Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[O:4][C:5]1[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH2:13][OH:14].[Br:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1>>[Br:33][C:34]1[CH:35]=[N:36][C:37]([O:14][CH2:13][CH2:12][O:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:2]=2[Cl:1])=[N:38][CH:39]=1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCO)c1
Reactant: Clc1ncc(Br)cn1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCOc2ncc(Br)cn2)c1
Yield: 48.4 %

Procedure:
Benzylsulfamic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (77 mg) (Example 212) was prepared from benzylsulfamic acid [5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (120 mg) (Example 211) and 5-bromo-2-chloropyrimidine (100 mg) according to the procedure described in Example 14. LC-MS: tR=5.29; [M+H]+=639.04.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCBr)c(Cl)c1
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a stirred solution of 2-chloro-4-nitrophenethyl alcohol (1.17 g) in dichloromethane (15 ml) were added carbon tetrabromide (2.12 g) and triphenylphosphine (1.67 g) at room temperature, and the mixture was stirred for 15 minutes. The solvent was removed in vacuo, and purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=9/1) gave 1-(2-bromo-ethyl)-2-chloro-4-nitrobenzene (1.30 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Cn1cc(C#N)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h

Procedure:
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66 g) was stirred in dry tetrahydrofuran (40 ml). Sodium hydride (50% oil dispersion, 2.28 g) was added and the mixture was stirred for 10 minutes. 2,5-Dichloronitrobenzene (5.76 g) was added and the solution stirred under nitrogen for 20 hours. Water was added dropwise to destroy any excess sodium hydride, then the solution was poured on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was filtered, washed with water and dried. Crystallization from ethanol-ethyl acetate afforded the product m.p. 205° C.
Reaction SMILES: [SH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:8](O)=[O:9])=[O:5].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH:11]1([N:6]2[C:4](=[O:5])[C:3]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:2]=3[S:1][C:8](=[O:9])[CH2:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1S
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1SC(=O)CN(C1CCCC1)C2=O
Reaction time: 2 h

Procedure:
N-(2-mercapto-3-methoxybenzoyl)-N-cyclopentylglycine (14.5 g, 0.0469 m) and triethylamine (4.7 g, 0.0469 m) in methylene chloride (500 ml) were cooled to 0° C., and ethyl chloroformate (5.1 g, 0.0469 m) was added over one minute. The mixture was stirred 2 hours at 0°-10° C., washed (water, then brine), dried (Na2SO4) and concentrated. HPLC purification using hexane/ethyl acetate (1/1) as eluent gave the desired product. Recrystallization from ethyl acetate provided 5.4 g analytically pure material (yield: 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OCC(=O)Cl
Temperature: 65 °C
Reaction time: 7 h

Procedure:
2,6-dimethylphenoxyacetylchloride is prepared in a separate vessel as follows: 2,6-dimethylphenoxyacetic acid, 5.4060 grams (29.99 mmol) is charged to a 50 mL round bottom flask equipped with a teflon-coated magnetic stir bar. Toluene, 15 mL is added stirring is initiated and thionyl chloride, 9.0 mL (123.3 mmol) is added followed by one drop of N,N-dimethylformamide at ambient temperature. After seven hours, the reaction mixture is heated to 65° C. for thirty minutes and allowed to cool to ambient temperature. The solution is concentrated at 60° C. and ca. 60 mm Hg pressure to remove all volatiles. The residue is diluted with toluene, 25 mL and reconcentrated. This is repeated a second time to give a final residue.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and 2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80° C. for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) to give the title compound (1.26 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH:16][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1cccc(-c2cnc3ccccn23)c1
Reactant: Clc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cnc(Nc2cccc(-c3cnc4ccccn34)c2)nc1
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture 3-imidazo[1,2-a]pyridin-3-yl-phenylamine (210 mg, 1.0 mmol), 2-chloropyrimidine (115 mg, 1 mmol) and NaOtBu (100 mg, 1.0 mmol) in dry dioxane (2 ml) was stirred and heated at 100° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The layers were separated and the aqueous layer was extracted with EtOAc (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (20 mg, solid). MS: [M+H]+ 288
Reaction SMILES: Cl[Si](C)(C)C.O.Cl.[CH3:8][N:9]([CH:11]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1(CC1C=CC=C(C(F)(F)F)C=1)[OH:18])[CH3:10]>CC(=O)CC>[CH3:10][N:9]([CH:11]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[CH3:8]
Reactant: CN(C)C(c1cccs1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: CCC(C)=O
Product: CN(C)C(c1cccs1)C1CCCCC1=O

Procedure:
0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (12.6 mmole) of 3-chloromethylbenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 mmole) of the 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to stage 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.33 g of crude base (79.6% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.63 g of crude base (15.0% of theory) was obtained, from which 0.39 g of 2-[dimethylaminothiophen-2-ylmethyl]-1(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride (8.5% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Product: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Chlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:39](=[O:40])[C:38]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:36]([C:35]([F:34])([F:49])[F:50])[CH:37]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and 3,5-bis(trifluoromethyl)benzoic acid (31.0 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:15](Cl)(Cl)=[O:16]>C(Cl)Cl.ClC1C=CC(C)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccc(Cl)cc1
Product: O=C=Nc1ccc(N2CCOCC2)c(F)c1

Procedure:
A mixture of 3-Fluoro-4-morpholinylaniline (PREPARATION 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) is added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) over 15 min, a while maintaining the temperature from about −12 to 3°. The material is rinsed in with methylene chloride (30 ml). The mixture is then warmed to 130° under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene and hydrogen chloride gas into a caustic scrubber. The mixture is cooled to 25° and filtered. The precipitate is washed with methylene chloride (3×15 ml). The filtrate is concentrated under reduced pressure. Heptane (200 ml) is added to the concentrated filtrate and the resultant slurry cooled to −32°. The product is collected by filtration with reduced pressure, washed with heptane cooled to −30°, and dried in a nitrogen stream to give the title compound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min. Upon derivatizing as N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; NMR (CDCl3) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 δ; MS (EI), m/z (relative intensity) 222 (37) and 164 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]1[CH3:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([NH:18][C:19]2[CH:40]=[CH:39][C:22]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]5[CH2:38][CH2:37]5)=[O:35])[N:32]=4)[CH:29]=3)=[C:21]([F:41])[CH:20]=2)=[O:16])=[CH:10][N:9]1[CH3:17]
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1Cl
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1Cl
Yield: 60.2 %

Procedure:
In the same manner as in Example 46 and using 2-(2-chlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (330 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (260 mg, 60%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Oc1ccccc1)c1cnn(CCN2CCOCC2)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnn(CCN4CCOCC4)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-morpholin-4-yl-ethyl)-1H-pyrazole-4-carboxylic acid phenyl ester, the title compound was obtained as white crystals 42% yield). MS: m/e=473(M+H+), mp 204-207° C.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](O)c1ccc(C(=O)NC=CC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propenoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=107.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:16](O)(=[O:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCCl>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16]([C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:26])=[CH:18][C:19]=2[O:20]1
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc3c(c1)OCO3)OCO2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a mixture of methyl 2-(3,4-methylenedioxyphenyl)propionate (1 g, 4.8 mmol) in 1,2-dichloroethane (50 mL) was added piperonylic acid (1.6 g, 9.6 mmol) and P2O5 (4 g). The reaction mixture was stirred for 15 h and then poured to ice water (200 mL) and the product was extracted with EtOAc (2×100 mL). The pure product was obtained by flash chromatography (453 mg, 27%). 1H NMR (CDCl3) 7.37 (s, 1H), 7.33 (d, J=8.0, 1H), 6.95 (s, 1H), 6.83 (d, J=8.0, 1H), 6.76 (s, 1H), 6.07 (s, 2H), 6.02 (s, 2H), 3.95 (q, J=7.1, 1H), 3.58 (s, 3H), 1.45 (d, J=7.1, 3H).
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH:30]=[CH:29]1>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:30]3[C:31](=[O:32])[O:33][C:28](=[O:34])[C:29]3=[CH:3]2)=[CH:6][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2c1cc1cc(OCc3ccccc3)ccc1c2-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the alcohol (112 g) from Step 1 in toluene (1.1 L) was added maleic anhydride (150 g). The reaction mixture was heated to reflux for 24 hours. After cooling to room temperature, the toluene was evaporated. The residue was triturated in EtOAc at 0° C., filtered and washed with Et2O to afford the title product as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)Cl
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2.79 g, 13.91 mmol, supplier Antlantic Scitech) in DCM (80 mL), DIPEA (3.64 mL, 20.87 mmol) was added under argon atmosphere at room temperature then 4-cyano-2-methylbenzenesulfonyl chloride (3 g, 13.91 mmol) was added at 0° C. The ice bath was removed and the reaction mixture was stirred overnight. The reaction mixture was partitioned between DCM (30 ml) and aqueous sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml) then it was dried (phase separator) and concentrated under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.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.[Cu](I)I>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1n[nH]c2cc(Cl)c(C#Cc3ccccc3)cc12
Temperature: 120 °C
Yield: 37.9 %

Procedure:
A mixture of methyl 5-bromo-6-chloro-1H-indazole-3-carboxylate (50 mg, 0.17 mmol), triethylamine (0.05 mL, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.009 mmol), copper iodide (3.0 mg, 0.017 mmol) and phenyl acetylene (20 mg, 0.20 mmol) in tetrahydrofuran (1.0 mL) was sealed and heated to 120° C. for 16 hours. The cooled reaction mixture was concentrated in vacuo and purified by flash chromatography utilizing heptanes/ethyl acetate (1:1 to 0:1) to give the title compound (20 mg) as a yellow solid. MS (ES−): 309.0 (M−H)− Step 2
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH3:16])[O:13][N:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH3:16])[O:13][N:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:30]1[CH:31]=[N:32][N:33]([CH3:34])[C:29]=1[OH:28])=[O:5]
Reactant: Cn1nccc1O
Reactant: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C)c3O)c2Cl)=NO1
Reaction time: 12 h
Yield: 33.5 %

Procedure:
At room temperature, initially 4.00 g (12 mmol) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of dioxane and then 1.20 g (12.2 mmol) of triethylamine in 30 ml of dioxane were added dropwise to a solution of 1.20 g (12 mmol) of 5-hydroxy-1-methylpyrazole in 30 ml of dioxane. The reaction mixture was stirred for 12 hours and then filtered through silica gel and the filtrate was admixed with 0.50 g (3.6 mmol) of potassium carbonate and heated under reflux for 12 hours. After a further 12 hours of stirring at room temperature, a spatula tipful of potassium carbonate was added, and the mixture was once again heated under reflux. After cooling, the solvent was distilled off under reduced pressure, the residue was taken up in water and washed with ethyl acetate, the pH was adjusted to 1-2 using 10% strength hydrochloric acid and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and dried and the solvent was removed. The residue was digested in cold ethyl acetate. 1.60 g (34% of theory) of 4-[2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.