Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)=[N:3]1.S(Cl)([Cl:21])(=O)=O.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([Cl:21])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2cccc(Br)c2)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1c(Cl)c(-c2cccc(Br)c2)nn1C

Procedure:
A reaction mixture was prepared from 13.5 g. of methyl 1-methyl-3-(3-bromophenyl)pyrazole-5-carboxylate and 6.2 g. of sulfuryl chloride in benzene solution. The reaction mixture was heated to refluxing temperature for about 36 hours, and was then cooled and poured into water. The aqueous mixture was extracted with ethyl acetate, and the ethyl acetate extract separated and dried. Removal of the ethyl acetate in vacuo yielded, as a residue, methyl 1-methyl-3-(3-bromophenyl)-4-chloropyrazole-5-carboxylate formed in the above reaction. Recrystallization of the residue from hexane yielded crystalline material melting at 91°-3° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[NH2:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: Nc1cccc(O)c1F
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 3-amino-2-fluorophenol (50 mg), 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (162 mg), potassium carbonate (65 mg), and N-methylpyrrolidone (1 mL) was stirred at 100° C. for 2 hours. To the reaction mixture was added water-saturated brine (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-amino-2-fluorophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (126 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:17])[CH:5]=2.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:2]([CH3:1])[N:3]2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=1)[CH3:26])[CH3:22]
Reactant: CCCn1c(C)c(-c2ccccc2)c2ccc(O)cc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccccc2)c2ccc(OC(C)(C)C(=O)OCC)cc21

Procedure:
The above compound was prepared from 2-methyl-3-phenyl-1-propyl-1H-indole-6-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10 (solvent: glycol dimethylether).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7]C(N)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C1(=O)CCCCC1>CCC(=O)CC>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH:2]([CH2:8][CH3:7])[CH2:3][CH3:4]
Reactant: Nc1ccc(Br)cc1
Reactant: Nc1ccccc1Br
Solvent: O=C1CCCCC1
Solvent: CCC(=O)CC
Product: CCC(CC)Nc1ccccc1Br
Yield: 61 %

Procedure:
The same procedure was carried out as in Example 2 except that 4-bromoaniline and 3-pentanone were used instead of 2-bromoaniline and cyclohexanone to obtain a colorless oil compound (61%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27].COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=4)=[CH:12][N:13]=3)[CH2:22][CH2:21]2)=[O:35])[CH2:30][CH2:29]1)=[O:27]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)CC1

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester was prepared from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and trans-1,4-cyclohexane dicarboxylic acid monomethyl ester in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexane-carboxylic acid methyl ester above. The product was obtained after a silica gel column purification with a 50-100% EtOAc in hexanes gradient. HRMS m/z calcd for C26H31N4O4I [M+H]+: 591.1463. Found: 591.1461.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-4-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)piperidine-1-sulfonamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=527.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([OH:9])[NH:8][C:4]=2[CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[N+:12]([C:11]1[C:2]([Br:1])=[CH:3][C:4]2[N:8]=[C:7]([OH:9])[NH:6][C:5]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: Oc1nc2ccc(Br)cc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2[nH]c(O)nc2cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
The procedure of Cheesman, G. W. H., J. Chem. Soc. 1170 (1962), was adapted. To a stirred suspension of 5-bromo-2-hydroxybenzimidazole (105 mg, 0.49 mmol) in concentrated H2SO4 (1 mL) at 0° C. for 30 min was added KNO3 (58.5 mg, 0.58 mmol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The mixture became a red solution. Then it was poured into ice (30 g) resulting in the separation of a brown precipitate, which was collected by filtration and washed with distilled water (2×1 mL) followed by ethanol (2×1 mL) to give 141 mg of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 103 mg of pure title compound (80.5%) as bright yellow needles: mp 290°-4° C. (dec.), changed color from 200° C. IR (KBr, cm-1): 3406, 3181, 1712, 1537. 1H NMR (DMSO-d6): δ 7.244 (s, 1H), 7.558 (s, 1H), 11.227 (s, 1H), 11.321 (s, 1H). HRMS: calcd for C7H4N3O3Br (M+) m/z 256.9433; found: 256.9439.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Br:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Reactant: O=C(O)COc1ccc(Br)cc1
Product: Cc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Br)cc5)CC4)nc(N)nc3s2)cc1
Yield: 47 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 47%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35](N2C=CN=C2)=[O:36])=[CH:5][CH:4]=1)#[N:2].[OH:42][CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][N:14]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([C:35]([O:42][CH2:43][C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])=[O:36])=[C:11]([CH3:34])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:13]1=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCC(=O)OCc2ccccc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 32 %

Procedure:
The title compound is synthesized in analogy to Example 64 from Example 15A using benzyl hydroxyacetate instead of tert.-butyl-N-hydroxyethyl carbamate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12].[CH3:21]I>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12]
Reactant: CI
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ccc(F)cc1Br)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Add sodium hydride (0.89 g, 22.4 mmol, 60% dispersion in mineral oil) to a solution of tert-butyl 1-(2-bromo-4-fluorophenyl)ethylcarbamate (4.75 g, 14.9 mmol) in DMF (10 mL). Stir the mixture for 30 min at RT. Add methyl iodide (1.86 mL, 29.9 mmol). Stir the mixture for 1 h at RT. Dilute with ethyl acetate, and wash with water and aqueous saturated sodium chloride. Dry over sodium sulfate and concentrate. Purify by column chromatography (hexane to 20% ethyl acetate in hexane) to give the title compound as a colorless oil (4.9 g, 98%). 1H NMR (400 MHz, CD3Cl) δ 1.32 (s, 9H), 1.45 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 5.39 (br, 1H), 7.00 (m, 1H), 7.28 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[CH2:19]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](Br)[CH:30]=1)(=[O:28])=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:18])[CH:30]=1)(=[O:28])=[O:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 4-(benzylsulfonyl)-2-bromo-1-methylbenzene (Intermediate 69), the title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)CCN
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCS(C)(=O)=O

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with 2-methanesulfonyl-ethylamine following general procedure B to afford 4-(2-methanesulfonyl-ethylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (305 mg). Thus obtained amino-ester (70 mg, 0.2 mmol) was subjected to reaction with 5-Isocyanato-benzo[1,3]dioxole according to general procedure C to furnish 3-Benzo[1,3]dioxol-5-yl-1-(2-methanesulfonyl-ethyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (43 mg). LCMS: m/z 471 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:31]=[CH:32][C:7]=1[CH2:6]2)=O.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1.O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[C:8]3[CH:9]=[C:10]4[C@:5]([CH2:3][OH:2])([CH2:6][C:7]=3[CH:32]=[N:31]2)[CH2:14][N:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:11]4)=[CH:34][CH:35]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-ylpyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (17 g) in dichloromethane (300 mL) under nitrogen at −78° C. was treated with a 1.0 M solution of diisobutylaluminium hydride in toluene (123 mL). After 1 hour at −78° C., the solution was diluted with water and the phases separated. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford the title compound as a white solid (16.7 g). 1H NMR (CDCl3): δ 8.56-8.53 (d, 1H, J=2.4 Hz), 7.81-7.77 (dd, 1H, J=9.0, 2.4 Hz), 7.44-7.38 (m, 3H), 7.19-7.12 (m, 3H), 6.65-6.60 (d, 1H, J=9.0 Hz), 6.31-6.28 (d, 1H, J=2.5 Hz), 4.08-4.03 (dd, 1H, J=12, 2.4 Hz), 3.99-3.92 (m, 1H), 3.84-3.79 (m, 4H), 3.69-3.64 (m, 4H), 3.37-3.30 (m, 1H), 3.14-3.08 (d, 1H, J=16 Hz), 2.82-2.70 (m, 1H), 2.58-2.48 (m, 1H), 2.42-3.34 (m, 1H), 2.28-2.16 (m, 3H).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]=1[C:7]1[S:11][C:10]2[CH2:12][CH:13]([NH:16]C(OC)=O)[CH2:14][CH2:15][C:9]=2[CH:8]=1.[OH-].[K+]>CO.O>[N:1]1[NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]=1[C:7]1[S:11][C:10]2[CH2:12][CH:13]([NH2:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)NC1CCc2cc(C3=NNC(=O)CC3)sc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1CCc2cc(C3=NNC(=O)CC3)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In 10 ml of methanol was dissolved 1.01 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-6-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene, and 560 mg of potassium hydroxide dissolved in 5 ml of water was added thereto. The mixture was stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture, the residue was extracted with ethyl acetate and dried, and the the solvent was removed to obtain 0.5 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-6-amino-4,5,6,7-tetrahydrobenzo-[b]thiophene as crystals.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.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>[N+:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
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: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc([N+](=O)[O-])c1-c1ccccc1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
A 250-mL 3-necked round-bottom flask was placed a solution of 2-chloro-3-nitrobenzaldehyde (5.3 g, 28.57 mmol, 1.00 equiv) in toluene (50 mL), phenylboronic acid (3.83 g, 31.39 mmol, 1.10 equiv), K2CO3 (7.88 g, 57.10 mmol, 2.00 equiv) in water (30 mL) and Pd(PPh3)4 (660 mg, 0.57 mmol, 0.02 equiv). The resulting mixture was heated to 110° C. for 30 hours. Upon completion, the reaction mixture was cooled and diluted with Et2O (1000 mL). After phase separation, organic layers were dried over anhydrous magnesium sulfate, filtered off and concentrated on rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50) affording 6-nitrobiphenyl-2-carbaldehyde as yellow solid (5.35 g, 82%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)/[CH:6]=[CH:7]\[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.Cl[C:36]1[C:37]([O:44][CH3:45])=NN=[N:40][C:41]=1OC.CN1CC[O:50]CC1.Cl.NCCC(O)=O>C(Cl)Cl.O>[CH3:45][O:44][C:37](=[O:50])[CH2:36][CH2:41][NH:40][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8](/[CH:7]=[CH:6]\[CH:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH2:4][CH2:3][C:2]([F:1])([F:33])[F:34])=[CH:9][CH:10]=1
Reactant: CN1CCOCC1
Reactant: COc1nnnc(OC)c1Cl
Reactant: O=C(O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: Cl
Agent: NCCC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
The cis-4-{6,6,6-Trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoic acid (214 mg, 0.45 mmol), chloro-dimethoxy-triazine (CDMT) (81 mg, 0.46 mmol), and 4-methylmorpholine (50 uL, 0.47 mmol) are combined in anhydrous DCM under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta-alanine hydrochloride (68 mg, 0.49 mmol) and 4-methylmorpholine (100 uL, 0.94 mmol) is then added to the reaction mixture, and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with DCM and water and rinsed with 1N HCl. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The cis-3-(4-{6,6,6-trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoylamino)-propionic acid methyl ester (197 mg, 0.35 mmol) is isolated after column chromatography, 78% yield.
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]([C:11]([OH:13])=O)=[C:8]([Cl:10])[N:9]=1)(=[O:4])=[O:3].[NH2:22][CH2:23][C:24]1[C:25]([F:41])=[C:26]([O:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([Cl:40])[CH:39]=2)[C:35]#[N:36])[C:27]([Cl:30])=[CH:28][CH:29]=1>>[NH2:1][S:2]([C:5]1[NH:6][C:7]([C:11]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][C:32]3[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[C:38]([Cl:40])[CH:39]=3)[C:25]=2[F:41])=[O:13])=[C:8]([Cl:10])[N:9]=1)(=[O:3])=[O:4]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1c(S(N)(=O)=O)nc(Cl)c1C(=O)O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(S(N)(=O)=O)nc3Cl)c2F)c1
Yield: 40.8 %

Procedure:
2-(aminosulfonyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.26 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.089 g, 0.29 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.055 g, 41%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, 1H), 7.35-7.43 (m, 2H), 7.27 (t, J=2.0 Hz, 1H), 7.24 (s, 1H), 4.63 (s, 2H). ES-LCMS: m/z 516.0, 518.0, 519.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]([OH:21])=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[CH:7]=1.[C:23](OC(=O)C)(=O)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:22])[O:21][C:23]([CH3:24])=[C:9]([C:10]1[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=1)[C:8]2=[O:20]
Reactant: O=C(Cc1ccc2c(c1)OCCO2)c1cc(Cl)c(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc2c(c1)OCCO2

Procedure:
This compounds was synthesised in the same manner as described above. 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (1.1.2.5) (0.3 g, 0.9 mmol), acetic anhydride (0.5 ml), potassium carbonate (0.5 g 3.6 mmol). 6-Chloro-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-hydroxy-2-methyl-chromen-4-one was obtained an off white solid (0.3 g, 96.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH2:63][C:64]1[CH:65]=[C:66]([F:76])[C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C>[F:76][C:66]1[C:67]2[C:71]([CH3:72])([CH3:73])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=[C:64]([CH2:63][NH:62][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:10][C:2]=2[CH3:1])[CH:65]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CN)cc(F)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1cc(F)c2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of crude 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (0.45 g, 1 mmol) in DMF (5 mL) at rt under N2 was added HBTU (0.76 g, 2 mmol), followed by DIPEA (0.39 g, 3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was purified by chromatography over silica gel eluted with PE-DCM (1:1) to give an activated intermediate from acid, which was used directly to mix with 6-(aminomethyl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (0.3 g, 1.44 mmol) in 5 mL of DMF. The reaction mixture was stirred at rt overnight. The reaction was monitored by LC-MS. The reaction solution was purified by pre-HPLC to give the final title compound (260 mg, 40.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.97 (t, 1H), 7.86 (s, 2H), 7.63-7.62 (m, 2H), 7.53-7.51 (m, 2H), 7.24 (d, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.43-4.31 (m, 2H) 2.42 (s, 3H) 1.53 (s, 6H) ppm; HPLC purity: 97.9% at 220 nm and 99.6 at 254 nm; MS (ESI+): m/z=643 (M+1).