Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][O:22][CH2:23]CN.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:2]([CH2:20][CH2:21][O:22][CH3:23])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: COCCN
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Temperature: 90 °C
Yield: 63.3 %

Procedure:
(Z)-Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (0.428 g, 1.09 mmol, Intermediate 24) and 2-methoxyethanamine (0.082 g, 1.09 mmol, Acros) were combined in DMF (3.0 mL). Potassium carbonate (0.151 g, 1.09 mmol, Fisher) was added and the reaction was heated in the microwave at 90° C. for 30 min After 30 minutes, LC/MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into water. The resulting precipitate was filtered, washed with water and dried overnight to yield a white solid (0.277 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C@H:17]4[CH2:18][CH2:19][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:21][CH2:22]4)[C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][N:8]=3)[N:3]=2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, trans-N1-[6-chloro-3-(methylsulfonyl)-1,5-naphthyridin-4-yl]-N4,N4-dimethylcyclohexane-1,4-diamine (40 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (45 mg, 75%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.12 (s, 2H), 5.65-5.55 (m, 1H), 3.50-3.41 (m, 1H), 3.39 (s, 3H), 2.91 (s, 6H), 2.67-2.57 (m, 2H), 2.33-2.27 (m, 2H), 1.87-1.73 (m, 4H). ESI MS m/z 509 [M+H]+; HPLC 98.0% (AUC), tR=9.95 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g) by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53(c)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate; MS: 569 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7]([CH:9]([CH3:11])[CH3:10])=[N:6][C:5](=[O:12])[CH:4]=1.ClCC(=O)CC(OCC)=O.C(N)(=N)C(C)C.[P:29]([S-:35])(=[S:34])([O:32][CH3:33])[O:30][CH3:31].[NH4+]>CO.ClCCl>[P:29]([S:35][CH2:2][C:3]1[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][C:5](=[O:12])[CH:4]=1)(=[S:34])([O:32][CH3:33])[O:30][CH3:31]
Reactant: COP(=S)([S-])OC
Reactant: CC(C)c1nc(=O)cc(CCl)[nH]1
Agent: CC(C)C(=N)N
Agent: CCOC(=O)CC(=O)CCl
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COP(=S)(OC)SCc1cc(=O)[nH]c(C(C)C)n1

Procedure:
The intermediate, 6-(chloromethyl)-2-(1-methylethyl)-4(1H)pyrimidinone, was prepared according to Swiss patent 524617 from ethyl 4-chloroacetoacetate and isobutyramidine. m.p. 123°-125°. The intermediate chloromethyl compound (25 g) was stirred with 50 ml methanol at room temperature. To this mixture was added, dropwise, a solution of 25 g ammonium dimethyl phosphorodithioate dissolved in 500 ml methanol. The mixture was then heated to reflux for 6 hours, then the solvent was evaporated under reduced pressure yielding a solid. The solid was dissolved in dichloromethane and washed with water, separated, dried, and the solvent was evaporated. The remaining solid was recrystallized from toluene; yield: 15.9 g, m.p. 89°-93°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then piperidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane/ethanol 95:5 as eluant, affording 1.2 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH:1]([C:4]1([CH2:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(CCO)OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Yield: 115.6 %

Procedure:
To a solution of 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethanol (11 g, 0.069 mol) and TEA (20.91 g, 0.207 mol) in dried CH2Cl2 (110 mL) was added MsCl (15.8 g, 0.138 mol) dropwise at 0° C. The mixture was stirred till the reaction was over. The reaction was quenched with water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4, and concentrated to give the crude methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (19 g, crude), which was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)C(OCC)=O)C.[Li+].[OH-].Cl>C1COCC1.O.CC(O)C.C(Cl)Cl>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:5][C:4]([OH:18])=[O:3])=[N:12][CH:13]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Br)cn1
Temperature: 60 °C

Procedure:
To a solution of diethyl(5-bromopyridin-2-yl)malonate (Preparation 84, 5.28 g, 16.70 mmol) in THF (50 mL) was added a solution of LiOH (2.10 g, 50.13 mmol) in water (12.5 mL) and the reaction was heated to 60° C. for 3 hours. The reaction was cooled and acidified to pH 3-4 with 2N HCl and diluted with 20% IPA in DCM. The organic layer was collected, dried over sodium sulphate and concentrated in vacuo. The crude residue was triturated with hexane to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[CH:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccnc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2ccnc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ccn4)CC3)c2)cc(OC)c1OC

Procedure:
2-Chloromethyl-4-(3,4,5-trimethoxyphenyl)pyridine (195 mg) and homopiperazine (32 mg) were reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]3)=[C:26]([F:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>CC(C)=O>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:16][CH:15]([F:17])[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]5)=[C:26]([F:37])[CH:25]=4)[N:19]=[C:18]23)=[CH:12][CH:11]=1
Reactant: Cc1nc(C)n(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OCC(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C)n(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OCC(F)F)cc3)cc2F)n1
Yield: 16 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-1H-1,2,4-triazol-3-amine (787 mg, 1.47 mmol), sodium iodide (1.10 g, 7.37 mmol), and diisopropylethylamine (1.29 mL, 7.37 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 3 h. The reaction was concentrated in vacuo. After an aqueous workup, the crude organic concentrate was purified using reverse phase preparatory HPLC (MeOH/water/TFA) to afford 145 mg (16% yield) of the titled compound as the TFA salt. LC-MS (M+H)+ 498.3. 1H NMR (500 MHz, CHLOROFORM-d) d ppm 9.45 (1 H, br. s.), 7.69 (1 H, dd, J=12.5, 2.1 Hz), 7.29 (1H, t, J=8.5 Hz), 7.18 (1 H, d, J=8.5 Hz), 7.04 (2 H, d, J=8.5 Hz), 6.93 (2 H, d, J=8.5 Hz), 6.08 (1 H, tt, J=55.1, 4.1 Hz), 4.40 (1 H, d, J=7.9 Hz), 4.30-4.37 (1 H, m), 4.21-4.30 (1 H, m), 4.17 (2 H, td, J=13.0, 4.1 Hz), 2.45 (3H, s), 2.42 (3 H, s), 2.25-2.35 (1 H, m), 2.06-2.17 (1 H, m), 1.84-2.04 (4 H, m).
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1
Yield: 77.9 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (2.8 g, 5.7 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (5 mL) and stir for 1 hour. Evaporate to dryness in vacuo and recrystallize the residue (ethyl acetate/hexane) to give the title compound as white needles (1.8 g, 82%); mp 195°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:17]1[CH:18]=[C:19]([CH3:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:17]1[CH:18]=[C:19]([CH3:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2cc(C)c(=O)n(C)c2)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 147, step 5, 5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as a colorless solid. MS (m/e)=376.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=2)=[CH:4][N:3]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:4][N:3]=1
Reactant: COc1cccc(-c2cnc(N)cn2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cnc(-c2cccc(O)c2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 17.9 %

Procedure:
2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in methylene chloride (10 mL). To this mixture was added under ice-cooling boron tribromide (530 μL) and the whole was stirred at room temperature for 14 hours. To the reaction mixture was added 1N aqueous sodium hydroxide. The whole was extracted with ethyl acetate (30 mL×2). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent provides the subject compound (94 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2].[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:26])[CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=4)[CH2:21]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCOC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of [4-(4-oxo-cyclohexyl)-phenyl]-acetic acid ethyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38](O)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28]
Reactant: COC(=O)c1ccc(NCC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(NCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
The mixture of the above methyl 4-(2-pyrrolidinylmethylamino)benzoate (397.8 mg, 1.69 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (587.1 mg, 1.87 mmol), EDC (HCl) (486 mg, 2.54 mmol), HOBt (23 mg, 0.17 mmol), and DMAP (21 mg, 0.17 mmol) in DMF (4 mL) was stirred overnight at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure. The residue was chromatographed on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to afford 882 mg (98%) methyl 4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethylamino]benzoate as a brown amorphous solid, which is used to the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1CCCCC1)C.Cl[C:22]1[N:27]([CH3:28])[S:26](=[O:30])(=[O:29])[N:25]=[C:24]([O:31][CH3:32])[N:23]=1>C(Cl)Cl>[CH3:28][N:27]1[S:26](=[O:30])(=[O:29])[N:25]=[C:24]([O:31][CH3:32])[N:23]=[C:22]1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Solvent: ClCCl
Solvent: CN(C)C1CCCCC1
Product: COC1=NS(=O)(=O)N(C)C(OCCCCc2ccccc2)=N1
Reaction time: 1 h

Procedure:
A mixture of 27 parts of 4-phenyl-n-butanol with 23 parts of N,N-dimethylcyclohexylamine, and 31.7 parts of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, were added side by side, in the course of 15 minutes, to 250 parts of methylene chloride at from 10° to 15° C., while stirring. Stirring was continued for one hour at room temperature, after which the reaction mixture was washed with 1N hydrochloric acid and with 10% strength sodium carbonate solution, and dried over magnesium sulfate. After evaporating down under reduced pressure, 40 parts of the 6-methyl-3-methoxy-5-(4-phenylbutoxy)-6H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 74°-78° C. were obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:45]([N:48]([CH2:54][S:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:57])=[O:56])[C:49](=[O:53])[C@@H:50]1[O:52][CH2:51]1)[CH:46]=[CH2:47]>O1CCCC1>[CH2:45]([N:48]1[C@H:54]([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)(=[O:57])=[O:56])[C@@H:50]([CH2:51][OH:52])[C:49]1=[O:53])[CH:46]=[CH2:47]
Reactant: C=CCN(CS(=O)(=O)c1ccccc1)C(=O)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C(=O)[C@H](CO)[C@H]1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
8 ml of a tetra-n-butylammonium fluoride/THF solution which has been prepared from 5 g of tetra-n-butylammonium fluoride trihydrate by drying at 60°/0.1 torr and making up to 20.0 ml with tetrahydrofuran is added to a solution of 201 mg (0.757 mmol) of N-allyl-N-phenylsulphonylmethyl-(R)-glycidic acid amide in 1 ml of tetrahydrofuran. The resulting reaction mixture is stirred for 2 hours at 0° and then partitioned between methylene chloride and phosphate buffer solution having a pH of 8.0. The crude product isolated from the organic layer by means of concentration by evaporation is chromatographed over preparative silica gel plates in ethyl acetate/hexane (2:1) and the title compound is obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCCCC3)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A mixture of 6-bromo-1-(piperidin-1-yl)phthalazine (0.12 g, 0.40 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and 2M potassium carbonate (0.6 mL, 1.2 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to silica gel and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give the title compound (0.13 g) as yellow solid. Found MS (ES+): 387(M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3[nH]ncc3c2)CC1
Temperature: 90 °C

Procedure:
A suspension of 5-bromoindazole (Combi-blocks; 3.0 g; 15.2 mmol; 1.0 eq.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific; 6.59 g; 21.3 mmol; 1.4 eq.), 1,1′-bis-(diphenylphosphino)ferrocene (1.11 g; 1.52 mmol; 0.1 eq.) and potassium carbonate (6.31 g; 45.7 mmol; 3.0 eq.) in degassed dioxane (60 mL) and water (30 mL) was heated at 90° C. for 24 h. The reaction mixture was cooled, diluted with DCM and filtered through a celite pad. Water was added to the filtrate and aqueous phase was extracted three times with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was adsorbed on silica and purified by flash chromatography on silica (heptane/EtOAc, gradient from 80:20 to 30:70) to give the title compound as an off white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.04 (brs, 1H), 8.04 (s, 1H), 7.78-7.71 (m, 1H), 7.53-7.44 (m, 2H), 6.14 (s, 1H), 4.10-3.92 (m, 2H), 3.56 (t, J=5.7 Hz, 2H), 2.60-2.51 (m, 2H), 1.41 (s, 9H). HPLC (Condition A): Rt 4.42 min (purity 93.6%). MS (ES+): 341.2. MS (ES−): 298.2.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:46]([O:48][C:49](=[O:59])[CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:47]>CN(C=O)C.O>[CH2:46]([O:48][C:49](=[O:59])[CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][N:55]([C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:32])[F:31])[CH2:54][CH2:53]1)[CH3:47]
Reactant: CCOC(=O)CC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
HOBt (1.38 g, 10.2 mmol) and DIPEA (3.68 mL, 21.3 mmol) were added to a stirred solution of 2-trifluoromethyl-benzoic acid (1.62 g, 8.5 mmol) in DMF (5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (1.96 g, 10.2 mmol) followed by 3-oxo-3-piperazin-1-yl-propionic acid ethyl ester hydrochloride (2 g, 8.5 mmol) were added. The reaction mixture was stirred at the room temperature overnight, then diluted with water and the product extracted with Ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography using silica gel 60-120 mesh (50% ethyl acetate in hexane) to afford 1.5 g (48%) of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester. LCMS: 373.13 (M+1)+, 90%