Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:21]1[C:20]([F:19])=[CH:25][C:24]([F:26])=[CH:23][C:22]=1[F:27])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc(F)c([Mg]Br)c(F)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1c(F)cc(F)cc1F)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 5.7 g) in tetrahydrofuran (30 mL), 2,4,6-trifluorophenylmagnesium bromide (0.24 M solution in THF; 100 mL) was added dropwise at −40° C. over one hour, and the reaction solution was stirred at −40° C. for 12 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 6.2 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (20 mL) and ethanol (10 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm for 21 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 4.34 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1O.[C:24](=[O:27])([O-])[O-].[K+].[K+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH:30]([O:27][CH:24]([C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:7][C:2]=1[Br:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC1CCC(C2CCC(c3ccc(O)c(Br)c3)CC2)CC1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CCC(C2CCC(c3ccc(C(OC(c4ccccc4)c4ccc(C5CCC(C6CCC(CCC)CC6)CC5)cc4Br)c4ccccc4)c(Br)c3)CC2)CC1
Yield: 148.3 %

Procedure:
The foregoing 2-bromo-4-(4-(4-propylcyclohexyl)cyclohexyl)phenol (250 mg), potassium carbonate (109 mg), and benzyl chloride (135 mg) were mixed, to which were then added DMF (2 ml) and tetrabutylammonium bromide (20 mg), and the mixture was refluxed by heating for 30 minutes. After completion of the reaction, the reaction mixture was added in water and extracted with toluene. The resulting toluene layer was washed with water, rinsed with a sodium hydrogencarbonate aqueous solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a colorless crystal (300 mg) of 2-bromo-4-(4-(4-propylcyclohexyl)cyclohexyl)phenylbenzyl ether.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([F:27])([F:26])[C:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH2:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C2CC(C(F)(F)F)=NN2c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 45 %

Procedure:
A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.82 g, 3.69 mmoles) and (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.79 g, 3.69 mmoles) in 15 ml of acetic acid is refluxed for 3 hours under a nitrogen atmosphere. It is cooled, poured over water and extracted with AcOEt. The organic solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude product thus obtained is crystallised from EtOH-petrol ether to give 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (0.65 g, yield: 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[NH:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[C:8]2=[O:21])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[N:11]([CH3:24])[C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C=C2NC(=O)N(c3cc(F)ccc3F)C2=O)cc1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C=C2C(=O)N(c3cc(F)ccc3F)C(=O)N2C)cc1
Yield: 186.3 %

Procedure:
The 5-(4-methylbenzylidene)-3-(2,5-difluorophenyl)-imidazolidine-2,4-dione (2.25 g, 7.16 mmol), cesium carbonate (1.22 g, 3.76 mmol) and methyl iodide (1.5 g, 3.76 mmol) were stirred together in DMF (20 mL) overnight. The solution was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 2.3 grams of 5-(4-methylbenzylidene)-3(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, m.p. 136°-140° C. (compound 104 under Table B).
Reaction SMILES: FC1C=CC([N:8]2C3C(=CC(C(C4C=CC=CC=4)C(CC)C(O)=O)=CC=3)C=N2)=CC=1.FC1C=CC(N2C3C(=CC(C(C4C=CC=CC=4)C(C)(C)CN)=CC=3)C=N2)=CC=1.[F:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[C:73]3[C:68](=[CH:69][C:70]([CH:74]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[CH:75]([CH2:79][CH3:80])[C:76](F)=[O:77])=[CH:71][CH:72]=3)[CH:67]=[N:66]2)=[CH:61][CH:60]=1.N>C1COCC1.O>[F:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[C:73]3[C:68](=[CH:69][C:70]([CH:74]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[CH:75]([CH2:79][CH3:80])[C:76]([NH2:8])=[O:77])=[CH:71][CH:72]=3)[CH:67]=[N:66]2)=[CH:61][CH:60]=1
Reactant: CCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(c)(d) 2-((1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid (60, mg, 0.154 mmol) was converted into the acid fluoride using the identical procedure to that for Synthetic Intermediate I above. A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanamide.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-fluoro-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C19H21FO5 [M+Na]+: 371.4.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:15]([C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH2:12]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Br)cc2CN1[C@H]1CC[C@H](O)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.500 g, 1.62 mmol), trans-4-aminocyclohexanol hydrochloride (0.295 g, 1.95 mmol), and potassium carbonate (0.44 g, 3.2 mmol) in ethanol (5.0 mL) was stirred in a sealed vial at 50° C. for 4 h. After cooling, the mixture was diluted with ethyl acetate (10 mL), and was filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether (3 mL). The precipitates were collected by filtration and washed with ethyl ether to afford the desired product. LCMS (M+H)+=309.9/312.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[CH:40])([CH3:34])([CH3:33])[CH3:32].N(C(C)C)C(C)C>C1COCC1.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.[Cu]I>[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[C:40][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([F:2])[CH:4]=1)[N:8]=[CH:9]2)([CH3:34])([CH3:33])[CH3:32]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(I)cc45)ccc32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
[1-(3-Fluoro-benzyl)-1 H-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.334 g, 0.628 mmol) and Prop-2-ynyl-carbamic acid tert-butyl ester (113 mg, 1.16 equiv.) is treated with i-Pr2NH (2 equiv.) in dry THF (4 ml) under N2. Pd(PPh3)4 (25 mg, 0.0356 mmol, 5.7 mol %) and solid CuI (5 mol %) are added next, and the mixture is stirred at r.t. for 3 hours. Workup: THF is removed under reduced pressure and DCM (10 ml) is added. The organic layer is washed with sat. aq. NH4Cl solution and brine, dried and concentrated. Chromatography on silica (EtOAc/hexanes) affords the desired pure product (293 mg, 89%).
Reaction SMILES: [Cl-].[S:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1)=O>O1CCCC1.CCCCCC>[S:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:31][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCS2)cc1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1ccc(C=C2CCCS2)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
(2-Tetrahydrothienyl)triphenylphosphonium chloride (5.8 g) was dissolved in tetrahydrofuran (30 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (9.5 ml) at −5° C., and then the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture was added dropwise a solution of ethyl 2-(4-formylphenyl)propionate (3.6 g) in tetrahydrofuran (5.0 ml) at −5° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give the title compound (2.5 g, 58%).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[CH:7]=[CH:6][CH2:5]1>C(O)(=O)C>[Br:1][C:7]1[C:8]([OH:14])=[C:9]([C:4]([CH3:3])=[CH:5][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: COC(=O)C1C(=O)C=CCC1C
Solvent: CC(=O)O
Product: COC(=O)c1c(C)ccc(Br)c1O

Procedure:
A solution of bromine (16.8 ml) in acetic acid (150 ml) was added dropwise to a stirred and cooled solution of methyl 6-methyl-2-oxocyclohex-3-enecarboxylate (prepared according to Hauser et al, Synthesis 1980 814, 28.2 g) in acetic acid at 0° C. The resultant mixture was stirred and heated at reflux for 24 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with sodium bicarbonate (saturated aqueous solution) and brine, then dried (MgSO4 and activated charcoal) and filtered through Celite. The filtrate was evaporated to dryness to give methyl 3-bromo-2-hydroxy-6-methylbenzoate (30.8 g) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][SH:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][S:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(SCc2ccccc2Cl)cc1
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.0 equivalent) and (2-chlorophenyl)methanethiol (1.0 equivalent) in DMF (1.0 M) at rt was added K2CO3 (2.0 equivalents). After 16 h, the rxn was transferred to EtOAc:water (1:1). The organic layer was separated and sequentially washed with water (2×) and brine. The material was dried (MgSO4), filtered and concentrated to afford (2-chlorobenzyl)(4-nitrophenyl)sulfane in 98% yield. The material was taken through without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=O)=O)=CC=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOCC>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2CCN(C)CC2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of {(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (9.427 g, 23.13 mmol) (Tetrahedron, 43(14), 3289, 1987) in toluene (150 mL), was added n-methyl-piperazine (12.8 mL, 115.65 mmol) and DBU (0.352 g, 2.313 mmol) and the solution was stirred at 140° C. overnight. The reaction was then diluted with ether and washed with brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified on Biotage flash 40M cartridge silica gel eluting with CH2Cl2/CH3OH/NH4OH (95.5/3/1.5) to give an off white solid (2.570 g, 55% ). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 338.1 [M+H]. m.p.: 96.5-97.7° C. Reference: (Tetrahedron, 43(14), 3289, 1987).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=O)=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.C(P(=O)([O-])OCC)#N.Br.Br[CH2:37][CH2:38][NH2:39]>C(N(CC)CC)C>[O:23]1[CH2:37][CH2:38][N:39]=[C:21]1[C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12
Reactant: NCCBr
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Agent: Br
Agent: CCOP(=O)([O-])C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCCC1)N1Cc2c(C3=NCCO3)ncn2-c2ccccc21
Reaction time: 0.67 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 322, 1.03 g) and 25 ml of dichloromethane cooled at 0° in an ice bath are added 1.15 ml of triethylamine and 0.650 ml) of ethyl cyanophosphonate, followed immediately by 0.811 g of 2-bromoethylamine hydrobromide. The ice bath is then removed and the reaction is stirred for 40 min. Aqueous sodium bicarbonate is then added. The mixture is stirred for 10 min and then partitioned with dichloromethane. The organic layers are dried over sodium sulfate and concentrated. The resulting mixture is stirred in 20 ml of THF and 3.3 ml of 1M potassium tert-butoxide is added dropwise over 2-3 min and the reaction is stirred an additional 10 min, at which time the reaction mixture is partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (4/96), the appropriate fractions are pooled and concentrated to give the title compound, mp 217°-220°; MS (m/z) at 337; IR (mineral oil) 1651, 1512, 1416, 1357, 1396 cm-1 ; NMR (CDCl3) 1.81, 3.27, 4.05, 4.42, 4.99, 7.11-7.18, 7.26, 7.51, 8.03 δ.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22](B(O)O)[CH:23]=2)[NH:18][CH:17]=1.[C:28]([O-:31])(O)=[O:29].[Na+]>O1CCOCC1>[C:28]([OH:31])([C:11]([F:14])([F:13])[F:12])=[O:29].[F:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:2]3[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]4[C:3]=3[CH:4]=[N:5][NH:6]4)[CH:23]=2)[NH:18][CH:17]=1
Reactant: O=C([O-])O
Reactant: OB(O)c1cnc2[nH]cc(F)c2c1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1c[nH]c2ncc(-c3cc(C(F)(F)F)cc4[nH]ncc34)cc12
Product: O=C(O)C(F)(F)F
Temperature: 130 °C
Yield: 18.1 %

Procedure:
A 20 mL microwave vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (60 mg, 0.226 mmol), (3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (61.1 mg, 0.340 mmol) and PdCl2(dppf)CH2Cl2 (9.31 mg, 0.011 mmol) in dioxane (4 mL) and aqueous saturated NaHCO3 (2 mL). The resulting brown suspension was heated at 130° C. for 30 minutes in microwave reactor. The reaction mixture was subsequently purified by preparative HPLC, eluting with a gradient of 65-80% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product fractions were collected and dried to give a TFA salt of the title compound as a dark purple solid (13.1 mg, 18.1%). 1H NMR (400 MHz, CD3OD) δ ppm 7.34 (d, J=2.27 Hz, 1H), 7.50 (d, J=1.01 Hz, 1H), 7.92 (s, 1H), 8.29 (d, J=1.01 Hz, 1H), 8.36 (d, J=2.02 Hz, 1H), 8.62 (d, J=2.02 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C15H8F4N4, 321.1. found 321.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(C[C@H]3COC(C)(C)O3)C=2)=C2C=1C(=[O:60])N(C)C2>>[CH2:40]([O:39][P:38]([CH2:37][C:36]1[CH:46]=[CH:47][C:33]([NH:32][C:24]2[N:23]=[C:22]([NH:21][C:13]3[CH:12]=[CH:11][C:10]([C:8]4[CH:7]=[N:6][N:5]([CH2:4][C@H:3]([OH:60])[CH2:2][OH:1])[CH:9]=4)=[C:18]4[C:14]=3[C:15](=[O:20])[N:16]([CH3:19])[CH2:17]4)[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=2)=[C:34]([O:48][CH3:49])[CH:35]=1)(=[O:45])[O:42][CH2:43][CH3:44])[CH3:41]
Reactant: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Yield: 48 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 7-amino-4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-4-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 5C, 337 mg, 742 μmol) to afford 254 mg of the desired product (48%). 1H NMR (400 MHz, CD3OD) δ 8.49 (br. s., 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.67-7.77 (m, 2H), 7.11 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 4.61 (s, 2H), 4.37 (dd, J=4.3, 13.9 Hz, 1H), 4.15-4.24 (m, 1H), 4.00-4.14 (m, 5H), 3.90 (s, 3H), 3.52-3.56 (m, 2H), 3.35 (d, J=7.1 Hz, 2H), 3.21 (s, 3H), 1.26 (dt, J=2.7, 7 Hz, 6H). MS (ESI): m/z 720.23 [M+H]+. UPLC: tR=1.12 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13].C([O-])(=O)C.[K+].[N:23](OCCCCC)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.ClCCl>[C:1]([N:8]1[C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][OH:13])[C:10]=2[CH:17]=[N:23]1)(=[O:4])[CH3:2]
Reactant: CCCCCON=O
Reactant: Cc1c(N)cccc1CO
Reactant: CC(=O)OC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)n1ncc2c(CO)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (1.68 mL, 17.8 mmol) was added to a suspension of 3-amino-2-methylbenzyl alcohol (0.82 g, 5.98 mmol) in chloroform (25 mL). Potassium acetate was added and the resulting mixture was stirred at room temperature for 3 h, under reflux for 2 h, and then at room temperature overnight. Amyl nitrite (1.82 mL, 13.7 mmol) and 18-crown-6 (79 mg, 0.3 mmol) were added and the pale yellow cloudy mixture was heated at reflux overnight, then allowed to cool to room temperature and stir for 5 h. The reaction mixture was poured into acetic anhydride (5 mL) and stirred at room temperature overnight. Dichloromethane (20 mL) was added and the solution was washed with sodium hydrogen carbonate solution, water, and brine (10 mL each), dried (Na2SO4), filtered, concentrated, and chromatographed (10-40% ethyl acetate/petroleum ether) to give 1-acetyl-1H-indazole-4-methanol, acetate ester (1.19 g, 86%) as a pale yellow solid.