Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].C(Cl)Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:32]2[C:31](=[O:33])[C:30]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]3[C:28]2=[O:38])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [K]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A suspension of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.35 g) and potassium phthalimide (0.7 g) in dimethylformamide (10 ml) is warmed at 50° to 60° C. for 3 hours. The reaction mixture is shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is crystallized from ethyl acetate/ether to give 5-chloro-2-[3-(2-phthalimido-acetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone as crystals melting at 251° to 253° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(Br)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-bromo-4-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a pale yellow crystalline solid of melting point 260° C. (decomposition).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [C:1](OC=C)(=O)[CH3:2].[CH3:7][C:8]1([CH3:20])[C@@H:10](/[CH:11]=[C:12](/[F:16])\[C:13](=[O:15])[OH:14])[C@H:9]1[C:17]([OH:19])=[O:18]>>[CH3:7][C:8]1([CH3:20])[C@@H:10](/[CH:11]=[C:12](/[F:16])\[C:13](=[O:14])[O:15][CH:1]=[CH2:2])[C@H:9]1[C:17]([OH:19])=[O:18]
Reactant: C=COC(C)=O
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C(/F)C(=O)O
Product: C=COC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C

Procedure:
Vinyl acetate and (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-hydroxy-1-propenyl]-cyclopropane carboxylic acid were reacted in the presence of mercuric acetate as a catalyst to obtain (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-ethenyloxy-1-propenyl]-cyclopropane carboxylic acid which was reacted with benzyl alcohol to obtain benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-ethenyloxy-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+26° (c=1.2% in chloroform).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:18])=[C:7]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1OC
Yield: 87 %

Procedure:
Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41 g, 45.0 mmol), potassium carbonate (9.34 g, 67.6 mmol), acetone (200 mL), and dimethyl sulfate (6.46 g, 67.6 mmol) were added together. The resultant mixture was then heated to reflux for 16 h. The mixture was then filtered and the solid was washed with ethyl acetate. The resulting organic liquid was then concentrated under vacuum to an oil and redissolved in ethyl acetate (600 mL). The organic solution was then washed with water, dried, filtered and concentrated under vacuum to an oil that was then subjected to purification via column chromatography (gradient of 5% to 40% EtOAc/Hexanes) to yield the title compound as an oil (10.42, 87%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[N:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[N:6]=[C:5]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:11][CH2:12][C:4]2=[N:3][C:2]=1[C:12]1[CH:11]=[CH:10][N:9]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(Cl)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 2) (100 mg, 0.247 mmol) and potassium carbonate (102 mg, 0.741 mmol) in dioxane (2 ml) was degassed by bubbling nitrogen through (×3). Pd(Ph3P)4 (28.6 mg, 0.025 mmol) was added and the mixture was degassed by bubbling nitrogen through (×3). The mixture was heated at 150° C. for 2 hours using microwave irradiation. The mixture was diluted with water and extracted with EtOAc (×2). The organics were washed with brine, dried (MgSO4) and evaporated under vacuum to a pale oil. The crude was purified by chromatography on silica eluting with 20-100% EtOAc/iso-hexane to give the title compound as a clear oil;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:43].[ClH:43].[CH3:31][N:28]1[CH2:27][CH2:26][C:21]2[N:22]([CH3:25])[C:23]3[CH:24]=[C:16]([N:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=5)=[CH:11][C:12]4=[O:30])[CH:17]=[CH:18][C:19]=3[C:20]=2[CH2:29]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc3n2C)C1
Yield: 78 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.19 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (71 mg, 78%) as a white solid: mp 215-230° C.; 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=2.6 Hz, 1H), 7.91 (overlapping ddd, J=9.6, 2.1 Hz, 1H), 7.83-7.20 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.09 (dd, J=8.4, 1.8 Hz, 1H), 6.59 (dd, J=7.5, 2.6 Hz, 1H), 6.36 (d, J=2.6 Hz, 1H), 5.41 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.39 (d, J=14.2 Hz, 1H), 3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H); ESI MS m/z 419 [M+H]+; HPLC (Method B) 95.8% (AUC), tR=110 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:21][CH2:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([CH2:7][CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: OC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.96 g of crude (trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl ]methanol in 20 ml of dry pyridine is treated at 0° C. with 2.1 g of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 15 hours, then diluted with 200 ml of methylene chloride and washed several times with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 1:9) gives [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl ]cyclohexyl]cyclohexyl]methyl p-toluenesulfonate.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH2:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.O>[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH2:34][S:35]([NH:10][C:9]1[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]2[S:12][C:2]([CH3:1])=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C:4]=12)(=[O:37])=[O:36]
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4Cl)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 2-chlorobenzylsulfonyl chloride (198 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 2-chlorobenzylsulfonyl chloride (79.2 mg, 0.352 mmol). The reaction mixture was then stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (6 mg). LCMS (A) m/z: 473 [M+1]+, Rt 1.07 min (basic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30]C(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[F:37][C:38]1[CH:46]=[CH:45][C:41](C(Cl)=O)=[CH:40][CH:39]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][C:11]5[CH2:35][CH2:36][N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:9][C:10]=5[C:18]=4[CH:17]=3)=[O:20])[CH2:23][CH2:24]2)=[O:30])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(c2ccc(F)cc2)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NC1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of tert-butyl 4-(2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (Compound 38, 50 mg, 100 μmol) in 4 N HCl/dioxane (3.0 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was then concentrated, MeOH (5.0 mL) was added and the volatiles were evaporated (2×). The resulting residue was dissolved in DMF (2.0 mL) and 4-fluorobenzoyl chloride (15 μL, 20 mg, 130 μmol) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give a yellow solid which was triturated with ethyl ether and then purified by reverse phase HPLC to provide N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 39) (46%). 1H NMR (DMSO-d6, 300 MHZ) 11.13 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.03 (s, 1H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (dd, J=8.5, 5.5 Hz, 2H), 7.28 (t, J=8.8 Hz, 3H), 7.10 (m, 4H), 4.43 (s, 3H), 4.18-4.03 (m, 2H), 3.70-3.54 (m, 3H), 3.16 (br s, 1H), 2.92 (br s, 2H), 1.87 (br s, 2H), 1.54 (br s, 2H) ppm; MS (ES) 515 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][CH:23]([F:35])[O:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH:23]([F:22])[F:35])[CH:26]=3)(=[O:33])=[O:32])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: Cc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
4-(5-Amino-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.065 g, 0.222 mmol) was dissolved in 5 ml of pyridine. 3-(Difluoromethoxy)-benzene-sulfonylchloride (0.051 g, 0.212 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated, and the residue purified via silica gel chromatography using dichloromethane-methanol (0-20%) to yield to title compound (0.097 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.I[CH2:24][CH3:25]>CN(C)C=O.ClCCl>[CH2:24]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:25]
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Reactant: CCI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccc(OC)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol) and iodoethane (405 μL, 5.0 mmol) in dimethylformamide (9 mL) was heated in a sealed tube at ˜100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (100 mL), transferred to a round-bottomed flask and evaporated. Ethyl acetate (100 mL) was added and the solution was washed with water, concentrated aqueous sodium thiosulfate (50 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 3% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with ethanol and dried under high vacuum to give (4S,7R)-1-ethyl-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (152 mg, 46%) as a light yellow solid. APCI(+)-MS (M+H) 327.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].[H-].[Na+].[CH3:22][O:23][CH2:24]Br.O>CN(C)C=O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][N:11]([CH2:22][O:23][CH3:24])[C:12](=[O:15])[O:13][CH3:14]
Reactant: COCBr
Reactant: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(Cc1cc(C#CC(C)(C)C)ccc1F)C(=O)OC
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
0.20 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]carbamate was dissolved in N,N-dimethylformamide (5 ml). To this solution, 0.10 g of sodium hydride (60 wt %) was added at room temperature, followed by stirring for 30 minutes. Then, 0.14 g of bromomethyl methyl ether was added at room temperature, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.13 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]-N-methoxymethylcarbamate as a colorless viscous liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)[C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[O:25]>>[S:40]1[CH:41]=[C:37]([CH2:36][N:26]([C@@H:27]([CH3:35])[CH:28]([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([CH3:55])([CH3:57])[CH3:56])=[CH:51][CH:52]=2)[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 84 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37].Cl>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:10][CH2:11][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[N:13]3[C:36]([C:32]3[NH:31][CH:35]=[CH:34][CH:33]=3)=[O:37])[CH2:20][CH2:21]2)=[CH:22][CH:23]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
In 6 ml of methylene chloride were dissolved 0.30 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 0.47 ml of triethylamine. After adding 0.18 g of 1H-2-pyrrolecarbonyl chloride at 0-5° C., the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After purifying the residue by column chromatography [eluent: chloroform:ethanol=200:1], isopropyl ether was added and the deposited crystal was collected by filtration. Thus, 0.14 g of (3R)-8-(4-isopropylphenoxy)-4-(1H-2-pyrrolylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a yellow crystalline product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25](S(C)(=O)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1.CO>C1COCC1>[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25]([NH:1][CH:2]5[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(S(C)(=O)=O)nc2n(C)c1=O
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
4-Amino-tetrahydropyran (11 mg, 0.106 mmol) was dissolved in 2 mL THF, and N-cyclopropyl-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-benzamide (21 mg, 0.051 mmol) was added. The reaction mixture was stirred for 6.5 hours at room temperature, and then 1 mL MeOH was added. The resulting mixture was loaded directly onto a preparative TLC plate and eluted with 5% MeOH in methylene chloride to give N-cyclopropyl-4-methyl-3-[8-methyl-7-oxo-2-(tetrahydro-pyran-4-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-benzamide: MS (M+H)=434; MP=239.3-241.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure III. Obtained as a yellow solid (0.2 g, 87%). MS (ISP) 462.2 [(M+H)+]; mp 244° C.