Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[C:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=1)[C:2]1[C:7]([CH3:8])=[CH:6][C:5](O)=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:26](=[O:29])([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C)C=O>[C:10]([C:4]1[C:5]([O:29][CH2:26][CH2:7][CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([CH3:8])=[C:2]([S:1][C:14]2[CH:15]=[C:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([O:21][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][C:19]=2[CH3:20])[CH:3]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Reactant: O=C([O-])[O-]
Reactant: CCCCCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1cc(C)c(Sc2cc(C(C)(C)C)c(OCCCCC)cc2C)cc1C(C)(C)C

Procedure:
4,4′-thiobis(2-(tert-butyl)-5-methylphenol) (4,4′-thiobis(6-tert-butyl-m-cresol)) (1 equivalent (eq), 10 g, 27.89 mmol), potassium carbonate (2.5 eq, 9.6363 g, 69.725 mmol, 138.205 g/mol), and 1-bromopentane (2.1 eq, 8.8463 g, 7.3 mL, 58.569 mmol, 151.04 g/mol, d=1.218 g/mL) were dissolved in N,N-dimethylformamide (DMF, 90 mL) at 90° C. The reaction was stirred until complete as determined by thin layer chromatography (TLC). The reaction was poured into water and extracted with ethyl acetate. The aqueous layer was discarded and the ethyl acetate was back-extracted three times with brine to remove residual DMF. The resulting organic solution was dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was recrystallized from methanol, filtered, and then washed with cold methanol. The product was dried at 50° C. under high vacuum for 12 hours to yield a fine white powder (compound characterized by Structure F: bis(5-(tert-butyl)-2-methyl-4-(pentyloxy)phenyl)sulfane). The yield was 8.4211 g (60.5%).
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:38])[F:37])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1.[BH3-][C:40]#N.[Na+].C(#N)C>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:37])[F:38])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][N:32]([CH3:40])[CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1
Reactant: O=C(Nc1cn(CC=C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 1.2 %

Procedure:
An aqueous solution of 40% formaldehyde (210 mg) was added to solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (360.00 mg, 0.700 mmol) in methanol (30 mL). The resulting solution was stirred at ambient temperature for 2.5 h and NaBH3CN (44.02 mg, 0.700 mmol) was added. The resulting solution was stirred at this temperature for 3 h and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with dichloromethane/MeOH (10/1). The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/10 mmol NH4HCO3=40% increasing to ACN/10 mmol NH4HCO3=75% within 6 min; Detector, UV 254 nm to obtain 4.3 mg (1%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 32): [M+H]+=528.1, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.44 (t, 1H, J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H), 2.52-2.50 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=3)[O:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:14]=2)=[CH:9][CH:8]=1.Cl>O.O1CCOCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=3)[O:25][CH2:26][C:27]([OH:29])=[O:28])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Yield: 64.6 %

Procedure:
In 5 ml of water was dissolved 0.97 g of sodium hydroxide, whereto 100 ml of ethanol was added. Thereto was added a solution of 8.0 g of ethyl 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetate dissolved in 60 ml of dioxane while stirring. After the mixture was stirred at room temperature for 4 hours, about 500 ml of water was added thereto and the mixture was neutralized with dilute hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from dioxane to give 4.8 g of 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid, m.p. 225°-226° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5]C=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)[N:3]=1.[CH:27]1[C:40]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.N[C:45]1N=C(N)C(CBr)=CN=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:5])[CH:9]=[C:10]([CH2:45][N:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39][C:40]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]2=3)[N:11]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1cc(CN2c3ccccc3Cc3ccccc32)nc(N)n1

Procedure:
N-[(2,4-Diaminopyrimidin-6-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminopyrimidin-5-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-bromomethylpyrimidine hydrobromide (86 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.O>C1COCC1>[N:26]([CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2c1CCC2O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cccc2c1CCC2N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.34 g (29.28 mmol) 4-methyl-indan-1-ol and 7.8 ml (35.14 mmol) diphenylphosphoryl azide are dissolved in dry THF at room temperature under argon. To this mixture is added slowly 5.0 ml (35.14 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is stirred for 6 h at room temperature (TLC monitoring). Then the mixture is poured into water and extracted three times with toluene. The organic layers are combined, dried over MgSO4 and concentrated in vacuo. Purification using silica gel chromatography (hexane/EtOAc 9:1) affords pure 1-azido-4-methyl-indane as light orange liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C.CO>[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1nc(N2CCOCC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (1.2 g), triethyl phosphite (2.1 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v), then ethyl acetate-methanol (10:1, v/v) to give diethyl {[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}phosphonate as a yellow oil (1.7 g, yield 95%). NMR (CDCl3) δ: 1.30 (6H, t, J=7.1 Hz), 2.27 (3H, d, J=4.1 Hz), 3.11 (2H, d, J=20.9 Hz), 3.31-3.43 (4H, m), 3.72-3.85 (4H, m), 3.99-4.20 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].Cl.[CH:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:38])=[CH:35][CH:34]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Cl)cc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. meythlene chloride is added 10.4 g. 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated an the residue is crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26].CO.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[NH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][CH:10]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:25]([NH:27][CH2:28][C:29]23[CH2:36][CH:35]4[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]4)[CH2:30]2)[CH2:38]3)=[O:26])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared from [[4-[[[4chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (0.26 g, Example 32a) methanol (5 ml) and 4N hydrochloric acid solution in dioxane (2 ml). Solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.191 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[CH:28]=[CH2:29].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:40]=[C:31]1[C:32]2[C:33](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:35])[N:30]1[CH2:27]/[CH:28]=[CH:29]/[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(I)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(/C=C/CN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 50.6 %

Procedure:
A mixture of intermediate (1) (0.012 mol), N-allyl-phthalimide (0.012 mol), palladium(II) acetate (0.001 mol) and triethylamine (0.024 mol) was stirred at 100° C. for 12 hours in a bomber, then dissolved in DCM and washed with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 3.2 g of N-[4-[(1E)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 2; mp. 190° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>C1COCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tryptamine (640 mg, 4.0 mmol) was initially introduced into abs. THF (30 ml). TEA (596 μl, 4.3 mmol) and nicotinic acid chloride hydrochloride (770 mg, 4.3 mmol) was then added and the mixture was stirred at RT for 5 h. The mixture was concentrated to dryness i. vac. The residue was taken up in EA (20 ml) and the mixture was washed with saturated NaHCO3 solution (2×20 ml) and with NaCl solution (2×20 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 482 mg (45%)
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][CH2:13][C:14](=O)[C:15]=3[CH:16]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.B(Br)(Br)Br.C[OH:23]>C(Cl)Cl>[OH:2][C:3]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:23]
Reactant: CO
Reactant: COc1cc2c(c3ccccc13)C=CCC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCCc2c(O)cc3c(c21)CCCC3
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
47.4 g (0.22 mol) of the 9-methoxy-phenanthrenone from Example 3 are dissolved in 605 ml of absolute methylene chloride and 440 ml of a 1 molar solution of boron tribromide in methylene chloride are added dropwise at -78° C. The mixture is stirred at -78° C. for 0.5 h, then at +20° C. for 3 h, cooled again to -78° C. and 620 ml of methanol is slowly added. The mixture is allowed to come to 20° C. and is evaporated. The residue is partitioned between 200 ml of CH2Cl2 and 200 ml of 1N NaOH solution, and the NaOH phase is separated and acidified to pH 1 using concentrated HCl solution with ice cooling. The precipitate is filtered off and dried in a high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Agent: [Pd]
Solvent: CCO
Product: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Yield: 85.8 %

Procedure:
A solution of 7-bromo-2-(3-pyridylmethylene)-1-tetralone (13.9 g) in ethanol (150 ml) containing 5% palladium on charcoal (0.50 g) was hydrogenated at 25° and 4 atm. pressure until the theoretical quantity of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated. The residue was distilled to give an oil (12.0 g), b.p. 200°-240° at 1.0 mm containing ca 40% of debrominated material. The product was purified by high pressure liquid chromatography using a silica gel column and a mixture of hexane and ethyl acetate (45:55) as eluent. Debrominated product was eluted first followed by pure 7-bromo-2-(3-pyridylmethyl)-1-tetralone, m.p. 63°-67°.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[N:3]=[C:2]1[NH2:14].I[CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>C(O)C>[CH2:16]([N:10]1[CH:11]2[C:6]([C:5]3[S:1][C:2]([NH2:14])=[N:3][C:4]=3[CH2:13][CH2:12]2)=[CH:7][CH2:8][CH2:9]1)[CH2:17][CH3:18]
Reactant: Nc1nc2c(s1)-c1cccnc1CC2
Reactant: CCCI
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCN1CCC=C2c3sc(N)nc3CCC21
Reaction time: 1 h

Procedure:
The free base of 4,5-dihydrothiazolo[5,4-f]quinolin-2-amine, 5.0 g (20 mmol), is refluxed in 250 ml ethanol with 6.8 g (40 mmol) of 1-iodopropane for 20 hours. The solvent is removed in-vacuo and the 2-amino-4,5-dihydrothiazolo[5,4-f]quinolinium iodide which remains is dissolved in 200 ml methanol and treated with 1.7 g (50 mmol) of sodium borohydride in small portions, at 0° C. After 1 hour, 50 ml of 10% hydrochloric acid is added dropwise and the volatile components are removed in-vacuo. The residue is made basic with ammonium hydroxide and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, evaporated and the residue is chromatographed to yield (±)-4,5,5a,6,7,8-hexahydro-6-propylthiazolo-[5,4-f]quinolin-2-amine.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23]1([S:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8](=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C1SC(=CC(=O)OC(C)(C)C)S1
Reactant: ClSc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1SC(=C(Sc2ccccc2)C(=O)OC(C)(C)C)S1

Procedure:
A mixture of methyl 2-(t-butoxycarbonylmethylene)-1,3-dithietane-4-carboxylate (689 mg), pyridine (430 μl) and benzenesulfenyl chloride is allowed to react in methylene chloride at 0° C. until no starting carboxylate is detected. The reaction mixture is washed with water, dried, and vacuum evaporated to give methyl 2-(1-t-butoxycarbonyl-1-phenylthiomethylene)-1,3-dithietane-4-carboxylate. Yield: 713 mg (73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:7])[CH:8]=[C:9]([I:11])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2cc(Br)cc(I)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A solution of 3-bromo-5-iodo-benzoic acid (5.0 g, 15.3 mmol) in 100 mL of thionyl chloride was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then dissolved in 100 mL of CH2Cl2. N-Methyl-piperazine (2.5 mL, 22.9 mmol) and DIPEA (5.3 mL, 30.6 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure and the crude material was purified by column chromatography (Isco™ 330 g) using 20% MeOH/EtOAc as eluting solvent to afford 5 g (80%) of (3-bromo-5-iodo-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid.
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1.CO.O>[CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)Nc1nc(-c2ccccc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCL, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1cncc(-c2cccc(N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 79% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[ClH:1].[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([S:14][C:13](=[NH:12])[NH2:15])=[N:3][CH:4]=1
Reactant: NC(N)=S
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1cnc(SC(=N)N)c([N+](=O)[O-])c1
Product: Cl

Procedure:
A solution of 23 g of 2-chloro-5-methyl-3-nitropyridine and 11.14 g of thiourea in 130 cm3 of ethanol is brought to reflux for 2 hours. After cooling and addition of 20 cm3 of petroleum ether (40°-60° C.), the precipitate obtained is collected on a filter, washed with petroleum ether and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([NH:20][C:21](=[O:22])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:18]([C:23](=[O:24])[C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:17]=1
Reactant: COc1cccc(F)c1
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155 mmol) in THF (180 mL), at −78° C., was added dropwise 2.5 M n-butyllithium in hexanes (62 mL, 155 mmol). The solution was stirred at −78° C. for 3 h and then added to a suspension of 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in THF (280 mL) at −20° C. The mixture was allowed to gradually warm until the solution became homogenous. 1N HCl (150 mL) followed by EtOAc (250 mL) were then added and the solution allowed to warm to room temperature. The organic portion was collected and washed with H2O (250 mL), saturated NaHCO3 (2×250 mL) and H2O (250 mL). The organic portion was then dried over Na2SO4 and evaporated to dryness, in vacuo, to provide the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as an orange solid (42.7 g). To a solution of N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7 g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in H2O (100 mL). The solution was allowed to reflux for 16 h. The solution was then allowed to cool to room temperature and the resulting precipitate removed by filtration. The filtrate was concentrated in vacuo, diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic portion was then dried over Na2SO4, concentrated in vacuo and then purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac (19.6 g, 47%) MS m/z=280 (M+H).