Azzindani/Open_Reaction_Data huggingface dataset:
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.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: BrCc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: c1ccc2cc(CN3CCNCC3)ccc2c1

Procedure:
Synthesized according to General Procedure A: 2-(bromomethyl)naphthalene (4{25}, 5 g, 22.6 mmol, 1 equiv.), piperazine (11.7 g, 135.7 mmol, 6 equiv.), THF (49.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{25} (4.67 g, 91%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 7.82-7.79 (m, 3H), 7.74 (s, 1H) 7.50 (dd, 1H, J=1.5, 8.5 Hz), 7.48-7.42 (m, 2H), 3.64 (s, 2H), 2.88 (t, 4H, J=5.0 Hz), 2.45 (br s, 4H), 1.52 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 135.6, 133.2, 132.6, 127.7, 127.5, 127.5, 127.5, 127.4, 125.8, 125.4, 63.7, 54.5, 46.0.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
While under argon, a solution of N,O-dimethylhydroxylamine hydrochloride (16.9 g, 0.173 mol) and triethylamine (53 mL, 0.381 mol) in dichloromethane (240 mL) was carefully treated with 4-chlorobutyryl chloride (20 g, 0.19 mol) over 40 minutes. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The solid triethylamine hydrochloride was removed by filtration and the remaining solution was washed successively with aq 2 N HCl (×2), 1M K2CO3 and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated to give 4-chloro-N-methoxy-N-methylbutanamide (21.8 g) of crude yellow oil that was used in the next step without further purification. ESI MS found for C6H12ClNO2 m/z [166.0/168.0 (M+1)].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:18][CH:17]([O:21][CH2:22][CH3:23])[CH2:16][CH2:15][NH:14][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: CCOC(CCN)OCC
Reactant: COc1cc(Cl)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNc1cc(OC)c2ccccc2n1)OCC
Temperature: 95 °C
Reaction time: 60 h
Yield: 12 %

Procedure:
To 2-chloro-4-methoxyquinoline (0.576 g, 3 mmol) was added 1-amino-3,3-diethoxypropane (0.515 g, 3.5 mmol) and diisopropylethylamine (5 ml). The mixture was stirred under argon at 95° C. for 60 h. Volatile material was removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate soluble material was purified by chromatography on silica gel eluting with 0-10% (9:1 MeOH/NH3) in dichloromethane to give the title compound as a yellow gum (110 mg, 12%). δH (CD3OD) 1.1 (6H, t), 1.85 (2H, m), 3.35-3.7 (6H, m), 3.9 (3H, s), 4.6(1H, t), 6.05(1H, s), 7.0(1H, t), 7.35 (1H, t), 7.45 (1H, d), 7.8 (1H, d); MS (ES+) 305 (63%, MH+). 259 (28), 213 (42), 187 (100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:3]=1.O=C1CCC(=O)N1[O:23][C:24](=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)[CH2:11][CH2:12]1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(NCC2CCNCC2)ncn1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine (0.15 g, 0.73 mmol), in DMF (1 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.18 g, 0.73 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (90:10:1 DCM MeOH NH4OH) to give 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):341.37
Reaction SMILES: II.Cl[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][CH2:18][CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH3:16])=[CH:11][CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][CH2:18][CH2:19][C:20]([OH:24])([CH2:6][C:5]([CH3:7])=[CH2:4])[CH:21]([CH3:23])[CH3:22])[CH3:16])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Reactant: C=C(C)CCl
Agent: II
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of Mg (11 g, 458 mmol) and I2 (0.5 g) in anhydrous tetrahydrofuran (50 mL) was added 3-chloro-2-methylprop-1-ene (1 mL) to initiate the reaction. Tetrahydrofuran (300 mL) was added, more solution of 3-chloro-2-methylprop-1-ene (15 mL) in tetrahydrofuran (20 mL) was dropped into the reaction at 0° C. under N2 over 30 min A solution of 1-[(S)-1-(4-bromophenyl)-ethylamino]-4-methyl-pentan-3-one (5 g) in tetrahydrofuran (50 mL) was added dropwise at −78° C. over 45 min. The reaction mixture was stirred at room temperature for 2 h. The reaction was cautiously quenched with saturated aqueous NH4Cl, and the reaction mixture was filtered. The filtrate was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3-{(S)-2-[1-(4-bromophenyl)-ethylamino]-ethyl}-2,5-dimethyl-hex-5-en-3-ol (6.4 g, 90% yield), which was used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:3]=[N:2]1.Cl[CH2:18][C:19]1[C:20]([CH3:25])=[N:21][O:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:25][C:20]1[C:19]([CH2:18][N:1]2[CH:5]=[C:4]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[CH:3]=[N:2]2)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)c3ccccc3C2=O)cn1
Yield: 39.9 %

Procedure:
2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (example 9-1a) (1.5 g, 7 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.5 g, 10 mmol), and cesium carbonate (3.3 g, 10 mmol) were stirred in DMF (20 mL) at 80° C. for 3 hours. The reaction was cooled, diluted with H2O (150 mL), and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and re-crystallized from refluxing absolute ethanol (30 mL) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindoline-1,3-dione (900 mg, 38%) as a bright, light yellow solid. 1H NMR (DMSO-d6, 400 MHz) 1.36 (d, 3H δ J2.16 (s, 3H), 2.41 (s, 3H)=7.2 Hz), 5.22 (s, 2H), 7.81 (s, 1H), 7.91-7.83 (m, 4H), 8.21 (s, 1H). MS M+H calculated 323.11. found 323.1. Melting point: 170-171° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:18][CH:19]1[CH2:22][NH:21][CH2:20]1>CN(C=O)C.CCOC(C)=O>[F:18][CH:19]1[CH2:22][N:21]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:20]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N2CC(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in DMF (5 mL) was added Cs2CO3 (1.9 g, 5.8 mmol) followed 3-fluoroazetidine (0.64 g, 5.8 mmol) and the reaction mixture was heated for 2 h at 80° C. The reaction mixture was then diluted with EtOAc and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.6 g, 92%). LCMS (ES+) 211.95 (M+H)+, RT 2.33 minutes (method 1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol) in 2,2-dimethyl-oxirane (3 mL) was added cesium carbonate (130 mg, 0.40 mmol). The reaction was heated at 120° C. for 30 minutes using microwave irradiation. The reaction was cooled then filtered through a plug of cotton wool, flushing with DCM. The filtrate was concentrated in vacuo giving 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol as a beige solid (620 mg, 90%). 1H NMR δ (ppm) (CDCl3): 7.82 (1 H, d, J=0.65 Hz), 7.69 (1 H, s), 4.07 (2 H, s), 1.32 (12 H, s), 1.15 (6 H, s). 1 Exchangeable proton not observed
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1>O1CCOCC1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH2:7][O:6][CH3:5])=[O:11])=[CH:14][N:15]=3)=[C:25]([CH2:26][OH:27])[O:24][N:23]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: COCCN
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reaction time: 8 h
Yield: 16 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.51 mL, 1.00 mmol) was added to a solution of 2-methoxyethylamine (88.0 μL, 1.00 mmol) in dioxane (4 mL). After stirring for 45 min at 50° C. a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (90.0 mg, 0.25 mmol) in dioxane (4 mL) was added and stirring was continued overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate) to yield the title compound (16.1 mg, 16%) as a white solid. MS: m/e=400.0 [M−H]−.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]#[CH:30]>C1(C)C=CC=CC=1>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:30][C:29]#[CH:28])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)n(O)c(=O)c2oc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with an 80% solution of propargyl bromide in toluene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.49 (t, J=2 Hz, 1H); 5.15 (d, J=2 Hz, 2H); 7.53 (dd, J=8 Hz, 1H); 7.70 (dd, J=8 Hz, 1H); 7.85 (d, J=8 Hz, 1H); 8.19 (d, J=8 Hz, 1H); Ret. time=1.86 min., m/z=257.0.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[Br:10]Br>CCOCC>[Br:10][CH:4]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH:3]=[O:2]
Reactant: COC=CC(OC)OC
Reactant: BrBr
Solvent: CCOCC
Product: COC(OC)C(Br)C=O
Reaction time: 0.5 h

Procedure:
To a solution of 25.0 g (0.19 mole) of 1,3,3-trimethoxy- 1-propene in 75 ml of ether at 5° C is added 22.4 g (0.14 mole) of bromine (bromine color begins to persist at this point) over a period of 40 minutes. The solvent is removed in vacuo at 25° C and the colorless liquid residue is added dropwise with stirring to a mixture of 25 g of sodium bicarbonate and 80 ml of 75% v/v dioxane at 0°-5° C. Stirring is continued for 30 minutes and the mixture is extracted with 200 ml and 150 ml portions of ether. The extract is dried over magnesium sulfate, evaporated in vacuo and the residue distilled through a Vigreux head to afford 2-bromo-3,3-dimethoxypropionaldehyde, b.p. 70°-73° C/8 mm.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3F)=[N+:2]=[N-:3].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:34]2[N:1]([C@H:4]3[CH2:24][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:35]=2)([OH:36])[CH3:33])=[CH:30][CH:31]=1
Reactant: C#CC(C)(O)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Product: CC(O)(c1ccc(F)cc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-100% EA/Hex afforded 2 esters. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=6.9 and 8.4 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.1 and 31.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD eluting with 20% iPrOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. Retention times=8.7 and 11.6 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.3 and 31.4 respectively. MS (+ESI) m/z: 453.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=[S:20])[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:2].IC.[CH:28](N(C(C)C)CC)(C)[CH3:29]>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([S:20][CH2:28][CH3:29])=[N:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:23])=[O:24])[CH3:2]
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(=S)NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 74d), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one. LC-MS m/e 409 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:6]([Cl:38])[CH:5]=1.[OH-].[Li+]>C(Cl)Cl.CCCCCCC>[Cl:38][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([C:20]1[N:21]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:22]=[C:23]2[C:28]=1[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]2)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:12])[C:3]([OH:39])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C(O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-{3-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-3-cyclohexyl-ureido}-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 24 h at 60° C. to give the title compound as off-white solid. MS: m/e=559.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[OH:13].Br[CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[O:13][CH:15]([CH3:16])[C:17](=[O:20])[CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(C)Oc1cc(C(=O)OC)ccc1OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy benzoate (19.3 g), 2-bromo-3-pentanone (19.2 ml), potassium carbonate (29.3 g), and DMF (193 ml) was stirred at 90° C. for 2 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with toluene. The organic layer was washed with a saturated saline and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:1) to give Compound IIk-a (25.8 g, 91.5%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=N)[CH:6]=[CH:7][CH:8]=1.Cl.N([O-])=[O:25].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=O)c1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
Product from Step 4 (20 g) was added to 5N hydrochloric acid and the reaction mixture was refluxed under argon purging. To this mixture was added in portions 160 g of sodium nitrite dissolved in water (200 mL). The reaction mixture was refluxed for 30 min further and cooled to 25° C. and extracted with chloroform (2000 mL). The organic layer was dried on anhydrous sodium sulfate, was filtered and then was concentrated under vacuum to obtain dark brown colored crude product of Step 5 (12 g). The crude product was purified on the BIOTAGE® AB ISOLERA™ flash chromatography system as follows: The crude product was dissolved in chloroform (10 mL) and was loaded on a SNAP cartridge containing 340 g silica gel. The column was eluted with a gradient of ethyl acetate and hexane. Fractions containing product were pooled and evaporated under vacuum to obtain viscous yellow oil (21 g). 1H NMR (CDCl3): 1.2 δ (3H, —CH—CH3 of isopropyl), 2.8 δ (3H, —N—(CH3)), 2.2, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 3.8 δ (3H, —OCH3), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=296 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10].[CH3:20][NH:21][CH2:22][C:23]([OH:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+].O>N#N>[C:23]([CH2:22][N:21]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10])([OH:25])=[O:24]
Reactant: CNCC(=O)O
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O)CC(=O)O

Procedure:
3.32 g of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, 1.0 g of CH3NHCH2CO2H, 3.5 g of Na2CO3 and 30 ml of water were heated at 80° C. in N2 for 1.5 hours. After purification, 1.01 g of product was prepared, calc for C17H28N2O5.2H2O: C, 54.24; H, 8.57; N, 7.44; found: C, 54.40; H, 8.34; N, 7.16.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[NH:38])[NH2:37])=[CH:30][CH:29]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[NH:37])[NH2:38])=[CH:30][CH:29]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: CC(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)CC(=O)Oc1ccc(C=CC(=N)N)cc1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Into 10 ml of dried pyridine, was dissolved 1.0 g of isovaleric acid. To the solution, while being cooled in ice, was added 2.5 g of DCC. After 30 minutes of stirring, 2.6 g of 4-(β-amidinoethenyl)phenol methanesulfonate was added and the mixture was stirred overnight at room temperature. The reaction mixture was removed of precipitated DCU by filtration and the DCU was washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate a white solid substance which was collected by filtration, washed with ethyl ether, and recrystallized from ethanol to yield 1.7 g of colorless flaky crystals of 4-(β-amidinoethenyl)phenyl isovalerate methanesulfonate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([N:11]([CH3:33])[C:12](=[O:32])[CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22]CC4C=CC(OC)=CC=4)[N:16]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][C:17]1[N:16]=[C:15]([NH:14][CH2:13][C:12]([N:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)[CH3:33])=[O:32])[C:20]([CH3:21])=[CH:19][N:18]=1
Reactant: COc1ccc(CNc2ncc(C)c(NCC(=O)N(C)C3CCN(CC4CC4)CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)nc1NCC(=O)N(C)C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Compound 107 (24.9 mg) was dissolved in methylene chloride (1 mL). While the solution was cooled with ice, trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature (20 to 30° C.) overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1 to 4:1) to give 12.6 mg (68% yield) of the desired product as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][C:3]1=[O:4].[OH-:9].[K+:10]>O>[K+:10].[OH:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[C:3]([O-:9])=[O:4]
Reactant: [OH-]
Reactant: CC1(C)CCOC1=O
Agent: [K+]
Solvent: O
Product: CC(C)(CCO)C(=O)[O-]
Temperature: 25 °C
Yield: 1783.1 %

Procedure:
Step A A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 mmol) in H2O (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and concentrated to dryness to give 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt as a white solid (10.2 g, 100%).