Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][C:48]=1[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>C1COCC1>[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:49][C:48]=1[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)Oc1cc(CBr)ccc1OCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOCc2ccccc2)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 327 mg (0.91 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in 10 ml THF was added 2 ml (2 mmol) lithium bis(trimethylsilyl)amide solution in THF drop by drop at −78° C. The reaction mixture was stirred for 2 hours. 300 mg (0.76 mmol) 1-[2-(benzyloxy)ethoxy]-4-(bromomethyl)-2-tert-butoxybenzene in 2 ml THF were added at −78° C. The reaction mixture was stirred for 2 hours. 4.5 ml aqueous hydrogen chloride solution (2N) is added drop by drop. The solution was allowed to be warmed to room temperature. The solution was extracted repeatedly with dichloro methane. The combined organic phases were washed with water, dried with sodium sulfate and concentrated in vacuo. The crude product is purified twice by column chromatography (silica gel, hexane/ethylacetate gradient: 7:1→1:1). The desired product was obtained in 48.7% yield (358 mg, 0.45 mmol).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51 mg, 0.13 mmol), 3-methyltetrahydro-4H-pyran-4-one (46 mg, 0.4 mmol) and triethylamine (0.037 mL, 0.27 mmol) in dry methylene chloride (5 mL) was treated with sodium triacetoxyborohydride (85 mg, 0.40 mmol) at room temperature under N2 overnight. The reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer; second isomer: MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1 for both isomers.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:14]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[N:4]([CH3:14])[N:3]=1
Reactant: CC(C)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-iodo-5-isopropyl-1H-indazole (0.75 g, crude) in 50 mL of THF at 0° C. was added t-BuOK (0.59 g, 5.2 mmol) in one portion. The mixture was stirred at 0° C. for 30 minutes. CH3I (1.1 g, 7.7 mmol) was added and the solution was stirred at room temperature overnight. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure to give crude 3-iodo-5-isopropyl-1-methyl-1H-indazole which contained some N-2 alkylation isomer (0.7 g) as oil. LCMS: (M+H)+=301.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Temperature: 110 °C

Procedure:
74.8 g (0.63 mol) of thionyl chloride in 50 ml of dry toluene were added dropwise at 50° C. to a solution of 139.0 g of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 1 l of dry toluene. After the mixture had been heated for 6 hours at 110° C., the solvent was distilled off. This gave 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in quantitative yield.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[CH2:7][NH2:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: NCc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: NCc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 5-iodo-2-(2-pyrrolidin-1-ylethoxy)benzylamine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 28 mg (11% of theoretical); C26H26ClN3O (M=431.957); calc.: molpeak (M+H)+: 432/434 (Cl); found: molpeak (M+H)+: 432/434 (Cl); HPLC-MS: 3.90 minutes (method B).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Temperature: 25 °C

Procedure:
(S)-N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.57 mmol, 692 mg) was dissolved in DCM (10 mL), thionyl chloride (5.14 mmol, 0.373 mL, 611 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with dichloromethane (4×10 mL) to give a yellow oil. This was used immediately in step f.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](#[N:21])[CH3:20]>>[CH2:12]([O:11][CH2:10][CH2:9][CH2:8][NH:21][CH:19]1[CH2:15][CH2:14][CH:13]([CH3:18])[CH2:12][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC#N
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CCC(NCCCOCc2ccccc2)CC1

Procedure:
4-Trans-methyl-cyclohexylamine (6.65 g, 44.4 mmol) and potassium carbonate (12.3 g, 88.8 mmol) in acetonitrile (50 mL) was heated to reflux before a solution of (3-bromo-propoxymethyl)-benzene (10.2 g, 44.4 mmol) in acetonitrile (25 mL) over a period of 30 min. The reaction mixture was refluxed for 2 hours before the solvent was removed in vacuo. The residue was divided between diethyl ether (100 mL) and aqueous sodium hydroxide (1N, 50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (SiO2, heptane-ethyl acetate 1:1) to give 8.4 g (3-benzyloxy-propyl)-(4-methyl-cyclohexyl)-amine. To this was added a solution of bis-tert-butyldicarbonate (32 mmol, 1N in THF) and the reaction mixture was stirred at room temperature for 18 hours before the solvent was removed in vacuo. The residue was dissolved in diethyl ether (150 mL) and washed with water (2×100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 10.6 g of (3-benzyloxy-propyl)-(4-methylcyclohexyl)-carbamic acid tert-butyl ester. This was subsequently dissolved ethanol (100 mL) and Pd/C (10%, 1 g) was added. The reaction mixture was stirred under H2 (1 atm) for 4 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give 7.9 g of (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:30][CH:31]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc(-n2cccc2)cc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-(1-pyrrolyl)benzoic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-(1-pyrrolyl)benzamide as an off white powder, m.p. 173.0-174.9° C. 1H NMR (300 MHz, DMSO-d6) δ8.52 (t, J=5.5 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.48 (t, J=2.2 Hz, 2H), 7.39 (m, 1H), 7.19 (dt, J=7.6, 1.1 Hz, 1H), 6.53 (broad s, 2H), 6.30 (t, J=2.2 Hz, 2H), 4.57 (t, J=7.0 Hz, 2H), 3.82 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 3.26 (s, 3H), 3.20 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.71 (m, 2H); MS (EI) m/e 482.2421 (482.2430 calcd for C28H30N6O2).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:19])[CH2:6]1)C.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:6][C:7](=[O:19])[NH:8][C:9]4[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:10]=4[C:11]=3[N:31]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: Cc1cc2c(cc1C)C(=O)C(=CN(C)C)CC(=O)N2
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(C)c(C)cc2NC(=O)C3)cc1
Yield: 79 %

Procedure:
Analogous to Scheme 1,from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 79%.
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OCC)=[O:18]>>[C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH:12]=[CH:17][OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Product: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO

Procedure:
3-benzoyloxy-2,4-pentanedione is reacted with ethyl formate to form 4-benzoyloxy-1-hydroxy-1-hexene-3,5-dione,
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].[CH3:14][C:15]([O:17]C(C)=O)=[O:16]>CCN(CC)CC>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C=CC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
An alternative procedure is as follows. A mixture of 4-trifluoromethylacetophenone (18.8 g) glyoxylic acid monohydrate (18.8 g), Ac2O (20 ml) and a drop of Et3N was heated to 135°, internal temperature. More Et3N (2 ml) was added, and the mixture was held at 135° for 20 minutes. The mixture was cooled and evaporated to dryness in vacuo. The solid residue was digested with H2O, filtered, dried and recrystallized from C6H6 to give the title compound, 12.2 g (50%), mp 149°-151°.
Reaction SMILES: [CH2:1]([CH:5]([O:10][C:11]1[CH:28]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:13](=[C:14]23)[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[Br:29]N1C(=O)CCC1=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:29][C:28]1[C:11]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:12][C:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:27])[C:19]3[C:14]=2[C:15]=1[CH:16]=[CH:17][CH:18]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 45 g (0.12 mole) of 2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one, 23.6 g (0.13 mole) N-bromosuccinimide and 265 g DMF. The mixture was agitated well, heated to 50° C. and held at 50° C. for two hours. Some of the DMF was stripped from the reaction using heat and vacuum and then 300 g chloroform were added to the flask. The resulting solution was washed three times with 250 g deionized water. The solvent was removed using a rotary evaporator; the yield was 52.5 g of a dark brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCCOCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of phenol 58 with methane sulfonic acid 3-benzyloxy-propyl ester gave 2-(3-(3-(3-(benzyloxy)propoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.643 g, 44%): 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.83 (m, 2H), 7.68-7.72 (m, 2H), 7.27-7.35 (m, 5H), 7.12-7.16 (m, 1H), 6.77 (d, J=7.6, 1H), 6.73 (s, 1H), 6.66 (d, J=8.0, 1H), 4.53 (s, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.2 Hz, 2H), 3.68 (t, J=5.0 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.0-2.10 (m, 4H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]1([CH2:20][CH:21]([C:27]([CH3:29])=O)[C:22](OCC)=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:27]([CH3:29])=[C:21]([CH2:20][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:22](=[O:23])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2cccc3ccccc23)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.47 g) and ethyl 2-(1-naphtylmethyl)-acetoacetate (1.00 g) in ethanol (20 ml) was treated with dry HCl at 0° C. for 3 hours and the solution kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water and recrystallized from isopropanol-water (1:1). Yield 0,96 g (78%). Melting point 275-280° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C1COCC1>[CH2:10]([NH:13][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
To an ice-cold solution of ethyl trifluoroacetate (15 mL, 142.2 mmol) in THF (40 mL) was added allylamine (12 mL, 57.1 mmol). The reaction was allowed to warm to room temperature then stirred for 55 min. After the mixture was concentrated under reduced pressure, the residue was dried under vacuum to give acetamide 30. Yield (18.79 g, 98%): 1H NMR (400 MHz, CDCl3) δ 6.46 (br s, 1H), 5.79-5.89 (m, 1H), 5.23-5.29 (m, 2H), 3.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C@@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C@@H:17]([NH2:29])[CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)Cn1cc(-c2ccc3cnccc3c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(C(F)(F)F)cc1)Cn1cc(-c2ccc3cnccc3c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of tert-butyl(S)-3-(4-(isoquinolin-6-yl)-1H-pyrazol-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (90 mg, 0.18 mmol) and TFA (5.00 mL, 64 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. After concentration by vacuum distillation, the residue was purified by reverse-phase HPLC (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 minute gradient) to give the product as an off-white solid (41 mg, 57%). HRMS (TOF) Calcd for C22H20F3N4+: 397.1635, found: 397.1642.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1)(=O)C.C(O)(=O)C.S(=O)(=O)(O)O>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2

Procedure:
Reflux 200 mg. of 8-acetamido-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid for 16 hours in a mixture of 5 cc. of acetic acid and 5 cc. of 50% aqueous sulfuric acid. Dilute with water and separate the solids by filtration. Wash with water and dry to obtain the title product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]([O:24][CH2:25][CH3:26])(=[O:23])[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>>[CH3:18][O:17][C:16]1[CH:15]=[C:14]([CH:22]=[CH:21][C:19]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)[C:13]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(=O)c1ccc(OCc2ccc3ccccc3c2)c(OC)c1
Yield: 54 %

Procedure:
2-Bromomethylnaphthalene was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 3-methoxy-4-(naphth-2-ylmethoxy)benzoate in 54% yield, m.p. 86°-87° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 20% yield, m.p. 124°-126° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(Cl)cc1)CC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(Cl)cc1
Yield: 91.1 %

Procedure:
A solution of 7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (5.4 g, 20.48 mmol) in concentrated ammonium hydroxide (59.8 mL, 1536 mmol) was stirred at 100° C. in a high-pressure vessel for 6 h. The formation of white precipitate was observed during the heating. The solvent was removed in vacuum to provide 7-(4-chlorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (4.9 g, 18.65 mmol, 91% yield) as a off-white solid. LC-MS (M+H)+=263.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.37 (2H, d, J=8.2 Hz), 7.19 (1H, d, J=8.5 Hz), 4.16 (1H, d, J=5.2 Hz), 3.79 (1H, br s), 3.17 (1H, s), 2.51 (2H, d, J=1.8 Hz), 1.75-1.85 (1H, m).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][C:8]=2[CH3:12])[C:3]1=O.[CH3:15][Li].Cl.O>C(OCC)C>[CH3:15][CH:3]1[C:4]2[C:9](=[C:8]([CH3:12])[CH:7]=[CH:6][C:5]=2[CH3:13])[C:10]([CH3:11])=[C:2]1[CH3:1]
Reactant: Cc1ccc(C)c2c1C(=O)C(C)C2C
Reactant: [Li]C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(C)c2c(C)ccc(C)c21
Reaction time: 8 h
Yield: 44.8 %

Procedure:
In a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser 2,3,4,7-tetramethyl-1-indanone (35) (19.52 g, 0.1 mol) was dissolved in dry diethyl ether (300 ml) under an argon atmosphere. The mixture was cooled with ice and methyllithium (45 ml, 3 M solution in diethoxymethane, 0.135 mol) was added dropwise via a syringe, then the mixture was refluxed for 3 h. When the yellow reaction mixture had cooled a mixture of concentrated HCl (20 ml) and H2O (60 ml) was added via an addition funnel. The resulting mixture was transferred to a separation funnel and extracted with diethyl ether (3×200 ml). The combined organic layers were stirred overnight with 15 ml concentrated HCl. After this time the reaction mixture was carefully adjusted to pH 7 with a saturated aqueous solution of sodium carbonate. The reaction mixture was transferred into a separation funnel. The organic layer was washed with H2O (3×100 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give a yellow liquid. This residue was purified via column-chromatography [(SiO2, 25×9 cm) eluent: cyclohexane] to afford 1,2,3,4,7-pentamethylindene (38) (8.35 g, 44%) as a yellow liquid; then (35) (starting material) (9.60 g, 49%) (eluent: cyclohexane:ethylacetate (10:1)) as a yellow liquid.