Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Dy+3]>C(#N)C.O>[C:2]1([C@@H:1]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:21]3[C@H:20]2[CH2:19][CH2:18][CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C=CCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H]1c1ccccc1N[C@H]2c1ccccc1
Reaction time: 1 h
Yield: 6 %

Procedure:
Benzaldehyde (531 mg, 5 mmol) was dissolved in acetonitrile (15 ml), aniline (466 mg, 5 mmol) was added at 0° C., and the mixture was stirred at the same temperature for 1 hr. tert-Butyl 3,4-dihydropyridine-1(2H)-carboxylate (917 mg, 5 mmol) and Dy(OTf)3 (153 mg, 0.25 mmol) were added at 0° C., and the mixture was further stirred for 1.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine and dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (19:1-6:1, v/v). The title compound (4aR*,5R*,10bR*) (109 mg, 6%) was obtained as a colorless amorphous form from the first eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][CH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][NH:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH:64]1[CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[F:3].[Li+].CC([N-]C(C)C)C.[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]I>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[F:1][C:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])([F:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][I:20]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: ICCOCCOCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl difluoromethylphosphonate (1.0 equiv.) in THF (0.8 M) at −78° C. was slowly added a solution of LDA (2 M, 1.1 equiv.) in heptane/THF/ethylbenzene, and the mixture was vigorously stirred for 30 minutes. In a separate reaction flask, a solution of 1,2-bis(2-iodoethoxy)ethane (1.0 equiv.) in THF (0.8M) was cooled to −78° C. To this solution was transferred, by cannula, the freshly prepared alkyl lithium solution and the reaction mixture was allowed to stir for 1 hour at −78° C. At this point, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then quenched with a 1 M aqueous solution of HCl. The resulting mixture was transferred to a separatory funnel and washed with CH2Cl2 three times. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using CH2Cl2 to provide diethyl 1,1-difluoro-3-(2-(2-iodoethoxy)ethoxy)propylphosphonate (I-1) as a yellow oil. 1H NMR (CDCl3): δ 4.23-4.31 (m, 4H), 3.75-3.80 (m, 4H), 3.60-3.67 (m, 4H), 3.26 (t, 2H), 2.33-2.50 (m, 2H), 1.38 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([CH2:18][C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(CN2CCOCC2)c1

Procedure:
N-(5-Bromo-3-nitropyridin-2-yl)-N-[3-(morpholin-4-ylmethyl)phenyl]amine was prepared from 5-bromo-2-chloro-3-nitropyridine and 3-(morpholin-4-ylmethyl)phenylamine as described in Example 3.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC.N1C=CN=N1>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(OCC)C>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: Cl[Pd]Cl
Agent: c1c[nH]nn1
Solvent: N#Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a 50 mL roundbottom flask equipped with a mechanical stirrer and a thermometer were added 8.12 grams (0.02 mole--1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 2.88 grams (0.02 mole--1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 7.4 grams (0.04 mole--2.0 equiv.) of tributylamine, and 0.077 gram (0.0002 mole--0.01 equiv.) of bis(benzonitrile)dichloropalladium(II). The reaction mixture was heated to 130° C., where it stirred for two hours. After this time TLC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. To the reaction mixture was then added 50 mL of diethyl ether. The resulting mixture was washed with 6M sulfuric acid, water, and an aqueous saturated sodium chloride solution and then concentrated, yielding 8.7 grams of 75.5% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (84.9% yield). The 75.5% pure product was distilled at 200° C. and 0.01 mm of mercury, yielding 6.0 grams of 95.5% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:10]2([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Yield: 110.7 %

Procedure:
The title compound (D29) (819.5 mg) was prepared according to the experimental procedure described in Description 28 starting from 1-Boc-3-azetidinone (500 mg, 2.77 mmol) and 4-Fluorophenylmagnesiumbromide (2M in diethylether) (1.67 ml, 3.33 mmol)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[C:3]=1[NH2:11].C(Cl)CCl.[CH:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.ClCCl>[NH2:11][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[C:4]=1[NH:10][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([CH3:17])[CH3:18])=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)c(N)c1N
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(Br)c(N)c1NC(=O)c1ccc(C(C)C)cc1
Yield: 98.9 %

Procedure:
A solution of 870 mg (4.01 mmol) 3-bromo-6-methoxy-benzene-1,2-diamine, 1.16 g (6.0 mmol) EDC, 744 mg (6.0 mmol) DMAP and 707 mg (4.01 mmol) 4-isopropylbenzoic acid in 20 ml dichloromethane is stirred at room temperature for 72 h. The reaction mixture is concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 1.44 g of the title compound as a slightly reddish solid.
Reaction SMILES: O[C:2]1C=C2C(=CC=1)C(C(O)=O)=CC=C2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([OH:29])=[O:28])=[CH:22][CH:21]=[CH:20]2>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:2])=[O:28])=[CH:22][CH:21]=[CH:20]2
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: COC(=O)c1cccc2cc(OC)ccc12

Procedure:
The process according to claim 1, wherein 6-hydroxy-1-naphthoic acid in the form of a mixture with 6-methoxy-1-naphthoic acid is reacted to give methyl 6-methoxy-1-naphthoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([OH:20])[CH2:18][CH3:19]>>[CH2:17]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: CCCO
Reactant: O=C(O)CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCOCCCCCCCCCC(=O)O
Temperature: 102 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
10-bromodecanoic acid (1g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893g, 15.9 mmol) in n-propanol (30 mL) and stirred at 102° C. for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a yellow oil. The product was purified by silica column chromatography in 2% diethyl ether/methylene chloride/0.2% formic acid, and then in 7% ethyl acetate/hexane/0.3% formic acid. Recrystallization from hexane at -20° C. yielded 10-(propoxy)decanoic acid (74 mg, 12%): mp <30° C.; 1H NMR (300 MHz, CDCl3) δ0.91 (t, 3H, J=7.5, CH3), 1.18-1.40 (br, 10H, methylene envelope), 1.48-1.67 (bm, 6H, CH3CH2CH2OCH2CH2, CH2CH2COOH), 2.33 (t, 2H, J=7.4, CH2COOH), 3.31-3.45 (bm, 4H, CH2OCH2), 10.37 (br, 1H COOH); 13C NMR (75.4 MHz, CDCl3) 10.67, 22.94, 24.72, 26.19, 29.09, 29.22, 29.41, 29.74, 34.11, 70.88, 72.53, 179.69; m/z 231 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[C:42]([F:48])[CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1C=NC=CN=1.[CH:57]1([CH2:63][C@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67][C:68]2[S:69][CH:70]=[CH:71][N:72]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([CH2:63][C@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][C:79]=3[F:48])[C:74]2=[O:82])[C:65]([NH:67][C:68]2[S:69][CH:70]=[CH:71][N:72]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[C:42]([F:48])[CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[C:36]([NH:67][C:68]2[S:69][CH:70]=[CH:71][N:72]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cccc(F)c2C1=O
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cnccn1
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2cccc(F)c2C1=O
Yield: 30 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (331 mg; 1.08 mmol, as a 1:1 mixture of regioisomers) and 2-aminopyrazine (232 mg; 2.41 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40M; eluent: 30% ethyl acetate/hexanes) (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide and (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3 dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide which were further purified by reverse phase HPLC (Rainin Dynamax SD-1 instrument) using a gradient of 40% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to provide 39 mg of pure (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C21H23FN4O2 (M+) 382.1805, found 382.1794 and 43 mg of regioisomer (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C21H23FN4O2 (M+) 382.1805, found 382.1810.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].O>C1COCC1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[C:5]3[C:6](=[CH:14][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:7]([C:21]([OH:23])=[O:22])[C:8]=2[CH:13]=1
Reactant: Cc1cccc2c1-c1c(C)cccc1C2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
A solution of 4,5-dimethylfluorene (5.2 g, 27.0 mmol) in 100 mL of THF at -78° C. was charged with butyl lithium (18.7 mL, 29.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred overnight. Water was added (150 mL) and the layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate was collected, washed with water and dried to give 2,7-dimethyl-9-fluorenecarboxylic acid (4.24 g, 65.9 %).