compound (0.64 mmol, 40.5%) was obtained using 1-(2-methoxyphenyl)piperazine (603 mg, 3.14 mmol), 3′-chlorobiphenyl-2-carbaldehyde (340 mg, 1.57 mmol) and NaBH(OAc)3 (1.0 g, 4.71 mmol) according to the synthesis method of Compound 1.