Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH:8]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1.[CH2:18]([C@H:20]1[C:24](=O)[O:23]C(=O)[N:21]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH3:19].C(O)(=O)C>O1CCCC1.O>[CH2:30]([O:29][C:27]([NH:21][C@@H:20]([CH2:18][CH3:19])[C:24]([C:8]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1)=[O:23])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: CC[C@H]1C(=O)OC(=O)N1C(=O)OCc1ccccc1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A solution of diisopropylamine (3.76 mL) in tetrahydrofuran (50 mL) was cooled to −78° C., n-butyllithium-hexane solution (16.56 mL, 1.6 mol/L) was added dropwise and, after the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of tert-butyl cyclopropanecarboxylate (3.77 g) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was further stirred at −78° C. for 30 min. A solution of benzyl(4S)-4-ethyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate (3.49 g) in tetrahydrofuran (50 mL) was added dropwise at −78° C. for 30 min and the mixture was stirred at −78° C. for 30 min. Acetic acid was added to the reaction mixture at −78° C., water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→2/1) to give the title compound as a colorless oil (yield: 1.16 g, 24%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Si:25]([O:32][C:33]1[CH:34]=[C:35](/[C:39](/[CH2:43][CH3:44])=[CH:40]/[CH:41]=O)[CH:36]=[CH:37][CH:38]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl.[Zn]>[C:28]([Si:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](/[C:39](/[CH2:43][CH3:44])=[CH:40]/[CH:41]=[C:20]([Br:24])[Br:21])[CH:34]=1)([CH3:27])[CH3:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC/C(=C\C=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C(=C\C=C(Br)Br)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
1.17 g (18 mmol) of zinc powder, 4.7 g (18 mmol) of triphenylphosphine and 5.9 g (18 mmol) of carbon tetrabromide are stirred for 45 minutes in 150 ml of dichloromethane. A solution of 2.6 g (9 mmol) of (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-en-1-al in 10 ml of dichloromethane is added drop by drop. The reaction medium is stirred for 1 hour, then extracted with a mixture of water and of dichloro-methane. The residue is filtered on a silica column (eluent dichloromethane). A yellow oil is obtained (m=3.3 g; Y=83%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][N:16]1[CH2:17][CH2:18][CH:14]([C:6]2[NH:7][C:8](=[O:13])[C:9]3[C:4]([CH:5]=2)=[C:3]([CH3:2])[CH:12]=[CH:11][CH:10]=3)[CH2:15]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Reactant: OCCBr
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)C3)cc12

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (200 mg) and 2-bromoethanol (270 μl), 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (39 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[C:4]1[O:8][CH2:7][CH2:6][CH:5]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([O:9][CH2:3][C:4]1[O:8][CH2:7][CH2:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: OCC1=CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(COCc2ccccc2)OCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.69 g of sodium hydride (as a 55% w/w suspension in mineral oil) were suspended in 150 ml of dimethylformamide, and 17.64 g of 4,5-dihydrofurfuryl alcohol (prepared as described in Preparation 48) in 30 ml of dimethylformamide were added dropwise at 5°-10° C. over 30 minutes, whilst ice-cooling. The mixture was stirred at room temperature for 1 hour, and then 20.93 ml of benzyl bromide were added dropwise thereto at 10°-15° C. over a further 30 minutes, whilst ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, poured into 2 liters of water and extracted twice with ethyl acetate. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, to give 17.8 g of an oily residue. This residue was purified by column chromatography through 400 g of silica gel. Those fractions eluted with a 7:100 by volume mixture of hexane and diethyl ether afforded 3.71 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:32](OC(C)C)(C)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH3:33])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CC(C)OC(C)C
Product: CCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde. Crystals (diisopropyl ether).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][O:19][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1>CN(C=O)C>[CH3:15][N:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:32]3[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:8][CH:7]=2)=[CH:10][C:11]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]1=[O:16]
Reactant: c1cc[nH]c1
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cn3cccc3)cc2)cc2onc(-c3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
To a solution of 198 mg (0.5 mmol) of 6-(4-bromomethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one in 2.5 ml of DMF is added 326 mg (1.0 mmol, 2.0 eq.) of caesium carbonate and 0.05 ml (0.6 mmol, 1.2 eq.) of pyrrole. After stirring 16 h at room temperature the solvent is removed in vacuo and the residue taken up in CH2Cl2. The organic phase is washed with NaHCO3-solution, dried over Na2SO4 and concentrated. Flash chromatography yields 34 mg (18%) of the desired compound as a white solid. Mass spectrum: m/z (M+H)+: 382.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:29])([F:28])[C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[C:21](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:21]([C:20]([F:24])([F:25])[C:19]([F:26])([F:27])[C:18]([F:29])([F:28])[F:17])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1N
Product: Fc1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 33 %

Procedure:
A solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (200 mg, 0.85 mmol) in heptafluorobutanoic acid (1.5 ml) was stirred overnight at 80° C. The reaction was then quenched by the addition of water (100 ml), adjusted to pH 7 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (116.6 mg, 33%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:11][O:12][C:13](=[O:20])[CH:14]([NH:15][C:8](=[O:10])[CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)C=Cc1cccs1
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)C(CC(C)C)NC(=O)C=Cc1cccs1

Procedure:
Prepared in a similar manner as described in example 4 from 3-thiophen-2-yl-acrylic acid and D-leucine methyl ester. MS (M+H, 282.2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[CH:30]=1>>[CH3:36][C:31]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.049, m/z=459.1; 1H NMR (CD3OD) 0.94 (s, 3H), 1.24 (s, 3H), 1.55 (d, 3H), 2.15 (s, 2H), 2.23 (m, 1H), 2.45 (m, 1H), 2.51 (s, 6H), 3.05 (m, 1H), 5.57 (m, 1H), 7.04 (d, 2H), 7.24 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (m, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1.O1CCCC1.Br[CH2:33][CH2:34][Cl:35]>>[Cl:35][CH2:34][CH2:33][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ClCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCl)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.8 M in THF, 3.9 mL) was slowly added to a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (1.50 g, 0.00583 mol) in tetrahydrofuran (20 mL, 0.2 mol) at −78° C. and the mixture was stirred for about 1 hour during which the temperature was allowed to rise to about −50° C. 1-Bromo-2-chloro-ethane (0.75 mL, 0.0082 mol) was slowly added to the mixture and then the resulting mixture was allowed to warm to rt (room temperature). After stirring for 2 h, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl ether twice. The combined organic layers were dried and concentrated in-vacuo to afford the crude product, which was purified by CombiFlash eluting with hexane/EtOAc (max. EA 20%).
Reaction SMILES: FC1C=C(C=CC=1)COC1C=CC(C=O)=CC=1.[F:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][NH:29][C@@H:30]([CH3:34])[C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=1.[CH3:40][S:41]([O-:44])(=[O:43])=[O:42]>>[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[F:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C@@H:30]([CH3:34])[C:31]([NH2:33])=[O:32])=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)[O-]
Agent: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: O=Cc1ccc(OCc2cccc(F)c2)cc1
Product: CS(=O)(=O)O

Procedure:
The product of the title is prepared in a 87% yield by following the same procedure of Example 12 a1) with the exception that the 4-(3-fluorobenzyloxy)benzaldehyde is prepared according to Example 11 and converted the thus obtained (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide into the methanesulfonate (Ic), having 99.7 (area %) purity, determined according to the method of Example 25A and the content of the C,O-dialkylated impurity (IIa) is 0.005% by weight, measured by the method of Example 25B.
Reaction SMILES: [NH2:1][C:2]1[C:6](=[N:7][NH:8][C:9]2[CH:10]=[C:11](S(N)(=O)=O)[CH:12]=C[CH:14]=2)[C:5]([CH:19]2[CH2:21][CH2:20]2)=[N:4][N:3]=1.[NH2:22]C1C=C(S(N)(=O)=O)C=CC=1>>[CH:19]1([C:5]2[C:6](=[N:7][NH:8][C:9]3[CH:14]=[N:22][CH:12]=[CH:11][CH:10]=3)[C:2]([NH2:1])=[N:3][N:4]=2)[CH2:20][CH2:21]1
Reactant: NC1=NN=C(C2CC2)C1=NNc1cccc(S(N)(=O)=O)c1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NC1=NN=C(C2CC2)C1=NNc1cccnc1

Procedure:
In a similar manner, 3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]benzenesulfonamide was prepared from 3-aminobenzenesulfonamide (0.51 g, 2.96 mmol) to yield 0.1 g of the product. MS (m/z, ES+): 307 (M+1, 100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]2[C:12]3[C:17]([CH2:18][CH:4]2[CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:29](OCC)=[O:30].O>O1CCCC1>[OH:30]/[CH:29]=[C:3]1\[CH:4]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:5]2[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]\1=[O:1]
Reactant: CCOC(=O)N1C(=O)CC2Cc3ccccc3C21
Reactant: CCOC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1C(=O)/C(=C/O)C2Cc3ccccc3C21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ethyl 2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (200 mg, 0.81 mmol) was dissolved in tetrahydrofuran (8 mL) was cooled to −78° C. Then, lithium bis(trimethylsilyl)amide (1 mol/L in THF, 1.22 mL, 1.22 mmol) was added. After 1 h at −78° C., ethyl formate (0.198 mL, 2.446 mmol) was added. The mixture was stirred for another 30 min and then allowed to warm to room temperature. After another 30 min, water was added. The mixture was extracted with diethylether, the pH of the aqueous layer was adjusted to 1 and the solution was extracted with EtOAc (2*20 mL), dried (Na2SO4) and concentrated to give a colourless oil ethyl (3E)-3-(hydroxymethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D12 (120 mg, 54%) which was used without further purification in the next step. LCMS (Method A): RT: 1.53 min; ES− 272 [M−H]
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:53])[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42]2>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:53]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1cc2cc(C(=N)NO)ccc2[nH]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 15 min. Ethyl 5-[(hydroxyamino)(imino)methyl]-1H-indole-2-carboxylate (D22) (173 mg) was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was heated to 80° C. and stirred at that temperature for 5 hours. Most of the DMF was evaporated. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. Trituration with ethanol provided ethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-2-carboxylate (D23) (85 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.37 (9H, m), 4.38 (2H, q), 4.89 (1H, m), 7.35 (1H, d), 7.45 (1H, d), 7.62 (1H, d), 7.98 (1H, dd), 8.12 (1H, dd), 8.20 (1H, d), 8.49 (1H, d), 12.27 (1H, s). MS (ES): C22H20ClN3O4 requires 425; found 426.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[N:37][C:36]=1[C:41]1([NH2:45])[CH2:44][O:43][CH2:42]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:45][C:41]2([C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:44][O:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: NC1(c2ncccn2)COC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)COC4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a yellow solution mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (30 mg, 0.066 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (12.5 mg, 0.067 mmol) DMF (1 ml) in a 25 ml round-bottomed flask was added PyBOP (50 mg, 0.096 mmol), followed by TEA (0.1 ml, 0.717 mmol), and the reaction mixture stirred for overnight. Ice cooled water was added to the reaction mixture, which was then stirred for 10-15 min. at 0° C. Precipitation was observed. The solid was collected by filtration, washed with cold water, and then dissolved in dichloromethane. The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield (6 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1>[F:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6]=1[OH:8]
Reactant: Nc1cc(O)c(F)cc1F
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(O)c(F)cc1F
Reaction time: 0.5 h
Yield: 91 %

Procedure:
18.9 g (130 mmol) of the resulting 5-amino-2,4-difluorophenol was dissolved in 45 ml of pyridine, 16.0 ml of pivaloyl chloride was added dropwise over 8 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed once with a 1N aqueous solution of hydrochloric acid, water and an aqueous saturated solution of sodium chloride, respectively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 27.0 g (91%) of 2,4-difluoro-5-pivaloylaminophenol.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][N:6]1[C:10]2[N:11]=[C:12]([O:15]C)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[OH:17])[CH3:2]>Br>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[N:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[OH:17])[CH3:19]
Reactant: CCN(CC)CCn1c(O)nc2ccc(OC)nc21
Agent: Br
Product: CCN(CC)CCn1c(O)nc2ccc(O)nc21

Procedure:
10 grams of 1-(2-diethylaminoethyl)-2-hydroxy-6-methoxy-7-aza-benzimidazole were boiled for 5 hours at reflux in 100 ml of 48% hydrobromic acid and the solution evaporated in a vacuum. The residue was stirred with isopropanol, filtered with suction and then recrystallized twice from ethanol under the addition of activated carbon.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH3:22])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[C:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(O)(C)C>[CH3:22][O:21][C:20]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:32]2[CH2:33][CH2:34][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[CH:14][C:13]=2[CH:19]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ccc(=O)oc2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 73 %

Procedure:
Method B (20 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-methoxy-2H-1-benzopyran-2-one (example 68) and 4-phenylpiperidine; yield 73%; fusion point 97°-99° C. (from isopropanol). Hydrochloride: method G; yield 93%; fusion point 198°-200° C. (from isopropanol).
Reaction SMILES: [NH3:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]2[N:12]=[C:13]([S:16][CH2:17][C:18]([O:20]CC)=O)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]2[N:12]=[C:13]([S:16][CH2:17][C:18]([NH2:1])=[O:20])[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1
Reactant: N
Reactant: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Product: NC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 92.5 °C
Reaction time: 8 h

Procedure:
Ethanolic ammonia (5 mL) was added to intermediate ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate (60 mg, 0.188 mmol), the reaction vessel sealed and the mixture stirred overnight at 90-95° C. The mixture was then evaporated to dryness, the solid residue was filtered, washed 3 times with EtOH, and dried to give the desired 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetamide.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]butanamide, the title compound, mp 80°-82° (from ether) in 68% yield.