Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:30]([O:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:28])[C@H:3]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:44][CH:43]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CCCCCCC(OC(=O)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(-c3ccc(C(=O)O[C@H](CCCCCC)C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
To a solution of 4'-(1,1,1-trifluoro-2-octyloxycarbonyl)biphenyl-4-carbonylchloride (1.3 g) and 4-n-octyloxyphenol (1.0 g) in methylene chloride (40 ml) were added triethylamine (0.5 g) and dimethylaminopyridine (0.032 g). The mixture was stirred for 24 hours at room temperature before it was poured in water. Extraction was made with methylene chloride and the extract was washed with dilute aqueous sodium carbonate solution and water, in this order and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developer hexane ethyl acetate 10 0.5) and recrystallized from ethanol to obtain the titled compound (0.8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.2 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[Na+].[Na+].[C:21](OC=C)(=O)[CH3:22].C>[Ir+].ClC1CCC=CCCC=1.C(OCC)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]([C:9]([F:10])([F:11])[F:12])([OH:8])[CH2:4][CH2:5][CH2:6][O:7][CH:21]=[CH2:22]
Reactant: C=COC(C)=O
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=COCCCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
1,1,1-Trifluoro-2-trifluoromethyl-2,5-pentanediol (11.3 g, 50 mmol), toluene (50 mL), sodium carbonate (10.6 g,100 mmol), chloro-1,5-cyclooctadiene iridium(I) dimer (0.34 g, 0.5 mmol), vinyl acetate(14 mL, 150 mmol) were placed in a dry 250 mL round-bottom flask equipped with a stir bar, condenser, and nitrogen inlet. The reaction mixture was heated to 100° C. and stirred for 3 hours, after which time it was cooled to room temperature. Diethyl ether (50 mL) was added to quench the reaction. After adding charcoal, the mixture was stirred for 1 hr and filtered with Celite 521. Diethyl ether, excess vinyl acetate, and solvent were distilled off under reduced pressure. The degree of the transetherification of the primary diol was found to be 52% by GC. Vacuum distillation (68-70° C., 15 mm Hg) afforded 3.13 g (25%) of colorless liquid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21][CH:20]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:25]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:26])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cncnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1cncnc1
Yield: 19 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and pyrimidine-5-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (23 mg, 15.7%) was isolated as off white solid; MS (ESI): 367 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][N:8]2[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=12)=[O:4].CO.O1CCCC1.Cl>[Li+].[OH-].O.C(OC(=O)C)C>[I:14][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([N:7]=[C:6]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:5]=2[C:3]([OH:4])=[O:2])[CH:13]=1
Reactant: COC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)nn2cc(I)ccc12
Temperature: 45 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Methyl-6-iodo-2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate (250 mg, 0.661 mmol) was dissolve in aqueous LiOH(2N,1 mL), methanol (2 mL) and tetrahydrofuran (7 mL). This solution was stirred overnight at 45° C. After 24 hours, 2 mL 2M LiOH and 2 mL methanol were added. Heated at 55° C. overnight. The reaction was cooled on an ice water bath and aqueous hydrochloric acid (10 mL, 1N) was added dropwise until acidic by pH paper. Ethylacetate (200 mL) and water (40 mL) were added. The organic portion was extracted with brine (20 mL) and was dried over magnesium sulfate. The solvent was removed by rotory evaporation. The residue was place under vacuum overnight to give of a white solid (204 mg, 85%). 1H NMR (500 MHz, DMSO-D6) δ ppm 7.47 (m, 3H) 7.77 (m, 2H) 7.97 (d, J=9.46 Hz, 1H) 9.27 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as an orange oil (95 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH2:8])[CH3:7])[CH3:2].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH:8][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)N
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)CC(C)NC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 1.5 g (0.010 mole) of (rac)-3-amino-butanoic acid ethyl ester (90% technical grade) and 0.93 mL (0.0105 mole) of cyclopentanone in 50 mL of dichloromethane was added 1.8 g (0.022 mole) of sodium acetate and 3.18 g (0.015 mole) of sodium triacetoxyborohydride. The mixture was stirred overnight at room temperature and then 50 mL of 10% sodium bicarbonate solution was added. The aqueous layer was extracted twice with 50 mL of dichloromethane and then combined dichloromethane layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5 gradient) to give 1.0 g of (rac)-3-cyclopentylamino-butanoic acid ethyl ester as a colorless oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.C([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)CC(N)Cc1cc(F)c(F)cc1F
Reaction time: 0.21 h

Procedure:
The methyl(Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (350.0 gm, 1.42 mol) (28) was charged in methanol (10.0 vol, 3.5 Ltr) at 25-30° C. and the reaction was stirred for 10-15 minutes to give a clear solution. To the clear pale yellow solution, controlled addition of sulphuric acid (70.0 ml, 0.2 vol) was done at 0 to −10° C. and the clear solution was stirred for 10-15 minutes at 0 to −10° C. After 10-15 minutes stirring at 0 to −10° C., sodium cyanoborohydride (2.0 eq, 170.0 gm) was charged in 10 lots. The clear white suspension was stirred at 0 to −10° C. for 2 hours. The methanol was distilled completely at 45-50° C. under reduced pressure to give a pale yellow residue. The pale yellow residue was further treated with a 1:1 mixture of 35% hydrochloric acid:water at 0-5° C. to give pH 2. The suspension was stirred at 0-5° C. for 10-15 minutes and the suspension was further basified by using 20% sodium carbonate to give pH 8-9. The product was extracted in ethyl acetate (2×10.0 vol, 2×3.5 Ltr). The combined ethyl acetate layers were washed with water (3×10.0 vol, 3×3.5 Ltr). The product was isolated by distillation of the ethyl acetate to give a pale yellow coloured oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[C:5]([O:9][C:10]([F:13])([F:12])[F:11])[CH:4]=2)[CH2:27][CH2:26]1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3(1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5-bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with water (1×100 mL). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.CN(C)CCCN=C=NCC.CN(C)CCCNC(NCC)=S>C(#N)C.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:20]1[O:8][CH2:9][C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[N:19]=1
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: CCNC(=S)NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1ccccc1CNC1=Nc2ccc([N+](=O)[O-])cc2CO1
Temperature: 23 °C
Reaction time: 0.06 h
Yield: 76.1 %

Procedure:
To a stirred solution of tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.0 g, 6.0 mmol; HPLC: 4.446 min) in acetonitrile (30 mL) at 23° C. was added 2-methoxybenzylamine (0.82 ml, 6.0 mmol; HPLC: 1.773 min) and the mixture was stirred at 23° C. for 15 min (HPLC: 3.487 min 100%). Added tetrabutylammonium fluoride trihydrate (TBAF.3H2O) (1.945 g, 6.0 mmol) and stirred at 23° C. for 1 h (HPLC: 2.188 min 100%). Added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (1.772 g, 9.0 mmol) and stirred at 90° C. for 4 to 18 h (HPLC product at 1.667 min, 1-(3-dimethylamino-propyl)-3-ethyl-thiourea at 0.31 min). Cooled to rt, diluted with ethyl acetate and water, added little 1 M NaH2PO4.2H2O solution to achieve pH 4, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow foam, which was purified by flash chromatography on silica gel with n-heptane and ethyl acetate to give the title compound as a yellow foam (1.43 g, 74%), MS (ISP) m/e=288.8 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][C@@H:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=2)[CH2:27]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1cnc(N2CC[C@@H](O)C2)nc1
Product: O=C(Nc1cnc(N2CC[C@@H](O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C19H16F3N5O3 m/e 419.37, obsd 420.1 (ES, M+H).
Reaction SMILES: Cl.[CH2:2]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[CH:6]2[CH2:5][NH:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[CH:27][CH:26]=1>C(N(CC)CC)C.CC(C)=O>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:4]2[CH2:3][CH2:2][N:7]3[C:8]4[C:13]([NH:14][C:15](=[O:16])[CH:6]3[CH2:5]2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:27][CH:26]=1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: BrCCCCCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N2CCN(CCCCCc3ccncc3)CC12

Procedure:
To a solution of 6.2 g. (0.03 mole) of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, hydrochloride in 200 ml. acetone is added 15 g. of powdered potassium carbonate, 0.5 ml. of triethylamine, 5 g. of potassium iodide, and 7 g. (0.038 mole) of 5-(4-pyridyl)pentyl bromide. The suspension is stirred and refluxed for 72 hours, cooled, and filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in methylene dichloride, washed with saline, and dried. The dried organic layer is concentrated and the residue purified by column chromatography using Silicar CC-7. This title compound is obtained as base and converted to hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:29][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:27][CH:26]=3)=[CH:21][CH:20]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[NH:29][C:28]([C@@H:30]5[CH2:34][CH2:33][CH2:32][N:31]5[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:27][CH:26]=4)=[CH:23][CH:24]=3)[S:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2ccsc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4ccc(Br)cc4s3)cc2)[nH]1
Temperature: 130 °C
Yield: 36.5 %

Procedure:
A mixture of 6-bromobenzo[b]thiophene (702 mg, 2.07 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (700 mg, 1.59 mmol), tetrakis(triphenylphosphine) palladium (0) (184 mg, 0.15 mmol), potassium carbonate (440 mg, 3.19 mmol) in water (2 mL) and dimethoxyethane (10 mL) was heated in a microwave reactor at 130° C. for 30 minutes. The dimethoxyethane was removed under reduced pressure. The resulting residue was partitioned between water (15 mL) and dichloromethane (15 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic extracts were dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography with eluant of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (S)-tert-butyl 2-(5-(4-(6-bromobenzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (302 mg, 0.58 mmol, 36%).
Reaction SMILES: C(NC1C(=O)OC2C(C=1)=CC(N)=CC=2)(=O)C.[N+:17]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25](=[O:30])[C:24]([C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=1)=[CH:23]2)([O-])=O.[BH4-].[Na+]>[Pd].O.CO>[NH2:17][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25](=[O:30])[C:24]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[CH:23]2
Reactant: O=c1oc2ccc([N+](=O)[O-])cc2cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC(=O)Nc1cc2cc(N)ccc2oc1=O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2cc3cc(N)ccc3oc2=O)cc1
Yield: 63 %

Procedure:
Following the same protocol used to obtain diamine 2, palladium on carbon (10% water) (0.322 g, 1/10th of the mass of 11) and a solution of sodium borohydride (1.21 g, 32.9 mmol) in water (22.6 mL) were used to reduce a suspension of compound 11 (4.03 g, 12.9 mmol) in methanol (775 mL). In this way, compound 12 (2.04 g, 8.1 mmol) was obtained as a yellow solid in 63% yield. FTIR (KBr) (cm−1): 3180, 3120, 1700, 1610, 850. 1H-NMR (DMSO-d6): δ (ppm) 7.84 (s, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 6.60 (d, J=7.8 Hz, 2H), 5.32 (ds, 3H), 5.15 (ds, 3H). 13C-NMR (DMSO-d6): δ (ppm) 163.34, 150.20, 146.43, 145.43, 137.99, 130.38, 127.88, 123.18, 11.33, 118.85, 116.94, 114.39, 111.04. HRMS: expected, 252.089878; found, 252.089846. Elemental analysis for C15H12N2O2: expected: C, 71.42; H, 4.79; N, 11.10; found: C, 71.30; H, 4.58; N, 10.92
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[N:32][N:31]=4)=[CH:40][CH:39]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnnc1-c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: N1CCCC1.[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[CH2:9][S:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[O:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[C:28](=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([S:10][CH2:9][C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[CH3:6])=[CH:12][CH:13]=2)[C:26](=[O:27])[O:25]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1ccccc1CSc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNC1
Solvent: CCOCC
Product: Cc1ccccc1CSc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1
Yield: 54 %

Procedure:
Pyrrolidine (0.45 mL, 5.27 mmol) was added to a solution of aldehyde 28.1 in diethyl ether (20 mL) and the mixture was sonicated for 5 minutes. The mixture was then added to a solution of Meldrum's acid (0.73 g, 5.08 mmol) in diethyl ether (20 mL) and the resultant mixture was sonicated for 5 minutes, forming a solid. The solid was filtered, rinsed with diethyl ether, and then suspended in DCM (10 mL). p-Toluenesulfonic acid (0.97 g, 5.10 mmol) was then added to the suspension and the suspension was sonicated until clear. The solvent was removed under reduced pressure, and the resulting residue was taken up in diethyl ether and partitioned between water and ethyl acetate. The aqueous layer was extracted 2 additional times with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4), and concentrated in vacuo to yield 1.05 g (54%) of 2,2-Dimethyl-5-[4-(2-methyl-benzylsulfanyl)-benzylidene]-[1,3]dioxane-4,6-dione (28.2) as a yellow oil The resulting yellow oil was used without further purification. LC/MSD m/e: 391.1 (M+Na).