Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:5][C:6]=1[C:7]#[N:8].C([OH:24])CC.[OH-].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:5][C:6]=1[C:7]([NH2:8])=[O:24]
Reactant: N#Cc1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Reactant: CCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Temperature: 130 °C

Procedure:
Into a microwave vial was added 2-amino-5-(6-piperidin-1-ylpyridin-3-yl)thiophene-3-carbonitrile (225 mg, 0.79 mmol), 1-propanol (6.2 ml), and 25% sodium hydroxide (1.8 ml) and the mixture was heated in the microwave to 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate and sodium bicarbonate to neutralize, extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol to afford the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1>>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(C(F)(F)F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-aminobenzotrifluoride (30 μl, 0.243 mmol) similar to Example 11 and isolated as a pale white solid (74 mg, 93%). 1H NMR (CDCl3): 8.84–8.82 (m, 1H), 8.49–8.45 (m, 1H), 7.95 (s, 1H), 7.90–7.85 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.45–7.40 (m, 2H), 6.78 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:33][C:34]1[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=1[O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:47]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]2([C:59](O)=[O:60])[CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1>CN(C=O)C.O>[C:47]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]2([C:59]([N:40]3[CH2:41][CH2:42][CH:37]([O:36][C:35]4[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=4[Cl:33])[CH2:38][CH2:39]3)=[O:60])[CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2ccccc2)cc1)C1(C(=O)N2CCC(Oc3ccccc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
HOBt (57 mg, 0.42 mol) and DIPEA (137 mg, 1.06 mmole), EDCI.HCl (82 mg, 0.42 mol) followed by 4-(2-chloro-phenoxy)-piperidine hydrochloride (105 mg, 0.42 mol) were added to a stirred solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid (100 mg, 0.35 mmol) in DMF (2.0 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water. The product was extracted with ethylacetate and the organic layers were washed with brine and concentrated to afford 78 mg (46%) of 1-[4-(2-chloro-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide. LCMS: 475.17 (M+1)+, 92.81%, 1H NMR (DMSO-d6): δ 9.8 (s, 1H), 7.8-7.5 (d, 2H), 7.7-7.6 (t, 4H), 7.5-7.4 (m, 3H), 7.4-7.2 (m, 3H), 7.0-6.9 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.4 (m, 2H), 1.3-1.2 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([I:19])[CH:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Temperature: 240 °C
Yield: 81.9 %

Procedure:
A mixture of 2-[(4-iodo-phenylamino)-methylene]-malonic acid diethyl ester (81 g, 0.21 mol) in diphenylether (60 mL) was refluxed at 240° C. for 14 h. After cooling, ethanol was added and the mixture was heated to reflux for 3 h. After cooling, the solid was collected by filtration, washed with hexane and dried to obtain 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (59 g, 83%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCBr
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCCC(=O)O

Procedure:
Reaction of 9-bromononanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidobutanoic acid 12. Saponification was not necessary. Used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[SH:10][CH2:11][CH:12]([CH2:14][OH:15])[OH:13]>C(N(CC)CC)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][CH2:8][S:10][CH2:11][CH:12]([OH:13])[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCC(O)CS
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCSCC(O)CO
Yield: 93.2 %

Procedure:
Acrylic acid t-butyl ester (15 g) and thioglycerol (15 g) were mixed together in the absence of solvent. To the reaction mixture, one drop of triethylamine was added to cause an exothermic reaction, yielding a homogeneous reaction mixture, which was then diluted with ethyl acetate, washed with water and dried, followed by solvent concentration under reduced pressure, to yield the title compound (25.79 g, yield 93%) as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:19]=2)=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:48]([O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH2:53])C.C(N(CC)CC)C>O1CCCC1>[CH3:48][O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH:53][C:29](=[O:30])[CH2:28][CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:12]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:19]1
Reactant: Cn1cc(C2=C(c3cn(CCC(=O)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)CCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[3-[4-(1-Methylindol-3-yl)-1H-pyrrole-2,5-dion-3-yl]-indol-1-yl)-propionic acid 272 mg (0.65 mmol) are dissolved in 3 mL anhydrous tetrahydrofuran and mixed with 145 mg (0.70 mmol) dicyclohexylcarbodiimide and a mixture of 90 mg (0.8 mmol) alanine ethyl ester hydrochloride and 85 mg triethylamine dissolved in 5 mL anhydrous tetrahydrofuran. The reaction mixture is stirred for 24 hours at ambient temperature, the solvent is then distilled off in a vacuum, the residue is taken up in 100 mL ethyl acetate, and the organic phase is washed with water. After drying over anhydrous sodium sulphate and distilling off the solvent in a vacuum, the crude product obtained is separated by thick layer chromatography (silica gel, dichloromethane/methanol=90:10%). The fraction with the RF of 0.31 is separated, the product is extracted and, after removal of the solvent in a vacuum, there are isolated 130 mg (40% of theory) of the desired product;
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[C:8]([C:17]2[C:18]([C:27](OC)=[O:28])=[CH:19][C:20]([O:25][CH3:26])=[CH:21][C:22]=2[O:23][CH3:24])=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:4][CH2:5][C:7]1[C:8]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[CH2:27][OH:28])=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)c1cc(OC)cc(OC)c1-c1c(OC)cc(OC)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CO)c(-c2c(CO)cc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
(6′-Hydroxymethyl-4,6,2′,4% tetramethoxy-biphenyl-2-yl)-methanol: 4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester (2.5 g) was dissolved in THF (96 mL), and 1M LiAlH4 in THF (9.6 mL) was added. After stirring at room temperature for overnight, the mixture was quenched with water and 2N HCl (24 mL) was added. The mixture was evaporated under vacuum and partitioned with DCM (300 mL) and water (200 mL). The organic layer was dried over Na2SO4 and crystallized with DCM to provide (6′-hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol (1.7 g, 77%) as a pale blue white triclinic crystals.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](N1C=CN=C1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1COCC1.C(Cl)CCC>[F:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:27]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: O=C(c1ccccc1)c1cc(F)ccc1NC(=O)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCOC1
Solvent: CCCCCl
Product: O=C1Nc2ccc(F)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide (30.00 g, 97.00 mmol) in THF (300 mL) was added 2,2,2-trifluoroethylamine (11.53 g, 116.39 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature. Butyl chloride (500 mL) and 10% citric acid (250 mL) were added and the reaction stirred vigorously for 40 min. The precipitate was then isolated by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a yellow solid. 1H NMR (CDCl3, 400 MHz) 8.59 (s, NH); d (7.47, J=6.96 Hz, 2H, ArH); 7.36 (m, 3H, ArH); 6.99 (m, 2H, ArH); 6.79 (m, 1H, ArH); 4.39 (m, 1H, CH2); 3.56 (m, 1H, CH2); 3.23 (s, OH); MS (Electrospray): m/z 363.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11]N(C)C)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][C:16]([NH2:18])=[O:17].Cl.[Cl-].[NH4+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:11]=[N:15][C:16](=[O:17])[NH:18][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=c1ncc(-c2ccc(Cl)cc2)c[nH]1
Yield: 29.7 %

Procedure:
A mixture of 2-(4-chlorophenyl)dimethylaminopropenal (Example 145a) (5.13 g), urea (2.4 g), concentrated HCl (10 ml), water (4 ml) and ethanol (150 ml) was refluxed for 4 hours. After cooling to room temperature concentrated ammonium chloride was added until the pH was 7. The resulting yellow solid was filtered off and dried yielding 1.5 g of 5-(4-chlorophenyl)-2-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([CH:15]=O)=[CH:8][CH:7]=1.Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[O:26][C@H:27]1[CH2:30][C@H:29]([NH2:31])[CH2:28]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[O:26][C@H:27]1[CH2:28][C@H:29]([NH:31][CH2:15][C:9]2[C:10]3[N:11]([CH:12]=[CH:13][N:14]=3)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[CH2:30]1
Reactant: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Reactant: COCOCc1ccc(C=O)c2nccn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCOCc1ccc(CN[C@H]2C[C@H](Oc3cccc(Cl)c3Cl)C2)c2nccn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of impure 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde (49 mg, 0.223 mmol) and trans-3-[(2,3-dichlorophenyl)oxy]cyclobutanamine hydrochloride salt (55 mg, 0.205 mmol) in a mixture of DCM (2 mL) and methanol (2 mL) was added DIPEA (0.039 mL, 0.223 mmol) and sodium triacetoxyborohydride (189 mg, 0.89 mmol). The reaction was stirred at ambient temperature for 3.5 hours when LCMS showed the reaction to be complete. DCM (10 mL) was added and the solution washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried (hydrophobic frit) and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (20 g) using a 0-10% methanol-DCM gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (26 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Ic1cnc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ncc(I)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-iodo-2-piperazin-1-ylpyrimidine (7.0 g, 24.1 mmol, CAS number 95847-41-9) and triethylamine (10 mL, 72 mmol) in dichloromethane (70 mL) at 0° C. was added methanesulfonyl chloride (1.93 mL, 138 mmol) dropwise over 10 minutes. The reaction was then stirred for 30 minutes at 0° C., before being allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was then quenched with water (70 mL) and the layers were separated. The organic phase was washed with water (100 mL) and the organics were dried (MgSO4), filtered and evaporated in vacuo. The residue was then triturated with ethyl acetate and the solid residue filtered and dried in vacuo to give 5-iodo-2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine as an off white solid (8.85 g, 24 mmol, 99%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([OH:23])[C@@H:12]([CH2:24][O:25]CC2C=CC=CC=2)[NH:11][CH2:10]1)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[NH:11]1[C@H:12]([CH2:24][OH:25])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@@H:9]([OH:8])[CH2:10]1
Reactant: O[C@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)CN[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2,3,6-Tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.2 g, 0.46 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml) under an inert atmosphere and palladium 10% on charcoal (0.4 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in methanol and the solution is filtered through a membrane (Millex-SR 0.5 μM). Evaporation of solvent gives a sticky solid which is further triturated in ethanol to give the expected 1,5-dideoxy-1,5-imino-D-glucitol as a beige powder (60 mg, 80%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:8](=[CH:9][N:10]([CH3:13])[N:11]=3)[CH:7]=[C:6]([N+:14]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[CH:1]1([C:4]2[C:12]3[C:8](=[CH:9][N:10]([CH3:13])[N:11]=3)[CH:7]=[C:6]([NH2:14])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc2cc([N+](=O)[O-])cc(C3CC3)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1cc2cc(N)cc(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Palladium on carbon (300 mg) was added to a solution of 7-cyclopropyl-2-methyl-5-nitro-2H-indazole obtained in the above-described Step 1 (311 mg) in ethyl acetate (5 mL) under nitrogen atmosphere, and the reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, then the solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-cyclopropyl-2-methyl-2H-indazol-5-amine as brown amorphous.
Reaction SMILES: O[C:2]1([C:7]#[C:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(NCC)C.C([OH:24])C>>[N:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[C:7](=[O:24])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=C(C#CC1(O)CCCC1)c1ccncc1
Reactant: CCO
Solvent: CCNCC
Product: O=C1C=C(c2ccncc2)OC12CCCC2
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl) prop-2-yn-1-one (0.42 g, 1.95 mmol) in ethanol (10 mL) was added diethyl amine (0.21 g, 2.9 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. Then the EtOH was removed, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.4 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31]S(C)(=O)=O)[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:37]([O:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:38].C(N(CC)C(C)C)(C)C.ClCCl.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([OH:31])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][O:39][CH2:37][CH3:38])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Agent: I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(O)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 16 h

Procedure:
Combine 1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.77 g, 1.46 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g, 4.4 mmol) in acetonitrile (36 mL). Heat to reflux. After 16 hours, cool and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:40])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CC#N)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg (0.37 mmol) of the compound from Example 54 were introduced into 20 ml of dichloromethane at 0° C., 92 mg (0.37 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 150 mg (96% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].[CH2:14](O)[CH3:15]>O>[NH:8]1[C:14]2[C:15](=[CH:4][C:5]([O:11][C:9](=[O:10])[NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:6][CH:7]=2)[CH2:3][CH2:2][CH2:1]1
Reactant: CCCCCCCNC(=O)O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2
Temperature: 50 °C

Procedure:
Ni—Al alloy (0.098 g.) was added portionwise during 1 min. to stirring mixture of heptyl-carbamic acid quinolia-6-yl ester (0.145 g.), 10% potassium hydroxide in water (3.54 ml) and ethanol (10 ml) at 0-4° C. The reaction mixture was continued to stir for additional 2.5 hours while the temperature of the reaction mixture was maintained at 50° C. The reaction mixture was filtered, Ni—Al alloy was discarded through filtration, and the filtrate was concentrated under vaccum. The residue so obtained was crystallized with methanol (or acetone) to give 2b; yield: 0.10 g. (67.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Br
Reactant: Clc1ccc([C@@H]2C[C@H]3CNC[C@H]32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1C[C@@H]2C[C@@H](c3ccc(Cl)cc3)[C@@H]2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (1R*,5S*,6R*)-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]heptane (Steiner, G., et al., Heterocycles, 1995, 40, 319-330) (1.0 g, 1.3 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (1.0 g, 7.5 mmol) and methyl 2-bromo-2-methylpropanoate (0.4 mL, 3.0 mmol, Aldrich). After stirring at 80° C. for 16 hours, the reaction mixture was cooled and quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% of ethyl acetate in hexanes) to obtain the titled compound. MS (ESI+) m/z 308 (M+H)+.