Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:29][N:28]([CH3:30])[CH2:27]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:27][N:28]([CH3:30])[CH2:29]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(Oc2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A mixture of 206g (93.6 mg, 0.15 mmol) and lithium hydroxide (65 mg, 1.5 mmol) in THF/i-propanol (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and diluted with water (3 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 206 (35 mg, 42%) as white solid. MS-ESI: [M+H]+ 582.3. 1H NMR (500 MHz, CHCl3) δ 8.62 (d, J=1.5 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.12-7.10 (m, 1H), 6.90 (s, 1H), 6.81-6.80 (m, 1H), 5.07-5.04 (m, 1H), 4.77 (t, J=5.5 Hz, 1H), 4.64-4.62 (m, 1H), 4.52-4.50 (m, 1H), 4.33-4.30 (m, 1H), 4.16-4.10 (m, 2H), 3.97-3.88 (m, 3H), 3.72 (s, 3H), 3.25-3.24 (m, 2H), 2.63-2.57 (m, 4H), 2.51 (s, 3H), 1.93-1.91 (m, 2H), 1.80-1.79 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1/[CH:8]=[CH:16]/[N:17]([CH3:19])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: COc1ncc([N+](=O)[O-])c(C)c1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc([N+](=O)[O-])c(/C=C/N(C)C)c1Br
Temperature: 90 °C

Procedure:
To a solution of 3-Bromo-2-methoxy-4-methyl-5-nitro-pyridine (3.00 g, 12.1 mmol) in DMF (0.6M) was added via syringe N,N-dimethylformamide-dimethylacetal (3.0 mL, 22.4 mmol, 1.8 eq) in a fast dropwise manner. The solution was heated for 2 hr at 90° C., cooled to 23° C., then diluted with Ethyl Acetate (200 mL). The washed reaction mixture was washed with water, brine, dried (Na2SO4), and concentrated giving [(E)-2-(3-Bromo-2-methoxy-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine as a red solid which was used without further purification (3.45 g, 10.9 mmol, 89%). MS ESI m/z 304.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.03 (d, J=13.5 Hz, 1H), 5.30 (d, J=13.5 Hz, 1H), 4.05 (s, 3H), 2.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].ClC1C=CC([O:27]CC(N)=O)=C(C=1)CN.ClC1C=CC(O)=C(C=1)C(N)=O.C(Br)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:27]
Reactant: NCc1cc(Cl)ccc1OCc1ccccc1
Reactant: NCc1cc(Cl)ccc1OCC(N)=O
Agent: [Cu]I
Agent: BrCc1ccccc1
Agent: NC(=O)c1cc(Cl)ccc1O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)ccc1OCc1ccccc1
Yield: 98 %

Procedure:
Compounds 72 and 73 were synthesized through a Sonogashira-type reaction in high yield using CuI and (Ph3P)PdCl2 as catalysts. Sonogashira et al., Tet. Lett. 1975, 4467-4470. For the preparation of both 5-chloro-2-benzyloxybenzylamine 76 and 5-chloro-2-(aminocarbonylmethyloxy)benzylamine 80, 5-chloro-2-hydroxybenzamide 74 was used as starting material. Compound 74 was treated with benzyl bromide in the presence of K2CO3 in N,N-dimethylformamide to obtain 5-chloro-2-benzyloxybenzamide 75 in 98% yield. Finally, the amide 75 was reduced to the corresponding amine 76 with LiAlH4 in tetrahydrofuran.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl>>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1CCl
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCc2ccccc2F)cc1

Procedure:
4-(2-Fluorobenzyloxy)benzaldehyde is prepared by alkylation of 4-hydroxybenzaldehyde (0.39 g) with 2-fluorobenzyl chloride by following the same procedure of Example 1, but using three different phase transfer catalysts.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O(C(C)(C)C)[Li]>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(C)C=CC=CC=1>[CH3:1][N:2]([CH3:4])[NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)N
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]OC(C)(C)C
Solvent: Cc1ccccc1
Product: CN(C)Nc1ccccc1
Temperature: 80 °C
Yield: 24 %

Procedure:
N,N-Dimethylhydrazine (2.0 equiv., 1.0 mmol, 0.075 mL), bromobenzene (1 equiv., 0.5 mmol, 0.05 mL), Pd2(DBA)3 (0.025 equiv., 0.0125 mmol, 12 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), LiOtBu (1.2 equiv., 0.6 mmol, 48 mg) and toluene (5 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (˜1 min.), and then heated to 80° C. under argon for 18 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (10% EtOAc/Hex) to give the title product as a yellow oil (17 mg, 0.12 mmol, 24% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.Br[CH2:37][C:38]([O:40]CC)=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([N:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:37][C:38]([OH:40])=[O:39])=[CH:35][CH:34]=2)=[O:11])[C@@H:13]([CH3:33])[CH2:14]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Temperature: 50 °C

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid was prepared from (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide. (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (0.036 g, 0.07 mmol) was dissolved in dimethylformamide, ethyl bromoacetate (0.008 mL, 0.07 mmol) and potassium carbonate (0.021 g, 0.14 mmol) were added. The reaction was heated to 50° C. for 17 h. The reaction was concentrated down and purified using 50% ethyl acetate/50% hexane to 100% ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)(C)C)(C)C)[C:5]2=[N:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: Cl
Solvent: CO
Product: Brc1cnc2[nH]ccc2c1
Yield: 92.3 %

Procedure:
To a stirred solution of the TBS derivative 26 (1.01 g, 3.3 mmol) in MeOH (10 mL) was added a 10% solution of HCl in MeOH (7 mL). After 8 min the solvents were evaporated and the residue was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted with AcOEt (3×). The combined organic solutions were dried (MgSO4), concentrated and purified by PTLC with CH2Cl2:MeOH=95:5 as eluent to afford the bromo derivative 27 (0.60 g, 94%). 1H NMR (400 MHz; CDCl3) δ 6.47 (dd, J=2.0, 3.5 Hz, 1H), 7.37 (dd, J=2.5, 3.5 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 10.24 (br s, H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.ClC1C=C(F)C2N(CCC(F)(F)F)C(CCl)=NC=2C=1.[CH3:40][S:41]([C:44]1[C:52]2[C:47](=[CH:48][N:49]=[CH:50][CH:51]=2)[NH:46][N:45]=1)(=[O:43])=[O:42].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9][N:46]3[C:47]4=[CH:48][N:49]=[CH:50][CH:51]=[C:52]4[C:44]([S:41]([CH3:40])(=[O:42])=[O:43])=[N:45]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: Fc1cc(Cl)cc2nc(CCl)n(CCCC(F)(F)F)c12
Agent: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)cc(F)c3n2CCCC(F)(F)F)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 5-1 by using 5-chloro-2-(chloromethyl)-7-fluoro-1-(4,4,4-trifluorobutyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine 5-chloro-2-(chloromethyl)-7-fluoro-1-(3,3,3-trifluoropropyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:32]#[N:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1C#N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
After dissolving trifluoromethanesulfonic acid 6-methoxy-4-(4-nitrophenoxy)quinolin-7-yl ester (500 mg) in dimethylformamide (5 ml), there were added zinc cyanide (260 mg) and tetrakistriphenylphosphine palladium (0) (130 mg) and the mixture was heated and stirred at 110° C. for 2 hours under a nitrogen atmosphere. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (300 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[C:22]12([CH2:32][N:33]=[C:34]=[O:35])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>O1CCCC1.[Cl-].[Na+].O>[C:22]12([CH2:32][NH:33][C:34](=[O:35])[C:15]3[C:14]([Br:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=3)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Temperature: 0 °C

Procedure:
n-Butyllithium (2.51 ml of a 2.5M solution in hexanes) was added to diisopropylamine (0.88 ml) in dry tetrahydrofuran,(15 ml) at 65° C. To this solution was added a solution of 5-bromo-2-methoxypyridine (0.82 ml) in dry tetrahydrofuran (10 ml) dropwise over 30 minutes at −65° C. A solution of 1-adamantylmethylisocyanate (1 g) in dry tetrahydrofuran (10 ml) was then added in small portions over 30 minutes at −65° C. The reaction mixture was allowed to warm to 0° C., diluted with saturated brine (20 ml) and extracted into ethyl acetate (3×20 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:acetone (19:1 to 2.5:1) to afford the sub-titled compound (1.1 g) as a colourless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(F)ccc1O
Yield: 58.7 %

Procedure:
Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:4][CH2:5][OH:6].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:4][CH:5]=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
A solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienol (400 mg, 1.59 mmol) in acetonitrile (5 ml) was added to a slurry of N-methymorpholine N-oxide (280 mg, 2.38 mmol) and powdered 4A molecular sieves in acetonitrile (10 ml) and the mixture stirred at r.t. for 10 min. Tetrapropylammonium perruthenate (28 mg, 0.00795 mmol) was added in one portion and the resulting dark green slurry stirred at r.t for 1 hr. The reaction mixture was filtered through a plug of silica gel eluting with ethylacetate and the filtrate evaporated in vacuo. The resulting oil was chromatographed over silica gel eluting with diethylether:hexanes (1:10, v:v) to afford the title compound (200 mg, 50%) as a clear colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([Cl:15])=[O:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Br)cc1CC(=O)O
Product: Cc1ccc(Br)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6.00 g (26.19 mmol) of (5-bromo-2-methylphenyl)acetic acid (EP 1791816 A1 and US 2006/29799 A1) were dissolved in 31.20 g (261.92 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for two hours and then concentrated under reduced pressure. Drying under fine vacuum gave 6.29 g (97% of theory) of the title compound as a brownish oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add dropwise trimethylacetyl chloride (3.3 mL, 27 mmol) to a mixture of 4-aminobenzonitrile (2.92 g, 24.7 mmol) and triethylamine (3.8 mL, 27 mmol) in anhydrous DCM (25 mL) at 0° C. Stir the mixture to room temperature overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash the combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (5 g, 100%). MS (ES+) m/z: 203.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]([CH2:29][C:30]([O:32]CC)=[O:31])[C:22]2=[O:35])O)=[O:10])C1C=CC=CC=1.I.C(Cl)(OC[CH:41]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)=O>CC(O)=O>[CH:43]1[C:42]2[CH:41]([CH2:1][O:8][C:9]([N:11]3[CH2:16][CH:15]4[CH2:17][CH:12]3[CH2:13][CH:14]4[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][N:23]([CH2:29][C:30]([OH:32])=[O:31])[C:22]4=[O:35])=[O:10])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]=2[CH:46]=[CH:45][CH:44]=1
Reactant: CCOC(=O)Cn1cnc2ccc(C3(O)CC4CC3CN4C(=O)OCc3ccccc3)cc2c1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: I
Solvent: CC(=O)O
Product: O=C(O)Cn1cnc2ccc(C3CC4CC3CN4C(=O)OCC3c4ccccc4-c4ccccc43)cc2c1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a mixture of 13 (22.4 g, 47 mmol) in HOAc (448 mL) was added HI (268 mL). The mixture was heated to reflux at 120° C. overnight. The reaction mixture was evaporated and its pH was adjusted to 6-7 with potassium carbonate and NaHCO3. Then 50 mL of tetrahydrofuran was added. To the mixture was added FmocCl (15.68 g, 61 mmol) and stirred at room temperature for 5 h. Then the reaction mixture was extracted with ethyl acetate and washed with water 3 times. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification by chromatography (eluant:methylene chloride to methylene chloride/MeOH/HAc 8/1/0.1) gave 10.3 g of crude 5-(3-carboxymethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid 9H-fluoren-9-ylmethyl ester which was further purified by preparative HPLC to give 2.7 g of pure 5-(3-carboxymethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid 9H-fluoren-9-ylmethyl ester (11% yield in 2 steps).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]2[CH:8]=[C:9]3[C:14](=[C:15]([OH:16])[C:5]=2[C:4](=[O:38])[CH:3]=1)[C:13]([OH:17])=[CH:12][C:11]([OH:18])=[C:10]3[C:19]1[C:34]2[C:23](=[C:24]([OH:35])[C:25]3[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[O:27][C:26]=3[CH:33]=2)[C:22]([OH:36])=[CH:21][C:20]=1[OH:37].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1>[OH:16][C:15]1[C:5]2[C:4](=[O:38])[CH:3]=[C:2]([CH3:1])[O:7][C:6]=2[CH:8]=[C:9]2[C:14]=1[C:13]([OH:17])=[CH:12][C:11]([O:18][C:41]([N:40]([CH3:44])[CH3:39])=[O:42])=[C:10]2[C:19]1[C:34]2[C:23](=[C:24]([OH:35])[C:25]3[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[O:27][C:26]=3[CH:33]=2)[C:22]([OH:36])=[CH:21][C:20]=1[O:37][C:41]([N:40]([CH3:44])[CH3:39])=[O:42]
Reactant: Cc1cc(=O)c2c(O)c3c(O)cc(O)c(-c4c(O)cc(O)c5c(O)c6c(=O)cc(C)oc6cc45)c3cc2o1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(=O)c2c(O)c3c(O)cc(OC(=O)N(C)C)c(-c4c(OC(=O)N(C)C)cc(O)c5c(O)c6c(=O)cc(C)oc6cc45)c3cc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 50 mg of 2-methyl-5,6,8-trihydroxy-9-(5,6,8-trihydroxy-2-methyl-4H-naphtho[2,3,b]pyran-4-one-9yl)-4H-naphtho[2,3,b]pyran-4-one in 2 ml of pyridine at 0° C. was added with 0.02 ml of dimethylcarbamoyl chloride. The mixture was then stirred at 0° C. for 2 hours and warmed to room temperature overnight. The mixture was quenched with 1 ml of 0.1N sodium hydroxide solution, stirred for 20 minutes and partitioned between chloroform and water. The chloroform layer was then washed with diluted hydrochloric acid solution, saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was purified on HPLC on a C-18 silical gel column to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]2[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]2[N:10]=[C:9]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=2)[CH:8]=1>CO>[OH:27][CH2:26][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:9]2[CH:8]=[C:7]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]3[N:10]=2)=[O:30])=[CH:24][CH:23]=1)([CH3:29])[CH3:28]
Reactant: C1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(N3CCCC3)n2n1
Yield: 76 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent) and pyrrolidine (4.0 equivalents) in DMF (0.10 M with respect to 4G) was stirred at 80° C. for 1 h. After cooling, the mixture was diluted with methanol and purified by preparative LC-MS to afford the titled compound (76%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6 H), 1.85-2.07 (m, 4 H), 2.33 (s, 3 H), 3.47 (s, 2 H), 3.96 (br. s., 4 H), 6.13 (s, 1 H), 6.75 (s, 1 H), 7.53 (d, J=8.59 Hz, 2 H), 7.97 (d, J=8.59 Hz, 2 H), 10.89 (s, 1 H). ESI-MS: m/z 394.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[Cl:28]>C(O)C>[Cl:28][C:20]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1Cl
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccc([N+](=O)[O-])c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (200 mg, 1.4 mmol) was dissolved in absolute ethanol (15 mL), then triethylamine (230 μL, 1.7 mmol) and 1-(bromomethyl)-2-chloro-3-nitrobenzene (350 mg, 1.4 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered, washed with methanol, and then dried in vacuo to afford 2-{[(2-chloro-3-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as white solid (277 mg, 64% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 4.56 (s, 2H), 6.00 (bs, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H); LRMS (ES+) m/z 312 (100%, M+1), 314 (45%, M+3).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18]>C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:6]([O-:9])=[O:7])=[CH:13][C:12]=1[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Cl

Procedure:
A sulphonitric mixture at 0° C., composed of sulphuric acid (3.8 ml) and nitric acid (1 ml), is added dropwise to a mixture, cooled to 10° C., of 2-chloro-1,4-xylene (1.4 g), acetic acid (17 ml) and 98% sulphuric acid (1 ml). The reaction medium is poured into a water/ice mixture and then filtered. The yellow precipitate is recrystallized from petroleum ether to give the title compound.