Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:13]2([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2ccc(F)cc2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
925 mg magnesium were stirred into 19 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 4.95 g 4-fluorobenzyl chloride in 19 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 29 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(4-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (5.76 g of yellow solid) was stirred, without further purification, with a mixture of 14 ml conc. hydrochloric acid (32 per cent by weight) and 8 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 30 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 40 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 4.70 g 4-dimethylamino-4-(4-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](N=CN(C)C)=[CH:4][CH:3]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:24])=[CH:21][N:22]=2)[N:19]=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[N:18]3[N:19]=[C:14]([C:3]4[CH:2]=[N:7][N:6]([CH3:5])[CH:4]=4)[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)c2cnc3ccc(Cl)nn23)cc1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Product: COc1ccc(C(=O)c2cnc3ccc(-c4cnn(C)c4)nn23)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of Example 1, starting with (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(4-methoxy-phenyl)-methanone (Stage 3.2) (tR 1.1 min (conditions 2), MH+=334)
Reaction SMILES: [O:1]=[C:2]1[O:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.C1OCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH:53]1[CH2:58][CH2:57][N:56]([C:59]([O:61][CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])=[O:60])[CH2:55][CH2:54]1.[Cl-].[NH4+]>C1COCC1>[O:1]=[C:2]1[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:3]1[CH:53]1[CH2:54][CH2:55][N:56]([C:59]([O:61][CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])=[O:60])[CH2:57][CH2:58]1
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(I)CC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](c2ccccc2)[C@H](c2ccccc2)OC(=O)[C@H]1C1CCN(C(=O)OCC[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4 g of tert-butyl (5S,6R)-2-oxo-5,6-diphenylmorpholine-4-carboxylate were dissolved in 50 ml of THF. 9 ml of 15-crown-5 were added, and the mixture was cooled to −78° C. Then 6.8 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 8 g of 2-trimethylsilanylethyl 4-iodopiperidine-1-carboxylate were added dropwise. The mixture was allowed to warm to 0° C. over the course of 6 h, and then the reaction was stopped by adding 200 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 150 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11]C)[C:8](OC(C)C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I-].[Li+].N1C(C)=CC(C)=[CH:21][C:20]=1[CH3:27]>[OH-].[Na+]>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([CH:20]([CH3:27])[CH3:21])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(F)c(C(=O)O)cc1OC(C)C
Reactant: Cc1cc(C)nc(C)c1
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Product: CC(C)c1cc(C(=O)O)c(F)cc1O
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-5-isopropoxy-4-methoxybenzoic acid (7.2 g) and lithium iodide (24 g) in collidine (120 mL) is heated at 150° C. overnight, cooled and dissolved in 2 N sodium hydroxide (200 mL) and washed with ethyl acetate (3×150 mL). The aqueous solution is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (magnesium sulfate) and concentrated to give an oil. The oil is subjected to mplc on silica gel using petroleum ether: ethyl acetate (2:1 v/v) as eluent to give 2-fluoro-4-hydroxy-5-isopropylbenzoic acid (5.7 g). [NMR (DMSO):— 7.32 (d, 1H, J=8 Hz), 6.67 (d, 1H, J=12 Hz), 4.47 (m, 1H), 1.24 (d, 6H, J=6 Hz)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18](C(O)=O)=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23].C([N:26](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18]([NH2:26])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2c(C)ccc3c(C(=O)O)c(C)nn23)c(Cl)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(C)ccc3c(N)c(C)nn23)c(Cl)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.5 %

Procedure:
A 0° C. solution of 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.58 g, 1.8 mmol) and triethylamine (0.30 mL, 2.2 mmol) in toluene (10 mL) was treated with diphenylphosphoryl azide (0.40 mL, 1.8 mmol) and stirred for 2.5 hours at 0° C. The reaction mixture was poured into H2O, extracted with Et2O, washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to remove the Et2O. Toluene (20 mL) was added and the reaction was heated to reflux for 3 hours. The reaction was treated with 2N HCl (5 mL) and stirred at reflux for 1 hour then cooled to room temperature. The layers were separated and the aqueous layer was basified with solid K2CO3. The residue was extracted with CH2Cl2, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 0.046 g (9%) of a yellow oily solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.1 Hz, 1H), 7.35 (d, J=9.3 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.5, 2.5 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H); MS (EI) m/z 302.18 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.S(=O)(=O)(O)O.[BrH:16]>O>[Br:16][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Br
Reactant: OCCc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: Fc1ccccc1CCBr

Procedure:
50 g 2-(2-fluorophenyl)ethanol, 19 ml concentrated sulfuric acid and 58 ml aqueous hydrobromic acid (47 per cent by weight) were heated at 100° C. overnight in a high-grade steel autoclave. After cooling, the mixture was diluted with 500 ml water and extracted twice with 250 ml methylene chloride each time, the combined extracts were dried over potassium carbonate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 61.8 g 1-(2-bromoethyl)-2-fluorobenzene were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])(O)=[O:2].C([NH2:23])=O>[Cl-].[Na+].O>[F:15][C:14]([F:17])([F:16])[C:13]([C:12]1[NH:23][C:1](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([I:10])[CH:9]=2)[N:11]=1)([OH:19])[CH3:18]
Reactant: NC=O
Reactant: CC(O)(C(=O)Nc1ccc(I)cc1C(=O)O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(O)(c1nc2ccc(I)cc2c(=O)[nH]1)C(F)(F)F

Procedure:
A solution of N-(2-carboxy-4-iodophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (5 g) and formamide (5 mL) was stirred and heated at 190°-200° C. for 3 hours. The cooled reaction mixture was poured into brine (150 mL) and extracted with ethyl acetate. The ethyl acetate solution was dried (Na2SO4) and evaporated. Chromatography, eluting with ethyl acetate, gave the title compound (2.86 g) as a white solid; mp 205°-207° C.; NMR: 1.75 (s,3), 7.48 (d,1), 7.5 (s,1), 8.13 (d,1), 8.42 (s,1), 12.05 (s,1); MS: m/z=385(M+1). Analysis for C11H8F3IN2O2 : Calculated: C, 34.40; H, 2.10; N, 7.29; Found: C, 34.48; H, 2.09; N, 7.26.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[C:18]3[N:19]([N:23]=[C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[CH2:28]4)[N:25]=3)[CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:15]=1[F:16]>>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[C:18]3[N:19]([N:23]=[C:24]([NH:26][CH:27]4[CH2:32][CH2:31][N:30]([C:2]5[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=5)[CH:29]([CH3:33])[CH2:28]4)[N:25]=3)[CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CC1CC(Nc2nc3c(-c4ccc(F)c(F)c4)cccn3n2)CCN1
Reactant: Cc1cc(Cl)ncn1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2C)ncn1

Procedure:
Prepared in analogy to example 57c) employing 4-chloro-6-methylpyrimidine instead of 4-bromo-2-methylpyridine and 8-(3,4-difluorophenyl)-N-(2-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine instead of 8-(2-chloro-4-fluorophenyl)-N-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. The title compound was obtained as a light brown foam.
Reaction SMILES: Br[C:2]1[CH:3]=N[N:5]([CH3:11])[C:6]=1[N:7]=[S:8]([CH3:10])[CH3:9].NC1N(C)N=C[C:14]=1[Br:19].N1C=CC=CC=1.ClS(C1N=C2N(C(OCC)=NC(F)=C2)N=1)(=O)=O>ClCCl>[Br:19][C:14]1[CH:3]=[CH:2][C:6]([N:7]=[S:8]([CH3:10])[CH3:9])=[N:5][CH:11]=1
Reactant: Cn1ncc(Br)c1N
Reactant: Cn1ncc(Br)c1N=S(C)C
Agent: CCOc1nc(F)cc2nc(S(=O)(=O)Cl)nn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(C)=Nc1ccc(Br)cn1
Temperature: -10 °C
Yield: 428.9 %

Procedure:
A mixture containing about 53 mmol of N-(4-bromo-1-methyl-5-pyrazolyl)-S,S-dimethylsulfilimine in about 28 mL of dichloromethane solution prepared in Example 7 omitting the recovery step was cooled to -10° C. and 1.0 g (5.7 mmol) of 5-amino-4-bromo-1-methylpyrazole, 0.54 g (6.8 mmol) of pyridine, 11.8 mmol of 2-chlorosulfonyl-5-ethoxy-7-fluoro[1,2,4]triazolo[1,5-c]pyrimidine, and 5 mL of dichloromethane were added sequentially with stirring and cooling at about -10° C. The mixture was allowed to stir at ambient temperature for 2 days. The solids present were recovered by filtration, washed with a small amount of 2-propanol, and dried to obtain 5.7 g of the title compound as a white solid. A purer sample amounting to 4.6 g (26 percent of theory) was obtained dissolving this in dimethyl sulfoxide and then adding water to reprecipitate it.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH:3]([OH:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=1)[CH2:19][C@H:2]([NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C@H:3]([OH:18])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCc1ccc2c(c1)C(NCC(O)C(N)Cc1cc(F)cc(F)c1)CCC2
Reactant: O=C1CCCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)CCCC(=O)O)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol (0.240 g, 0.64 mmol), triethylamine (0.268 mL, 1.92 mmol), and chloroform (3 mL) was added glutaric anhydride (0.073 g, 0.64 mmol) and reaction was stirred overnight at 60° C. Reaction was washed with 1N HCl, 10% NaHCO3, brine, dried over MgSO4, filtered, concentrated in vacuo to give 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (100 mg). Purified via prep-HPLC. 1H NMR (400 MHz, CD3OD) δ 1.26 (t, J=8 Hz, 3 H), 1.73 (m, 2 H), 1.89 (m, 1 H), 2.01 (m, 1 H), 2.17 (m, 6 H), 2.68 (d, J=8 Hz, 2 H), 2.93 (d, J=6 Hz, 1 H), 3.02 (m, 1 H), 3.30 (m, 2 H), 3.88 (m, 1 H), 4.09 (m, 1 H), 4.57 (m, 1 H), 6.79 (m, 1 H), 6.88 (m, 3 H), 6.93 (d, J=6 Hz, 1 H), 7.20 (m, 2 H), 7.31 (s, 1 H); OAMS: ES+488.9 ES−486.9
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:11]1=[O:19])[CH3:3].[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[CH:31]=2)=[C:23]([F:43])[CH:22]=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.C(OCC)(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:21]([NH:20][C:16]([C:12]5[C:11](=[O:19])[N:10]([C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:2]([CH3:1])[CH3:3])[CH:15]=[CH:14][CH:13]=5)=[O:18])=[CH:22][C:23]=4[F:43])=[CH:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CC(C)c1ccccc1-n1cccc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
1-[2-(1-Methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.39 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.35 mmol) and HATU (170 mg, 0.45 mmol) were suspended in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.12 mL, 0.71 mmol) was added. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate (5.0 mL) and tetrahydrofuran (5.0 mL). The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=65/35→85/15). The fractions containing the object product were mixed. The solvent was evaporated under reduced pressure, and a small amount of hexane/ethyl acetate (=2/1) was added. The resulting precipitate was collected by filtration to give the title compound (53 mg, 27%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:5]3[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14-7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:29][CH3:30])=[O:28]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 1.37 g. of 4-aminobenzoic acid, 3.50 g. of methyl 16-bromohexadecanoate, 2.12 g. of sodium carbonate and 140 ml. of hexamethylphosphoramide is stirred at 120° C. for 18 hours, allowed to cool, and poured into dilute hydrochloric acid. The precipitate is collected by filtration, dried, and crystallized from acetonitrile to yield 4-(15-carbomethoxypentadecylamino)benzoic acid as a white solid.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7]O.[N:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O.FC(F)OC1C=C(C=CC=1OC(F)F)CCl.[C-]#N.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: c1ccncc1
Reactant: OCc1ccc(OC(F)F)c(OC(F)F)c1
Agent: FC(F)Oc1ccc(CCl)cc1OC(F)F
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 45 °C
Yield: 98.5 %

Procedure:
A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argon atmosphere was treated with thionyl chloride (9.62 mL, 130 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a purple oil. To a solution of this 3,4-bisdifluoromethoxybenzyl chloride in dimethylformamide (200 mL) under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol). The resulting mixture was stirred and gently heated at 45° C. for 3 h, was cooled and was concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and was extracted five times with ether. The organic extract was washed once with brine, was dried (sodium carbonate) and the solvent was removed in vacuo to provide an oil (27 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][C@H:16]1[CH2:18][C@@H:17]1[C:19](OC)=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.O>[CH2:7]([O:14][CH2:15][C@H:16]1[CH2:18][C@@H:17]1[CH2:19][OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H]1C[C@@H]1COCc1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1C[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
Lithium aluminium hydride (0.238 g, 6.27 mmol) was added to a solution of methyl (1S,2S)-2-((benzyloxy)methyl)cyclopropanecarboxylate (1.38 g, 6.27 mmol) in THF (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hr, and ethyl acetate (5 mL) and saturated aqueous potassium sodium tartrate solution (25 mL) were added thereto at 0° C. The mixture was stirred at room temperature for 30 min, water (60 mL) was added thereto, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 37→58% ethyl acetate/hexane) to give ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl)methanol (1.01 g, 5.25 mmol, 84%) as a colorless oil.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[S:21](Cl)(=[O:23])=[O:22].Br[CH:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[S:21]([CH:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: O=C1OCCC1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 150 °C
Yield: 17.7 %

Procedure:
A solution of sodium sulfite (153 mg, 1.21 mmol) and sodium bicarbonate (306 mg, 3.63 mmol) in water (3 mL) was treated with 2,4,5-trifluorobenzenesulfonyl chloride (280 mg, 1.21 mmol) and heated in a microwave reactor at 150° C. for 400 seconds. The resulting mixture was treated with 3-bromodihydrofuran-2(3H)-one (299 mg, 1.82 mmol) and then heated in a microwave reactor at 150° C. for 500 seconds. The mixture was cooled to 10° C. and the resulting solid filtered off and dried in vacuo to give the title compound (60 mg).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[S:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[S:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide (74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86 μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.