Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:39]2[CH2:38][CH2:37][N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH2:41][CH2:40]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:23]C1N=C(F)N=C(F)N=1>ClCCl>[CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([F:23])=[O:16])[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1noc(C(=O)O)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Cc1noc(C(=O)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 70.8 %

Procedure:
To a mixture of 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.070 g, 0.295 mmol) and pyridine (0.029 mL, 0.354 mmol) in dichloromethane (2.5 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (0.030 mL, 0.354 mmol). The reaction mixture was stirred at room temperature for 5.5 h. The heterogeneous reaction was complete by HPLC and was diluted with dichloromethane, washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane, and the combined organic layers were dried with anhydrous sodium sulfate and concentrated to afford 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (0.050 g, 0.209 mmol, 70.8% yield) as a yellow solid. The product had an HPLC ret. time=2.52 min (methyl ester)-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27]>>[CH:9]([OH:24])=[O:8].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:26]([CH3:27])[CH3:25])=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(OCCCCBr)cc1
Product: CN(C)CCCCOc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1
Product: O=CO

Procedure:
In analogy to example 17.1, reaction of [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester with 10 eq dimethylamine (33% in ethanol, 5.6 M) yielded [4-(4-Dimethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester; compound with formic acid, MS: 377 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:26])[C@H:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.[Cl:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>CC#N>[Cl-:27].[F:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]([O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:26])=[CH:24][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccc(F)cc1)c1ccccc1
Reactant: O=C(CCl)c1cccs1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccc(F)cc1)c1ccccc1)C2)c1cccs1
Product: [Cl-]
Temperature: 100 °C
Yield: 36.1 %

Procedure:
To a solution of (R)-(4-fluoro-phenylamino)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (C254) (200 mg, 0.56 mmol) in CH3CN (2 mL), is added 2-chloro-1-(thiophen-2-yl)ethanone (100 mg, 0.62 mmol). The reaction is heated at 100° C. for 1 hour under MW irradiation. The solvent is evaporated and the crude is purified by flash chromatography (DCM/MeOH=9/1) recovering the title compound as a white solid (104 mg, 36% yield, chloride salt, single diastereoisomer).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9]N.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>>[Br:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1F
Product: CC(C)C(=O)NC1CCc2[nH]c3c(F)cc(Br)cc3c2C1
Yield: 32 %

Procedure:
Prepare the tide compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-fluoro-4-bromophenylhydrazine (Preparation 14) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a tan foam in 32% yield. MS (ES): m/z 353, 355 (M+H), 351, 353(M−H); HPLC (Method A): Rt=2.34, (89%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=O>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:27]([C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=2)[O:15][N:14]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(OC(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-[(trifluoromethyl)oxy]benzoic acid: MS (APCI): m/z 453 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNc1ccc(CCN)cc1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCNc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Triethylamine (0.28 g, 2.77 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.30 g, 1.40 mmol) in toluene (10 ml). The mixture was stirred at room temperature. Then, 4-butylaminophenethylamine (0.40 g 2.08 mmol) was added after stirring for 3 hours, water (20 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butylaminophenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.30 g, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)=[C:11]([N+:28]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CO>[Zn].C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:28])[C:12]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3N)cc2s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (2.8 g, 6.42 mmol) from the previous step, HOAc (7.5 mL), MeOH (7.5 mL) and DCM (50 mL) at 0° C. was added portionwise zinc dust (4.25 g, 65.4 mmol). The reaction mixture was stirred at 5° C. for 1 h. The mixture was filtered and the filtrate was diluted with DCM and washed sequentially with water and saturated aq NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-(benzyloxy)-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (2.49 g, 95%) as a light orange solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.26-7.44 (m, 7H), 6.59 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 6.38 (m, 1H), 4.97 (s, 2H), 4.34 (s, 2H), 3.54 (br s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:16])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C(O)C>[CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]3[S:15][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:16]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(-c2ccccc2)cs1
Temperature: 75 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (41 mg, 0.16 mmol) in 5 mL of ethanol was added 2-bromoacetophenone (33 mg, 0.16 mmol) and the reaction was heated at 75° C. overnight. After 16 hours, the reaction was cooled and concentrated and the crude product was purified by flash chromatography on silica gel loaded with CH2Cl2 and eluted with 2:1 hexanes/ethyl acetate followed by 1:2 hexanes/ethyl acetate to provide the title compound as a solid (32 mg, 94%). HPLC, tR, 3.54 min.(6 minute method); MS, m/z 350.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH-:17].[Na+].[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24]Br>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCCCCCCCCCC)(C)C)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:17][CH2:24][CH2:23][O:22][C:21]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:20]=1[Cl:19])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: [OH-]
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Agent: CCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC(Cn1cncn1)(OCCOc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
12.95 g (0.05 mole) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanol are dissolved in 100 ml of toluene, and 100 ml of 40% strength sodium hydroxide solution and 1 ml of benzyl-dodecyl-dimethylammonium chloride are added. 13.5 g (0.05 mole) of 2,4-dichlorophenoxyethyl bromide are then added dropwise and the mixture is subsequently stirred at room temperature for 48 hours. The organic phase is separated off, washed with three 100 ml portions of saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is taken up in 100 ml of diethyl ether, and crystallizes after the mixture has stood for a short time. 7.8 g (35% of theory) of 1-(2,4-dichlorophenyl)-1-(2,4-dichlorophenoxyethoxy)-2-(1,2,4-triazol-1-yl)-1-ethanol of melting point 88°-90° C. are obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3C=[CH:40][CH:41]=[CH:42][C:21]=3N(C3C=CC=CC=3)[C:19]2=O)=[CH:9]1)=O)(C)(C)C.[H-].[Na+].CI.[CH3:54][N:55]([CH:57]=[O:58])[CH3:56]>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:19])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:21]=[CH:42][CH:41]=[CH:40][C:54]=3[N:55]([C:56]3[CH:18]=[CH:17][CH:10]=[CH:11][CH:12]=3)[C:57]2=[O:58])=[CH:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2c[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 210 mg (0.32 mmol) of 2-[3-(N-tert-butoxycarbonyl-indol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 38, in 4 mL of DMF at 0° C. is added 19 mg (0.48 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 30 mL (0.48 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 14 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then dissolved in 2 mL of dichloromethane, 2 mL of TFA is added, and the reaction mixture is stirred 1 h at RT. The volatiles are removed in vacuo and the resulting crude oil purified via MPLC using a Si60 silica gel column and hexane/EtOAc 5/2 as eluent followed by lyophilization afforded 37 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.11 (s, 1H), 7.61-7.00 (m, 18H), 6.76 (d, 1H, J=5.1), 5.10 (m, 1H), 4.50 (d, 1H, J=16.4), 3.95 (d, 1H, J=16.4), 2.91 (dd, 2H), 1.58 (s, 3H), 1.14 (m, 6H); low resolution MS (FAB)m/e 571 (MH+).
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[CH:29]=[N:30][N:31]2[CH:36]=[CH:35][C:34](=O)[NH:33][C:32]=12.[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47][NH2:48])[CH3:45])([CH3:41])([CH3:40])[CH3:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:38]([O:42][C:43](=[O:49])[N:44]([CH3:45])[CH2:46][CH2:47][NH:48][C:34]1[CH:35]=[CH:36][N:31]2[N:30]=[CH:29][C:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[C:32]2[N:33]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=c1ccn2ncc(-c3cccs3)c2[nH]1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CN(CCNc1ccn2ncc(-c3cccs3)c2n1)C(=O)OC(C)(C)C

Procedure:
1,8-Diazabicycloundec-7-ene (DBU) [6674-22-2] (0.4 mL, 2.5 mmol) was added to an ambient temperature, stirred, turbid solution of 3-thiophen-2-yl-4H-pyrazolo[1,5-a]pyrimidin-5-one (354.3 mg, 1.6 mmol), (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester [121492-06-6] (852.2 mg, 4.9 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) [56602-33-6] (937.7 mg, 2.1 mmol) in acetonitrile (16 mL). Upon addition of the DBU the turbidity clears and the solution was permitted to stir for 2 d then partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel, eluted with 10% (v/v) methanol/ethyl acetate). Evaporation of product fractions yielded an oil which was crystallized from heptane to provide methyl-[2-(3-thiophen-2-yl-pyrazolo[1,5-a]pyrimidin-5-ylamino)-ethyl]-carbamic acid tert-butyl ester as 333.6 mg of yellow, fine crystalline powder, mp. 140-141° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.16-1.28 (m, 5 H) 1.37 (br. s., 3 H) 2.51 (s, 1 H) 2.85 (br. s., 3 H) 3.47 (br. s., 1 H) 3.55 (br. s., 3 H) 6.28 (d, J=6.82 Hz, 1 H) 7.04 (dd, J=5.05, 3.54 Hz, 1 H) 7.30 (dd, J=5.05, 1.01 Hz, 1H) 7.41 (br. s., 1 H) 7.80 (br. s., 1 H) 8.19 (s, 1 H) 8.48 (d, J=7.07 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 27.81, 27.96, 33.75, 38.41, 46.32, 78.13, 100.28, 100.76, 120.16, 121.75, 126.90, 135.01, 135.20, 140.78, 143.74, 154.91, 155.81. LRMS (ESI) m/z 374.1 [(M+H)]+, calc'd for C18H23N5O2S: 373.48.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1>C(O)(C)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:5][CH:4]([OH:8])[CH2:3][CH3:2])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: CCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 53.6 %

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25 mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (100 ml) was heated at 65 C for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, 1 l and MeOH:DCM 2%: 98%) to give an off-white solid weighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals, m.p. 87°-88° C.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.[CH3:14]I.[CH3:16][C:17]([CH:19]=[CH2:20])=[CH2:18]>C(OCC)(=O)C>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:20][CH2:19][CH:17]=[C:18]([CH3:14])[CH2:4]2)[CH:6]=1.[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:20][CH2:19][C:17]([CH3:18])=[CH:16][CH2:4]2)[CH:6]=1
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Reactant: CI
Reactant: C=CC(=C)C
Solvent: CCOC(C)=O
Product: CC1=CCC2(C=C(C)C(=O)C(C)=C2)CC1
Product: CC1=CCCC2(C=C(C)C(=O)C(C)=C2)C1
Temperature: 135 °C
Yield: 54.4 %
Yield: 33 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (70 mLs) solution of N,N-dimethyl,2,6-dimethyl-4-aminomethylphenol (3.58 g; 20 mmols), there was added methyl iodide (20 mmols) to give a colorless slurry. The vessel was sealed and 2-methyl-1,3-butadiene (100 mmols) was introduced into the system. The reaction mixture was heated to 135° C. and the pressure was increased from atmospheric to 75 psig. The reaction mixture was maintained at these conditions for approximately 4 hours. The reaction vessel was then allowed to cool to room temperature. After cooling the black reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was purified by column chromatography (silica gel eluted with heptane) to give 1.1 g of 2,4,8-trimethylspiro[5.5]undeca-1,4,8-trien-3-one and 2,4,9-trimethylspiro[5.5]undeca-1,4,8-trien-3-one (33% yield based on N,N-dimethyl,2,6-dimethyl-4-aminomethylphenol starting reactant).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:27][C:25]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:24]=1[CH2:23][C:22]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCC(C)=O
Reactant: Cc1ccc(C(=O)c2c(-c3ccccc3)csc2N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2scc(-c3ccccc3)c2c1-c1ccc(C)cc1
Yield: 85.2 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4-phenylthiophen-3-yl)(p-tolyl)methanone (0.264 g; 0.9 mmol), methyl levulinate (0.127 mL; 0.99 mmol), chlorotrimethylsilane (0.460 mL; 3.6 mmol) in DMF (3.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.297 g (85%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=2Br)[C:6](Br)=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=2[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:6]([C:24]2[S:23][CH:22]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1ccc(Br)c2c(OC)ccc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccs2)c2c(OC)ccc(-c3cccs3)c12
Yield: 81 %

Procedure:
1,5-Dimethoxy-4,8-dibromonaphthalene (1.19 g., 0.0034 mol.) and 2-(tributylstannyl)thiophene (3.85 g., 0.0103 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 81%. M.p. 216-218° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.64%; H, 4.48%; S, 17.49%. Mass spectrum: 351.75 (M+). 1H-NMR (CDCl3; in ppm): 3.59 (s, 3H), 6.81 (d, 2H), 6.89 (d, 2H), 7.00 (dd, 2H), 7.26 (dd, 2H), 7.38 (d, 2H). 13C-NMR CDCl3; in ppm): 55.6, 106.5, 123.1, 123.5, 125, 125.5, 126.1, 131.1, 147.5, 156.8.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCNCC1
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
A solution of tert-butyl 4-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)piperidine-1-carboxylate (Ex. 47, 80 mg, 0.168 mmol) in DCM (1.7 mL) was stirred at 25° C. before adding TFA (12.47 μl, 0.168 mmol, Sigma Aldrich). The resulting solution was stirred for 30 min before carefully adding saturated aq. NaHCO3 (10 mL) and stirring for an additional 30 min. The reaction mixture was then concentrating under reduced pressure, and the residue was taken up in DMSO and purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%). The product-containing fractions were concentrated under reduced pressure, and the residue was loaded onto a pre-washed (MeOH, 1 volume) functionalized Si-carbonate column (Silicyle) and allowed to percolate through, providing 2-(2-methyl-3-(piperidin-4-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (4.3 mg, 6.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.92 (1H, s) 7.83-7.91 (1H, m) 7.52-7.58 (2H, m) 7.28-7.35 (1H, m) 7.11-7.16 (1H, m) 3.98-4.11 (3H, m) 3.41-3.49 (2H, m) 2.97-3.06 (2H, m) 2.89 (2H, s) 2.59-2.71 (2H, m) 2.54 (3H, s) 1.93-2.04 (2H, m) 1.43-1.59 (2H, m). m/z (ESI, +ve) 377.1 (M+H)+.