Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl>O1CCOCC1.[Pd](Cl)Cl.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>[C:28]([C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:30])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (40 g, 108 mmol, as described in Example 1.00) in dioxane (300 mL) was added tributyl(1-ethoxyvinyl)stannane (38.5 mL, 114 mmol) and bis(triphenylphosphine) palladium (II) chloride (3.05 g, 4.35 mmol). The mixture was purged with nitrogen and heated at 90° C. overnight. More tributyl(1-ethoxyvinyl)stannane (20 mL) and bis(triphenylphosphine) palladium (II) chloride (1.5 g) were added and the reaction mixture heated for an additional 3 hrs. The mixture was cooled to room temperature, HCl 2N (81 mL, 163 mmol) was added and the dark suspension heated at 45° C. for 30 min. The dioxane was evaporated under vacuum, the residue was dissolved in DCM and a saturated solution of sodium bicarbonate was added until pH 4. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford a crude compound which was triturated in diethylether, filtered and dried to afford methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (25.0 g, 69.5%) as an off-white solid. Mass Spectrum: M+H+ 332.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:19])=O>CN(C)C=O>[CH3:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1csc(Nc2nc(C)c(C)c(O)n2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1csc(Nc2nc(C)c(C)c(Cl)n2)n1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
The mixture solution of 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-hydroxypyrimidine (1.15 g, 4-78 mmol), phosphorus oxychioride(7 ml), and dimethylformamide(5 ml) was heated to 70° C. for 30 minutes, cooled to a room temperature and then poured into ice water. The aqueous layer was extracted with dichloromethane, washed with 1N sodium hydroxide solution, and then washed with water. The separated organic layer was concentrated and the residual oil was suspended in a mixture solution of ethyl ether and hexane. The resulting solid was filtered and dried to give 0.42 g of the titled compound. (Yield: 33.9%)
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:34]([O:36][CH3:37])=[O:35])=[N:12][C:13]([C@@H:17]2[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].S(OC)(O[CH3:44])(=O)=O.Cl>O1CCOCC1>[CH3:37][O:36][C:34]([C:11]1[N:12]=[C:13]([C@@H:17]2[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[N:14]([CH3:44])[C:15](=[O:16])[C:10]=1[O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35]
Reactant: COC(=O)c1nc([C@@H]2C[C@@H](OC)CN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)c1nc([C@@H]2C[C@@H](OC)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.67 h

Procedure:
To methyl 5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate, dissolved in dioxane, LiH (1.4 eq.) was added and the reaction mixture stirred at 38° C. for 40 minutes. The temperature was raised to 60° C. and dimethyl sulphate (1.3 eq.) was added dropwise. After two hours the reaction mixture was cooled down to 0° C. and HCl 1 N was added to quench the reaction. The reaction mixture was extracted with ethyl acetate and the organic phase washed with HCl 1N, saturated aqueous NaHCO3 and brine, dried on Na2SO4, filtered and concentrated in vacuo. The desired product was isolated by flash chromatography on silica gel (eluent ethyl acetate:petroleum ether=30:70) as a 1:1 mixture of rotamers by NMR:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:9]([CH:10]=O)[C:8]([OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>C(#N)C>[C:22]([C:23]1[O:13][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][C:9]=2[CH:10]=1)(=[O:24])[CH3:21]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc2cc(C(C)(C)C)ccc2o1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
5-tert-Butylsalicylaldehyde (163 g) was dissolved in 1.5 liters of acetonitrile, 252.5 g of anhydrous potassium carbonate was added and 84.6 g of chloroacetone was dropped into the mixture with stirring at room temperature. After completion of the dropping, the reaction mixture was stirred for 8 hours and then insoluble matters were filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate followed by washing with water twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized by adding isopropyl ether thereto followed by filtering to give 120.5 g of crystals. M.p. 99°-101° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@H:25]1[C@H:32]2[C@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]2)[C@@H:27]([CH2:35][F:36])[CH2:26]1.CCN(CC)CC>CCO>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[C@H:25]3[C@H:32]4[C@H:28]([O:29][C:30]([CH3:33])([CH3:34])[O:31]4)[C@@H:27]([CH2:35][F:36])[CH2:26]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CCN(c2cccc(Cl)c2)C1
Reactant: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(N[C@H]5CCN(c6cccc(Cl)c6)C5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1-(3-Chloro-phenyl)-pyrrolidin-3(S)-ylamine hydrochloride (300 mg, 1.29 mmoles) prepared as in step 4 of example 1 and 6-chloro-9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purine (420 mg, 1.29 mmoles) prepared as described above were combined in EtOH (12 ml), NEt3 (730 μl, 5.15 mmoles) was then added and the resulting brown solution was stirred at reflux under an argon atmosphere. After 22 h, the reaction mixture was cooled to room temperature, evaporated to dryness, the residue was partitioned between water and EtOAc, the aqueous layer was separated and extracted two times with EtOAc. The combined organic layers are washed with brine and dried over magnesium sulfate. The filtrate is concentrated under reduced pressure to give a residue which is purified by flash chromatography on silica gel eluting with 40% EtOAc in cyclohexane followed by 5% MeOH in CH2Cl2 to yield [(S)-1-(3-chloro-phenyl)-pyrrolidin-3-yl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl -tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O>C(OCC)C>[CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([CH3:11])[C:7]=1[NH2:8]
Reactant: CSc1scc(C)c1[N+](=O)[O-]
Solvent: CCOCC
Product: CSc1scc(C)c1N

Procedure:
6 g (0.22 gram atoms) freshly prepared aluminium amalgam are added over a period of about two minutes to 18.9 g (0.1 mol) of 2-methylthio-4-methyl-3-nitrothiophene dissolved in 200 ml of moist diethylether. The vigorous reaction which sets in after 5-10 minutes is kept under control by cooling the flask in ice.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][N:20]=[C:21]=[O:22]>C1COCC1>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:21]([NH:20][CH3:19])=[O:22])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CN=C=O
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.5 g, 1.77 mmol) was dissolved in THF (5 ml). To this was added NaH (60%, 0.14 g, 3.54 mmol) as a suspension in THF (2 ml) and the reaction mixture was stirred for 5 min. After this time methyl isocyanate (0.2 g, 3.55 mmol) was added in one portion and the reaction mixture was stirred at RT for a further 48 hours. After this time, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.47 g, 78% yield) as a light brown solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH2:10][NH:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([N:11]([OH:12])[CH2:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: ONC[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N(O)C[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of N-[(trans-2-phenylcyclopropyl)methyl]-N-hydroxylamine (3.26 g, 20 mM) in methylene chloride (50 ml) was added chloroacetyl chloride (4.52 g, 40 mM) and triethylamine (4.04 g, 40 ml) at room temperature. After stirring for 5 hours, it was poured into saturated aqueous sodium bicarbonate. The whole was extracted with chloroform (2×100 ml). The extracts were washed with water and brine, then were added and evaporated in vacuo. Chromatographic purification (eluent chloroform:ethanol=15:1) of the residue provided 2 g (41.8% yield) of the desired product as a pale yellow oil.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][C@@H:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:5]1.C([Li])CCC.[CH:23](=[O:25])[CH3:24]>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@@H:6]2[CH2:7][CH2:8][C@H:4]([C:3]#[C:2][CH:23]([OH:25])[CH3:24])[CH2:5]2)=[CH:11][CH:12]=1
Reactant: CC=O
Reactant: Fc1ccc(O[C@@H]2CC[C@H](C=C(Br)Br)C2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)C#C[C@H]1CC[C@@H](Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1 -dibromo-2-{cis-3-(4-fluorophenoxy)cyclopentyl}ethene (6.12 g, 18 mmol) in dry THF (50 ml) at -78° C. under an argon atmosphere was added n-butyllithium (24.5 ml, 39 mmol, 1.6M n-hexane solution). The mixture was stirred for 0.5 h at the same temperature and then allowed to warm to room temperature over 1 h. The mixture was cooled to 0° C., a solution of dry acetaldehyde (1.76 g, 40 mmol) in dry THF (20 ml) added to the mixture and the whole stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (100 ml) and the whole extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography {SiO2, 250 g; hexane/ethyl acetate (4:1)} afforded 2.18 g (49%) of title compound as a yellow oil: 1H NMR δ7.05-6.92 (m, 2H), 6.86-6.77 (m, 2H), 4.78-4.62 (m, 1H), 4.60-4.48 (m, 1H), 2.81-2.65 (m, 1H), 2.52-2.36 (m, 1H), 2.12-1.81 (m, 5H), 1.65 (br.s, 1H), 1.45-1.40 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-bromosuccinimide (213 mg, 1.2 mmol) in Tetrahydrofuran (5.99 ml) was stirred in a sealed tube for 1 h at 70° C. Aqueous sodium hydroxide (4.0 ml, 23.97 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (378 mg, 1.2 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 314, 316 (M, M+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:37]([CH3:36])(=[O:39])=[O:38])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and methanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspension was stirred for 18 h at ambient temperature. Further N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol) and methanesulfonyl chloride (54 μL, 0.689 mmol) were added and stirred was continued for 24 h at 50° C. The reaction mixture was then extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (34 mg, 14%) as a light yellow solid. MS: m/e=427.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][CH:24]=[C:25]4[C:28]([O:30]CC)=[O:29])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7].[Li+].[OH-]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][CH:24]=[C:25]4[C:28]([OH:30])=[O:29])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(C(=O)OCC)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(C(=O)O)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of ethyl 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-1-naphthoate (Example 9, 9.4 mg, 0.012 mmol) in EtOH (0.5 mL) and THF (0.5 mL) was added 2N LiOH (58 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 30 min and then at 40° C. for 2 h. The reaction mixture was quenched with 6N HCl, and then extracted with CHCl3 (4×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (9.0 mg, 94%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 9.90 (s, 1H), 8.40 (d, J=7.3 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.17 (d, J=1.1 Hz, 1H), 8.08 (dd, J=8.4, 1.8 Hz, 1H), 7.98 (t, J=2.2 Hz, 1H), 7.79-7.74 (m, 1H), 7.71-7.64 (m, 1H), 7.24-7.04 (m, 4.5H), 6.90-6.88 (m, 0.5H), 4.53 (br s, 2H), 3.58-3.39 (m, 4H), 3.13 (d, J=1.3 Hz, 1H), 3.05-2.94 (m, 1H), 2.82 (br s, 1H), 2.79-2.66 (m, 1H), 2.33 (s, 2H), 2.28 (s, 1H), 1.49-1.20 (m, 6H), 1.13-0.98 (m, 2H), 0.96-0.84 (m, 3H), 0.80-0.64 (m, 3H); MS(ESI−) m/z 782.5 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22]([O:24][C:25](=[O:31])[CH2:26][CH:27]([CH3:30])[CH2:28]Br)[CH3:23]>CN(C=O)C>[CH3:28][CH:27]([CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:31]
Reactant: CCOC(=O)CC(C)CBr
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.02 g) in dry DMF (10 ml) was added sodium hydride (60% dispersion in mineral oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours. Solvent was evaporated and the residue partitioned between water and dichloromethane. Insoluble material was removed by centrifugation. The organic layer was filtered through phase separating paper (Whatman IPS) and the residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml) for 2 hours at room temperature. The solution was evaporated and the residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA gradient) to give a glass which crystallised on trituration with ether to give the title compound (0.08 g): m.p. 169°-171° C.; NMR(d6DMSO) δ13.45(1H,broad), 12.07(1H,broad) 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+ ; calculated for C22H25N3O4F3. 0.5 H2O: C, 55.2; H, 5.6; N, 8.9. Found: C, 55.3; H, 5.6; N, 8.7%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:29]=[CH:12]2
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 3, at 0° C. and under nitrogen atmosphere, in chloroform (0.3M) was added acetic anhydride (2.3 equiv.) drop wise and the resulting mixture was stirred for 1 h at r.t. Then potassium acetate (0.2 equiv.) was added followed by addition of isoamyl nitrite (2.2 equiv.) and the resulting mixture was heated at reflux for 16 h. After, the reaction was cooled down to r.t. While cooling, a solid precipitation was observed. The solid was filtrated and dried under vacuum to give the title compound 4. (0.324 g, 75%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.Br>>[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[OH:2])[CH2:8][CH2:9][NH:10]1
Reactant: COc1cccc2c1CNCC2
Agent: Br
Product: Oc1cccc2c1CNCC2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Combine 8-Methoxy-tetrahydroisoquinoline (665.7 mg, 4.08 mmol) and 48% HBr at room temperature. Reflux the reaction for 3 hours and then cool to room temperature. Recrystallize the product from EtOH and Diethyl ether to afford 754.2 mg, 3.28 mmol (80% yield) of the title compound as a tannish white solid: 1H NMR (500 MHz, DMSO); 2.9 (2H, t, J=6.16, 5.86), 3.2-3.4 (2H, m), 4.0 (2H, s), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m), 8.8-9.1 (2H, b m), 9.9 (1H, s); MS m/z 148 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[CH:17][S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1-B; 67 mg, 0.258 mmol) in 1 mL CH2Cl2 at room temperature under nitrogen was added diisopropylethylamine (68 μL, 0.387 mmol) followed by 2-(benzyloxy)acetyl chloride (41 μL, 0.258 mmol). After 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a yellow oil (68 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 8.44 (br s, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.39 (m, 5H), 7.24 (m, 3H), 6.50 (d, 1H), 4.68 (s, 2H), 4.13 (s, 2H). LRMS (ESI pos) m/e 409.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].[NH2:25][C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:28]([O:30][CH3:31])=[O:29]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:25][C:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1
Reactant: COC(=O)C=C(N)CC(=O)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(2,6-dichlorophenylmethylidene)-3-oxo-5-phenylpentanoate(the crude product from the preceding experiment) and dimethyl 2-amino-1-propene-1,3-dicarboxylate (8.4 g, 48.5 mmol) was heated without solvent at 120° C. for 18 h. TLC showed a strong fluorescent spot at Rf=0.3 (dichloromethane/ethyl acetate: 24/1). This reaction mixture was chromatographed on 1.5 kg silica gel to yield 3.93 g of product. An additional 2 g of slightly impure product was also obtained.