Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[O:5]CC)C>Cl>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([P:4](=[O:3])([OH:5])[OH:8])=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(P(=O)(O)O)cc1
Yield: 100 %

Procedure:
A solution of diethyl(4-nitrophenyl)phosphonate (60 g, 230 mmol) in 250 mL of concentrated HCl (aq) was stirred at reflux overnight. The excess HCl was removed under reduced pressure and the product used in further chemistries without purification (46.8 g, yield: 100%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]CCCC.[C:15](Cl)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C>C1COCC1>[O:5]=[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
A stirred solution of monoethyl malonate (1.26 g, 9.6 mmol) in 25 mL anhydrous THF was cooled to −78° C. under an argon atmosphere, and n-BuLi (2.5 M, 8 mL, 20 mmol) was added drop-wise via an air-tight syringe. After the addition, the temperature was raised to 0° C., and the stirring was continued for 1 hour. The mixture was then re-cooled to −78° C., and decanoyl chloride (1.044 mL, 5 mmol) was added drop-wise via an air-tight syringe. The mixture was stirred for one hour at −78° C., 30 minutes at 0° C. and 30 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was re-dissolved in 50 mL ethyl acetate. The solution was washed with 1 M HCl (100 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to give ethyl 3-oxododecanoate (1.456 g). The crude product was used for the next reaction. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.38 (m, 12H), 1.50-1.68 (m, 2H), 2.53 (t, J=7.5 Hz, 2H), 3.43 (s, 2H), 4.20 (q, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.975, 13.988, 22.5, 23.4, 28.91, 29.14, 29.26, 29.29, 31.8, 42.9, 49.2, 61.2, 167.2, 202.9.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:6][CH:5]([NH:7]S(C(C)(C)C)(=O)=O)[CH:4]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[F:26][C:2]1([F:1])[CH2:3][CH:4]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=2)[CH:5]([NH2:7])[CH2:6]1
Reactant: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4,4-difluoro-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-methylpropane-2-sulfonamide (45 mg, 0.11 mmol) in DCM (3 ml) at 0° C. was added anisole (CAS number 100-66-3; 0.22 ml, 2.01 mmol) followed by the drop wise addition of trifluoromethanesulfonic acid in DCM (0.2M, 2.5 ml, 0.500 mmol). The reaction mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. A further portion of trifluoromethanesulfonic acid in DCM (0.2M, 0.5 ml, 0.100 mmol) was added, the reaction mixture stirred for another hour at room temperature then quenched with sodium hydroxide (0.1M) until pH 11 was obtained. The reaction mixture was then extracted with DCM. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by SCX chromatography (2M ammonia in methanol) to afford the title compound.
Reaction SMILES: C1(S)C=CC=CC=1.[Cl:8][C:9]1[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=1[CH2:11][CH2:12][N:13]([CH2:26][C@H:27]([NH:29][S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]2)(=[O:32])=[O:31])[CH3:28])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:8][C:9]1[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=1[CH2:11][CH2:12][NH:13][CH2:26][C@H:27]([NH:29][S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]2)(=[O:32])=[O:31])[CH3:28]
Reactant: C[C@H](CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-])NS(=O)(=O)c1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@H](CNCCc1ccccc1Cl)NS(=O)(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
0.1 mL of thiophenol was added to a suspension of 300 mg of (R)—N-[1-{N-(2-chlorophenethyl)-2-nitrophenylsulfonamido}propan-2-yl]isoquinoline-6-sulfonamide and 360 mg of potassium carbonate in 20 mL of acetonitrile, and the mixture was stirred at room temperature for 16 hours. 50 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 179 mg of the title compound as a white solid (87%).
Reaction SMILES: [Li].[CH3:2][N:3]([CH3:7])[CH2:4][C:5]#[CH:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>C(N)CN.O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])([C:6]#[C:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: [Li]
Solvent: NCCN
Solvent: C1CCOC1
Product: CN(C)CC#CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
In 500 ml of ethylene diamine there is dissolved 13.88 g of lithium wire. After the disappearance of the blue color, the grey suspension obtained is dropwise treated, at 5° C., with 166.3 g of 3-dimethylamino-1-propyne. After 1 hour at room temperature, a solution of 50 g of p-bromoacetophenone in 250 ml of tetrahydrofuran is added. After 2 hours at room temperature, the mixture is poured onto ice and extracted with chloroform to give 62.9 g of crude, 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol which is dissolved in 500 ml of acetone and treated with 18 ml of methyl iodide. After 18 hours at 5°, the solution is evaporated to dryness and the residue triturated with chloroform-ether to give 68 g of pure 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol methiodide, mp 185°-190°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:17]=1[C:25]#[N:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:17]=1[C:25]#[N:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
To a solution of (R)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 15e, 10.8 g, 29.85 mmol) in ethyl acetate (86 mL) was added 10% Pd/C (1.08 g, 3 mmol). H2 was added by balloon, and the mixture was stirred for 48 hours at room temperature. Upon completion, the mixture was filtered through a pad of celite, and the solvent was removed in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford (R)-tert-butyl-2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (8.65 g, 88%) as an off white solid. MS 323 (MH+-boc).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(F)c(C=O)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(F)c(/C=C/C(=O)O)c1
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (10.00 g, 64.9 mmol), malonic acid (13.4 g, 128.8 mmol), piperidine (2.00 mL) and pyridine (100 mL) was heated to 110° C. for 2 h. After this time the solvent was removed in vacuo and the residue taken up in ethyl acetate and washed with aqueous hydrochloric acid (2N, 100 mL). The organic solvent was dried (MgSO4) and the solvent evaporated in vacuo. The solid was recrystallised from hot etahanol to give a white solid (12.2 g, 95%); δH (300 MHz, DMSO) 7.60 (1H, d, J 7 Hz, CH═C), 7.31-7.28 (1H, m, Ar), 7.20 (1H, t, Ar), 7.07-6.97 (1H, m, Ar), 6.62 (1H, d, J 8 Hz, CH═CH), 3.80 (3H, s, OCH3).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99%), mp >250°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1ccc(C(=O)OC)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Methyl 3-cyano-4-ethyl-benzoate (D45) (1.92 g) was dissolved in MeOH (50 mL) before adding 1M NaOH solution (15.24 mL) and stirring the resulting mixture overnight at room temperature, under argon. The reaction mixture was diluted with water, and extracted with EtOAc. The aqueous layer was acidified to pH1 using 2M HCl before extracting with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and the solvent evaporated to dryness in vacuo to afford the title compound (1.63 g). 1H NMR (CDCl3) δ 1.35 (3H, t), 2.97 (2H, q), 7.49 (1H, d), 8.24 (1H, dd), 8.36 (1H, d).
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](=[O:32])[N:10]([CH2:14][C:15]1[CH:20]=[C:19]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[OH:22])[C:18]([CH3:30])=[C:17]([Br:31])[CH:16]=1)[CH:11]1[CH2:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>CCOCC>[C:4]([O:8][C:9](=[O:32])[N:10]([CH2:14][C:15]1[CH:20]=[C:19]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:18]([CH3:30])=[C:17]([Br:31])[CH:16]=1)[CH:11]1[CH2:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(O)c1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (0.1 M) solution of tert-butyl{3-bromo-5-[(3-fluorophenyl)(hydroxyl)methyl]-4-methylbenzyl}cyclopropylcarbamate (1 eq.) from the previous step was added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 1 h, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([OH:15])([C:13]#[N:14])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[H][H].C([O-])(O)=O.[Na+]>CO>[C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([CH2:13][NH2:14])([OH:15])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1CCC2(CC1)CC(O)(C#N)CO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(O)(CN)CO2
Yield: 82.9 %

Procedure:
8-t-Butyl-3-hydroxy-3-cyano-1-oxaspiro(4,5)decane (2.37 g, 10 mmol) in methanol (25 ml), containing conc. hydrochloric acid (1 ml), was hydrogenated on platinum oxide (0.1 g, 40° C./5 bar hydrogen pressure) until the uptake of hydrogen ceased. Saturated NaHCO3 (3 ml) was added and the solvent was evaporated in vacuo. To the residue was added methanol (30 ml) and MgSO4. The mixture was filtrated and the filtrate was evaporated in vacuo to yield a pale greenish solid (2.0 g). The fairly polar compound was not further purified. It was characterised via its N-cyclohexyl derivative.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:19]1[N:20]=[CH:21][CH:22]=[N:18]1)[N:6]2[CH3:16]
Reactant: CCCC(O)c1nc(N)c2nc(Br)n(C)c2n1
Reactant: c1c[nH]nn1
Solvent: CN(C)C=O
Product: CCCC(O)c1nc(N)c2nc(-n3nccn3)n(C)c2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To the solution of 1-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)-butan-1-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added CsCO3 (5.9 g, 18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 ml, 18.24 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: Cl[C:2]([CH2:4][O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:3].[CH3:11][C:12]1(C)[O:17]C(=O)[CH2:15][C:14](=O)[O:13]1.N1C=CC=CC=1>ClCCl>[CH3:10][O:9][C:7]([CH2:6][O:5][CH2:4][C:2](=[O:3])[CH2:11][C:12]([O:13][CH2:14][CH3:15])=[O:17])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)COCC(=O)OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Methyl 2-(chloroformylmethoxy)acetate (216.6 g) was added over 45 minutes to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (173.9 g) and pyridine (189.6 g) in dichloromethane (1000 ml) keeping the temperature below 5° C. The mixture was stirred at 5° C. for 30 minutes, allowing to warm up to room temperature over one hour, washed with 2.4M hydrochloric acid and water, dried over magnesium sulphate and evaporated. The resulting browm oil was dissolved in ethanol (300 ml) and the solution heated under reflux for 2.5 hours and evaporated. The residual oil was distilled to give the title compound (32.5 g), b.p. 138°-140°/l torr which was characterised by its N.m.r. spectrum in CDCl3, δ values: 4.27 (2H,s); 4.20 (2H, q, J 7 Hz); 4.16 (2H,s); 3.75 (3H, s); 3.54 (2H, s); 1.29 (3H, t, J 7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[N:14]([O-])=O.[Na+].[OH-].[Na+].C(Cl)(Cl)Cl>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([F:11])[F:12])=[CH:7][C:5]([NH:6][NH2:14])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1cc(OC(F)F)c(Cl)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NNc1cc(OC(F)F)c(Cl)cc1F
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A mixture of 13.3 g of 4-chloro-2-fluoro-5-difluoromethoxyaniline XIII-1 and 106 ml of hydrochloric acid was stirred at 0° C. A solution of 4.76 g of sodium nitrite in 35.4 ml of water was dropwise added in 10 minutes to the mixture, which was stirred at 0° to 5° C. for an hour. A solution of 35.4 g of stannous chloride dihydrate in 35.4 ml of hydrochloric acid was dropwise added in 15 minutes to the mixture, which was stirred at 0° to 5° C. for 2 hours. The reaction mixture was basified with 10% aqueous sodium hydroxide and shaken with chloroform. The chloroform layer was dried and concentrated, and 12.7 g of the titled compound XIV-1 thus obtained was used for the subsequent reaction without purification.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[CH2:14]([NH:21][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Solvent: C1COCCO1
Product: O=C(O)c1c(F)cc(F)c(F)c1NCc1ccccc1

Procedure:
A mixture of 19.4 g of 2,3,4,6-tetrafluorobenzoic acid, 200 ml of dioxane and 35.3 ml of benzylamine was heated under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and hydrochloric acid was added to adjust the pH of the solution to 3. The solution was then extracted with ethyl acetate. The extract was dried, treated with activated carbon and concentrated. Ether and n-hexane were added to the residue, and the crystals were collected by filtration to give 20.2 g of 2-benzylamino-3,4,6-trifluorobenzoic acid. m.p. 140-141° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[C:23][Si](C)(C)C.[F-]>ClCCl.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:16])([F:18])[F:17])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trimethylsilylethynylpyrazole (0.4657 g) in dichloromethane (5 ml) cooled in an ice-water bath was slowly added tetra-n-butylamntmonium fluoride (1.07 ml of a 1M solution in tetrahydrofuran). After five minutes the ice-water bath was removed. Stirring was continued for ten minutes then the reaction mixture was washed with water. The aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide the title compound as an oily solid which upon drying in an oven crystallised to a white solid, m.p. 175.7-176.1° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and morpholine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and morpholine (0.017 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (30 mg). 1H-NMR (300 MHz, DMSO-d6), 11.68 (br s, 1H), 9.85 (br s, 1H), 8.64 (s, 1H), 8.33 (d, J=9.0 Hz, 2H), 7.89 (t, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.66 (t, 1H), 7.32 (d, J=9.0 Hz, 1H), 3.68 (d, 4), 3.17 (s, 2H), 2.55 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][C:4]=1[O:5][CH2:6][CH:7]1[CH2:11][O:10]C(C)(C)[O:8]1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][C:4]=1[O:5][CH2:6][CH:7]([OH:8])[CH2:11][OH:10])[CH3:2]
Reactant: CCCCCCCCCCCCCCc1ccc(CC)c(OCC2COC(C)(C)O2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(O)CO)c1

Procedure:
A mixture of 14.2 g of 4-[(2-ethyl-5-tetradecylphenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 50 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran was heated at reflux for 8 hours, then allowed to cool and the tetrahydrofuran removed under reduced pressure. Ethyl acetate was added, the mixture washed with water, dried and the solvents removed. The residue was chromatographed on silica gel, eluting impurities with hexane:ethyl acetate (16:1) and then (4:1) to elute the desired compound, giving 11 g, 55.5°-56.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Br[Mg][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH2:34]>C1COCC1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH2:34])[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: C=C([Mg]Br)c1ccccc1
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Br)nn23)ccc1C(=O)NC1CC1
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cc(NCCC(F)(F)F)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 24 mg (50 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a in 1 mL THF is dropwise added 1.0 mL (0.5 mmol) of a 0.5 M solution of bromo(1-phenylethenyl)magnesium in THF at rt. After stirring overnight at rt, the mixture is heated at 50° C. and stirred for 3 more days to give after working up and purification 1.7 mg (5%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1)[CH3:2].Cl.[CH3:16]O>C(=O)(O)[O-].[Na+]>[CH3:16][O:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]2[N:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=1)=[O:14]
Reactant: CCn1nnc2ccc(C(=O)O)cc21
Reactant: CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1nnc2ccc(C(=O)OC)cc21
Temperature: 65 °C

Procedure:
3-Ethyl-3H-benzotriazole-5-carboxylic acid (0.15 g) was diluted with methanol and treated with HCl (gas). The reaction was then heated to 65° C. for 18 hours. The mixture was allowed to cool to 23° C. and was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated to give 3-ethyl-3H-benzotriazole-5-carboxylic acid methyl ester (0.143 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.CO>>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:16]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (2.0 g, 0.0094 mol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate hydrochloride (4.7 g, 0.019 mol) and methanol (80 mL, 2 mol). The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was stirred overnight. LC-MS showed the starting material was completely consumed. Volatiles were removed and the resulting oil was purified by silical gel in a methanol:methylene chloride (0-10%) gradient. Fractions containing the desired product, as determined by TLC and LC-MS, were combined and concentrated to yield a yellow solid (3.22 g). MS m/z=388.1 (M+1).