Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]#[C:19][CH3:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:19]([CH3:20])=[C:18]([C:17]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC#CC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
Benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (10.78 mL, 42.12 mmol) and ethyl but-2-ynoate (5.89 mL, 50.54 mmol) were stirred in DCM (500 mL) at 0° C. under nitrogen, then trifluoroacetic acid (161 μL, 2.11 mmol) was added dropwise. The reaction mixture stirred at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature overnight. The mixture was concentrated and purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (2.76 g, 27%). δH (500 MHz, DMSO-d6) 7.38-7.32 (m, 4H), 7.30-7.23 (m, 1H), 4.13 (q, J 7.1 Hz, 2H), 3.75 (s, 2H), 3.60-3.51 (m, 4H), 2.05 (s, 3H), 1.22 (t, J 7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: Cc1ncc[nH]1
Reactant: Fc1cc(CBr)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nccn1Cc1ccc(Br)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step A (ca. 42 mmol) in 50 mL of dimethylformamide was added 2-methylimidazole (3.47 g, 82.1 mmol) and potassium carbonate (7.53 g, 54.6 mmol). After stirring for two hours, the mixture was poured into EtOAc and washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was taken up in 100 mL of EtOAc, and excess HCl gas was bubbled through the solution. The precipitate was removed by filtration, partitioned between dichloromethane and dilute NaHCO3 solution, and the water phase was extracted repeatedly with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the desired product as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH2:15][N:16]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:17])[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH2:15][N:16]([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH3:17])[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(=O)N(C)CC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)N(C)CC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
tert-Butyl{1-(3,4-dichlorophenyl)-3,4-dihydroxy-1-[(isobutyryl-methylamino)-methyl]-butyl}-methyl-carbamate (1.41 g) was dissolved in a mixture solvent of tetrahydrofuran (8 mL) and water (8 mL). Sodium periodate (1.3 g) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (1.33 g, quantative amount). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (2.7 g, 10 mmol) and p-fluorobenzoyl chloride (4.0 g, 3.0 mL, 25 mmol) in methylene chloride (10 mL) was added titanium tetrachloride (1M in methylene chloride, 50 mL, 50 mmol). The reaction mixture was stirred at room temperature for 3 d, poured into ice (100 g), and stirred 1 h. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with 5% sodium carbonate (200 mL), brine (150 mL), dried and concentrated. The residue was triturated with ether-petroleum ether. The solid was collected by filtration to give the title compound of Step A (2.1 g) as a tan solid. MS (APCl−Calc.: 395.2, Found: 394.2 (M−1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[C:2]1([C:1]([C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (957 mg, 2.6 mmol) in dioxane (20 mL) was added 4 M HCl-dioxane (20 mL). The reaction mixture was stirred at room temperature overnight and concentrated to afford crude phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone which was used in the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[NH2:21][C:17]1[N:16]=[C:15]([N:7]2[C:6]3[CH:22]=[C:2]([C:32]#[C:31][C@:29]([C:26]4[CH:25]=[C:24]([CH3:23])[O:28][N:27]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:14][O:13][CH2:12]2)[CH:20]=[CH:19][N:18]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3nc(OC4COC4)n(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by the method described in Example 142-b, by reacting 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 2.40 (3H, s), 4.80-4.71 (2H, m), 4.96 (2H, t, J=7.1 Hz), 5.87-5.78 (1H, m), 6.37 (1H, s), 6.46 (1 H, s), 7.22-7.04 (3H, m), 7.28 (1H, dd, J=8.2, 1.5 Hz), 7.45 (1H, d, J=8.2 Hz), 8.18 (1H, s), 8.42 (1 H, d, J=5.5 Hz); LC-MS: m/z=+433.15 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].S(Cl)([Cl:15])=O>>[F:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([Cl:15])=[O:9]
Reactant: N#Cc1ccc(F)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(F)c(C(=O)Cl)c1

Procedure:
A solution of Example 59B (535 mg, 3.24 mmol) in thionyl chloride (3855 mg, 32.4 mmol) was heated at 90° C. for 2 hours. The solution was cooled, concentrated, diluted with toluene, and concentrated to afford 2-fluoro-5-cyanobenzoyl chloride which was used without purification. The title compound was prepared and isolated as described in Example 22B, substituting 2-fluoro-5-cyanobenzoyl chloride for 2-fluoro-5-(trifluoromethyl)benzoyl chloride, in 61% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H) 1.58-1.72 (m, 1H) 1.82 (qd, J=7.01, 6.74 Hz, 2 H) 1.90-1.97 (m, 1 H) 3.61-3.70 (m, 1 H) 3.74-3.83 (m, 1H) 4.24-4.35 (m, 3 H) 7.33 (s, 1 H) 7.52 (dd, J=10.71, 8.72 Hz, 1 H) 8.02-8.07 (m, 1 H) 8.40 (dd, J=6.94, 2.18 Hz, 1 H); MS (DCI/NH3) m/z 388 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][N:18](C)[C:19](=O)OC(C)(C)C.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH:18][CH3:19]
Reactant: CN(Cc1ccc2c(ncn2C2CCCCO2)c1Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 146700.41 %

Procedure:
To a solution of 218 (363 mg, 0.96 mmol) in MeOH (6 mL) was added 4N HCl/dioxane (2.87 ml, 11.5 mmol) and the reaction was stirred at RT for 2 h then concentrated in vacuo to afford 394 g (100%) of 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)-N-methylmethanamine (220) as its bis-HCl salt: MS (ESI) m/z=280.1 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH:11]2[OH:14]
Reactant: COC(=O)CC1CC(=O)c2cc(F)ccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1Cc2ccc(F)cc2C(O)C1

Procedure:
To a mixture of 8 g. of sodium borohydride and 150 ml. of methanol, 23.5 g. of 7-fluoro-3-(methoxycarbonylmethyl)-1-tetralone are added. The mixture is diluted with 250 ml. of 2N hydrochloric acid after standing for four hours at 25°C; the aqueous mixture is then extracted with chloroform. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-fluoro-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate. The latter compound is dehydrogenated by the process described in Part B of Example 2 to furnish methyl 6-fluoro-4-hydroxy-2-naphthylacetate.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]2([F:55])[CH:52]3[CH2:53][CH:48]4[CH2:49][CH:50]([CH2:54][CH:46]2[CH2:47]4)[CH2:51]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C:45]3([F:55])[CH:52]4[CH2:51][CH:50]5[CH2:49][CH:48]([CH2:47][CH:46]3[CH2:54]5)[CH2:53]4)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(F)C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(F)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.24 g, 74%): 1H NMR (300 MHz, CDCl3) δ8.77-8.65 (m, 1H), 7.63-7.56 (m, 1H), 6.68-6.58 (m, 1H), 4.30 (d, J=24.85 Hz, 2H), 3.42 (s, 3H), 2.34-2.16 (m, 4H), 2.14-2.01 (m, 1H), 1.97-1.85 (m, 4H), 1.84-1.72 (m, 4H), 1.72-1.62 (m, 2H), 1.00-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 438.1 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH3:20])[C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1Br
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c(Br)cn(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 97) (150.0 mg) and potassium carbonate (181.6 mg) in N,N-dimethy formamide (4.0 ml) was added at room temperature, methyl iodide (0.042 ml) and the resulting mixture was stirred at 70° C. for two and a half hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (20.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-3-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (153.6 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(#N)C>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)[CH:28]=1
Reactant: NCc1cccnc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cncc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-(aminomethyl)pyridine and acetonitrile essentially as described above in example 18 except that the Waters Sep-Pak filtration is eluted with 10% methanol in dichloromethane and the column is eluted using a graded solvent mixture of 2% methanol in dichloromethane, to 6% methanol in dichloromethane. Purity by LC/MS (APCI)=100%, [M+H]+=352.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][F:21])=[CH:32][CH:31]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(OCCF)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OCCF)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-(2-fluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 388.05 g/mol.
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-])=[O:27])=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41])=[O:27])[N:10]([CH2:29][C:30]([F:33])([CH3:31])[CH3:32])[N:9]=[CH:8]2
Reactant: N[C@H]1CCCNC1=O
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1000.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (100 mg, 0.217 mmol; prepared according to Example 26) in dichloromethane (1 mL) was added (S)-3-aminopiperidin-2-one (prepared according to Example 3; 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 461 (M+1). 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.09 (br, 1H), 4.56 (d, 1H), 4.53 (m, 1H), 3.36 (m, 2H), 2.70 (m, 1H), 1.97 (m, 1H), 1.66 (m, 1H), 1.39 (d, 3H), 1.38 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2ccc(F)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)c(F)cc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-2; 15 g, 0.090 mol) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (19.22 g, 0.108 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (150 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.0 (bs, 1H), 7.34-7.32 (d, J=7.2 Hz, 1H), 6.59-6.57 (d, J=8.8 Hz, 1H), 2.95-2.91 (t, J=7.6 Hz, 2H), 2.65-2.61 (t, J=−7.6 Hz, 2H). MS (M+1): 245.9.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:36]([O:35][C:33](=[O:34])[CH2:32][O:23][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]=3[N:15]=2)=[CH:21][C:20]=1[CH3:22])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 60 °C

Procedure:
A mixture of 1.5 g of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol (example 17), 690 mg of tert-butyl bromoacetate and 1.96 g of potassium carbonate in 50 ml of dimethylformamide was heated to 60° C. for 1 h. After cooling to room temperature, the solids were removed by filtration. The solvent was distilled off in vacuo and the residue was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH3:24]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6]([O:9][CH3:24])=[CH:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.3 g, 0.96 mmol) in dimethylformamide (3 mL) at 0° C. under an argon atmosphere was added potassium t-butoxide (0.11 g, 0.96 retool) and, 0.5h later, dimethyl sulfate (0.09 mL, 0.96 mmol). After 5 min, ammonium chloride was added, the mixture was extracted three times with ether, the organic extract was washed three times with water, once with brine, was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 9:1 hexanes/ethyl acetate, provided a white solid (0.06 g, 19%): m.p. 123°-125° C. Analysis Calc. for C20H25NO3 ·0.35 H2O:C 71.98, H 7.76, N 4.20; found: C 71.98, H 7.66, N 3.95
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19].O>C1(C)C=CC=CC=1>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: CCN1CCNCC1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(-c3ccccc3)c3ccccc3n2)CC1
Yield: 86.8 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (2.0 g) and 1-ethylpiperazine (2.7 g) in toluene (15 ml) is heated under reflux for 10 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (25 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=1
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 13.5 mmol) in anhydrous DMF (20 mL) was stirred at 0° C. Sodium hydride (60% in mineral oil, 0.8 g, 20.3 mmol) was added portion-wise and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.4 g, 20.3 mmol) was added to the solution dropwise and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was concentrated in vacuo, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography on silica gel (eluting with 1% EtOAc in petroleum ether) to give 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 70%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.08 (d, J=10.0 Hz, 2H), 4.67 (m, 1H), 4.6 (d, J=12.8 Hz, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.8 Hz, 3H), 0.95 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:13]1([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:19]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:26]=[CH:25][CH:24]=[C:21]([C:22]2[N:23]=[C:3]3[C:4]4[C:9]([CH:10]=[CH:11][N:2]3[N:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:20]=1
Reactant: N#Cc1cccc(-c2ccccc2)c1
Reactant: Nn1ccc2ccccc2c1=O
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc(-c3nc4c5ccccc5ccn4n3)c2)cc1
Yield: 49 %

Procedure:
This compound was prepared according to the procedure of the foregoing Example, starting from 2-amino-isoquinoline-1(2H)-one and 3-phenyl-benzonitrile. Yield 49%. M.p. 167°-69° C. (from ethyl acetate).