Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:8]([C:7]2[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=2[Cl:1])=[O:9])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
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: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (1.93 g, 10 mmol), 4-tert-Butyl-phenylamine (1.49 g, 10 mmol), DIEA (3.5 mL, 20 mmol), and HATU (4.56 g, 12 mmol) were added to DMF (20 mL). The reaction was stirred at rt for 15 h. The resulting dark brown solution was extracted with DCM (2×10 mL), washed with H2O (2×10 mL), and dried over sodium sulfate. The curde product was further purified using Flash Chromatography (2% MeOH/DCM), affording the desired product as yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:8]([CH2:7][CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(O)C2)C(=O)Nc2nccs2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A solution of 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 37, 155 mg, 0.393 mmol) in methylene chloride (3 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 508 mg, 0.471 mmol). The resulting reaction mixture was stirred at 25° C. for 3 h, at which time, thin layer chromatography indicated a small amount of the 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. The reaction mixture was then treated with an additional amount of pyridinium chlorochromate (20 wt. % on basic alumina, 127 mg, 0.118 mmol). The reaction mixture was allowed to stir at 25° C. for 1 h and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate to 100% ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (46 mg, 30%) as a white foam: mp 94–97° C.; FAB-HRMS m/e calcd for C18H20N2O4S2 (M+H)+ 393.0943, found 393.0948.
Reaction SMILES: CN(OC)[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]#[C:13][CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[O:18])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]([C:12]#[C:13][CH2:14][CH:15]([CH3:16])[CH3:17])[CH:6]=1
Reactant: COc1ccc(C(=O)N(C)OC)c(C#CCC(C)C)c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2ccccc2)c(C#CCC(C)C)c1
Yield: 91 %

Procedure:
N-Methyl-N,4-bis(methyloxy)-2-(4-methyl-1-pentyn-1-yl)benzamide (103) (0.72 g, 2.62 mmol) was treated with benzylmagnesium chloride in THF to give 0.73 g (91%) of the title compound (104) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.04 (d, J=6.6 Hz, 6H), 1.85-2.00 (m, 1H), 2.35 (d, J=6.6 Hz, 2H), 3.83 (s, 3H), 4.44 (s, 2H), 6.82 (dd, J1=8.8 Hz, J2=2.5 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 7.19-7.25 (m, 3H), 7.26-7.32 (m, 2H), 7.65 (d, J=8.8 Hz, 1H). LCMS (APCI): m/z 307 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[CH:9](O)[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].C(O)C.S(=O)(=O)(O)O>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCCCc1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
300 mg of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol were introduced into ethanol in a 50 ml flask, and 1 ml of concentrated sulphuric acid was added. The mixture was then heated to reflux for 4 hours. After cooling, 10 ml of water were added, the ethanol was distilled off, and the mixture was extracted with dichloromethane. Washing of the organic phase with sodium bicarbonate solution, drying over sodium sulphate and removal of the solvent in vacuo resulted in 220 mg (80% of theory) of 2-(n-butyl)-5-nitrobenzofuran as yellow oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:34])([Cl:35])[Cl:36])=[O:30])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: O=C(CCCCCCCCCCCO)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 29.9 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (2.0 g; 8.6 mmol), the product of 14a (3.0 g; 8.6 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.1 g; 10.0 mmol), and pyridine (4.0 mL) in dichloromethane (75 mL) using Procedure E. The crude product was purified on a 90×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:3), collecting 13×50 mL fractions. Following evaporation of fractions 6-11, 1.44 g (30%) product was obtained (yellowish oil).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]([CH3:31])[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([N:15]([CH3:31])[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCC1CCNCC1)Cc1ccccc1
Reaction time: 1 h

Procedure:
TFA (2.78 ml) was added dropwise at 0° C. to a solution of tert-butyl 4-(2-(benzyl(methyl)-amino)ethyl)piperidine-1-carboxylate (600 mg, 1.8 mmol, 1 eq) in dichloromethane (30 ml), and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH (50 ml), Amberlyst A-21 ion-exchanger resin (2 g) was added, and stirring was carried out for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure and used in the next stage without being purified further.
Reaction SMILES: O.[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([N:14]3[CH:18]=[CH:17]N=C3)[NH:8][C:7]=2[CH:19]=1.[CH:21]1(N)CC[CH2:22]1>>[CH:18]1([NH:14][C:9]2[NH:8][C:7]3[CH:19]=[C:3]([Cl:2])[C:4]([Cl:20])=[CH:5][C:6]=3[S:11](=[O:12])(=[O:13])[N:10]=2)[CH2:17][CH2:22][CH2:21]1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2cc(Cl)c(Cl)cc21
Reactant: NC1CCC1
Solvent: O
Product: O=S1(=O)N=C(NC2CCC2)Nc2cc(Cl)c(Cl)cc21

Procedure:
6,7-Dichloro-3-(imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate was treated with cyclobutylamine according to the general procedure Method D to give the title compound; m.p. 320-326° C.; IR (KBr): 3290, 3163, 3068, 2979, 2952, 1631, 1580, 1556, 1460, 1331, 1251, 1166, 1152, 1137, 1128 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1.[Li+].[OH-]>C1COCC1.CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2Br)cc1
Temperature: 45 °C

Procedure:
To a THF/MeOH/water solution (ca. 40 mL/40 mL/10 mL) of the intermediate from Step F (8.53 g, 17.84 mmol) was added LiOH (3.66 g, 89.2 mmol). The solution was stirred at 45° C. until no starting material remained by HPLC (ca. 2 hrs). The solution was concentrated to remove the majority of MeOH/THF and then partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with water (2×), brine and dried over Na2SO4. The solution was filtered and concentrated to give the title compound. The crude material was use in the next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=[CH:39][N:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:41]3[CH:40]=[CH:39][N:38]=[C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)[CH:42]=3)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccnc(N5CCN(C)CC5)c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=468.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]C(=O)C(C)(C)C.[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(Cl)Cl>C(Cl)Cl.CO>[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19]([C:3]2[C:2]([NH2:7])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH2:17]1
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncccc1C1=CCC(C(F)(F)F)CC1
Yield: 26 %

Procedure:
Prepared in analogy to example 262 step a-b), starting from N-(pyridin-2-yl)pivalamide and 4-(trifluoromethyl)cyclohexanone. 3-(4-Trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine was obtained after column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent as a white solid (yield: 26% over 2 steps).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:23]3[CH2:28][CH2:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: C1=C(c2ccccn2)CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CC=C(c4ccccn4)CC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (450 mg, 1.42 mmol) in DMSO (5.0 ml) was added 2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (300 mg, 1.87 mmol) and DIEA (361 mg, 2.79 mmol), and the reaction mixture was stirred overnight at 90° C. The reaction mixture was extracted with ethyl acetate (3×50 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified by preparative silica gel plate chromatography (dichloromethane:ethyl acetate:petroleum ether (40:1:12)) to afford methyl 2-(4-fluorophenyl)-3-(4-(pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoxaline-6-carboxylate as a yellow solid (410 mg).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C[O-].[Na+]>CO>[OH:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])[CH2:6]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](O)C3)nc12

Procedure:
(cis)-2-(3-Acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide (first eluting isomer, 64 mg, 0.15 mmol), potassium carbonate (82 mg, 0.59 mmol) and sodium methoxide (5.4M in methanol, 1.37 ul, 0.0074 mmol) are stirred together in methanol (6 ml) for 4 h at ambient temperature. Evaporation of the solvent, dissolution in methylene chloride and extraction with saturated sodium carbonate afforded, after drying and evaporation of the methylene chloride, a crude material. After crystallization from diethyl ether, the title compound was obtained as light yellow crystals (91% yield). MS: m/e=392(M+H+), mp 168-171° C., α589=−4.87 (CH2Cl2, c=1.1%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([C:9]([O:11]C)=O)=[CH:6][S:7][CH:8]=1)=O.C([O-])=O.[NH4+:16]>O>[N:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[NH:16][CH:1]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cscc1NC=O
Agent: O=C[O-]
Solvent: O
Product: O=c1[nH]cnc2cscc12
Temperature: 140 °C

Procedure:
A stirred mixture of methyl 4-formamido-3-thenoate (see below) (3.39 g) and ammonium formate (3.4 g) in formamde (5 ml) was heated at 140° C. for 7 hours. On cooling, the mixture was poured into water, and the mixture filtered to give a solid which was washed with water followed by light petroleum (b.p. 60-80° C.) and air dried to give the title product, m.p. 275-278° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH2:43][C:44]1[CH:56]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:54]=[CH:53][C:45]=1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:43][C:44]1[CH:56]=[C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:54]=[CH:53][C:45]=1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Fc1ccccc1I
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccccc1F
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To 1-fluoro-2-iodobenzene 0.11 g were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 0.90 mg, tert-butyl 2-amino-4-phenylbenzoate 54 mg, cesium carbonate 0.13 g and toluene 1.0 mL at room temperature, and it was heated and refluxed for 9 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent];hexane:ethyl acetate=200:1] to give tert-butyl 2-(2-fluoroanilino)-4-phenylbenzoate 42 mg of a white solid.
Reaction SMILES: Cl.NO.C([O-])(=O)C.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2=[O:20])=[CH:13][CH:12]=1.COC1C=C2C(CCC2=[N:32]O)=CC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CS(ON=C1C2C(=CC=C(OC)C=2)CC1)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl.O.CO>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][NH:32][C:17]2=[O:20])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(=NO)CC2
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: COc1ccc2c(c1)C(=NOS(C)(=O)=O)CC2
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Under argon, hydroxylamine hydrochloride (514 mg, 7.40 mmol) and sodium acetate (607 mg, 7.4 mmol) were initially charged in abs. methanol (15 ml), and after 5 minutes of stirring at room temperature, a solution of 6-methoxy-1-indanone (1000 mg, 6.17 mmol) in abs. methanol (10 ml) was added. The resulting reaction mixture was stirred at room temperature for 3 h. After removal of the solvent under reduced pressure, the residue was taken up in dichloromethane, and water was added. The aqueous phase was extracted repeatedly with dichloromethane and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Without further purification, the resulting 6-methoxyindan-1-one oxime (1000 mg, 5.64 mmol) was dissolved in dichloromethane (15 ml), triethylamine (1.02 ml, 7.34 mmol) was added and the mixture was stirred under argon at room temperature for 20 min. After cooling to 0° C., methanesulphonyl chloride (840 mg, 7.34 mmol) was added. The reaction mixture obtained in this manner was stirred at room temperature for 4 h, and water was then added. After repeat extraction of the aqueous phase with dichloromethane, the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Without any further purification, the 6-methoxyindan-1-one methanesulphonyloxime (1000 mg, 3.92 mmol) that remained was dissolved in dichloroethane (3 ml) under argon, and boron trifluoride etherate complex (0.50 ml, 3.95 mmol), methanesulphonyl chloride (0.50 ml, 6.46 mmol) and titanium tetrachloride (0.50 ml, 4.56 mmol) were added, in each case dropwise. Under argon, the resulting reaction solution was stirred at room temperature for 6 h and then cooled to 0° C., and water and saturated sodium bicarbonate solution were added carefully. After repeated thorough extraction of the aqueous phase with dichloromethane, the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (380 mg, 55% of theory) in the form of a colourless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.59 (d, 1H), 7.12 (d, 1H), 7.00 (dd, 1H), 6.30 (br. s, 1H, NH), 3.83 (s, 3H), 3.54 (m, 2H), 2.93 (m, 2H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: COCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Oxalyl chloride (16.0 g, 70 mmol) was added dropwise to a solution of 12-methoxydodecanoic acid (9.8 g, 77 mmol) in 300 mL of anhydrous toluene. After stirring at room temperature for 16 hours the solvent was removed on a rotary evaporator. The residue was taken up in anhydrous toluene and concentrated to give the title compound (17.4 g) as a yellow liquid. The structure was verified by infrared spectroscopy (1796 cm-1) and NMR.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]2[C:22]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:23]3[C:27](=[C:28]([CH3:32])[C:29]=2[O:30][CH3:31])[CH2:26][O:25][C:24]3=[O:33])(=[O:16])[O:9]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CCOC(C)=O>C1COCC1>[C:1]1([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]2[C:22]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:23]3[C:27](=[C:28]([CH3:32])[C:29]=2[O:30][CH3:31])[CH2:26][O:25][C:24]3=[O:33])(=[O:9])[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(O)Oc1ccccc1)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH (0.1 mL) solution. The mixture was allowed to stir at room temperature for 16 hours. EtOAc was added and the resulting mixture was washed with 1H HCl. The organic layer was concentrated to dryness and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24.8 mg (38%) of the desired product. MS (m/z) 517 [M−H]−, 541 [M+Na]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([NH2:16])[C:12]=1[C:13]([OH:15])=[O:14]>O1CCCC1.Cl>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[NH:16][C:1](=[O:2])[O:15][C:13](=[O:14])[C:12]=12
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(F)c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2c(=O)o1

Procedure:
Phosgene is conducted at 35°-40° C. for 3 hours into a solution of 23 g (0.148 mol) of 6-fluoroanthranilic acid hydrochloride in a mixture of 300 ml of tetrahydrofuran and 150 ml of 4 N hydrochloric acid. After removal of the phosgene, the mixture is diluted with 500 ml of water and the precipitate is filtered off. There is obtained crude 6-fluoroisatoic acid anhydride of melting point 265°-267° C. (decomposition).