Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:28][CH:29]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoate (325 mg, 0.803 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (0.62 mL, 8.0 mmol). The solution was stirred at room temperature for 17 hours then concentrated under reduced pressure. Toluene (3 mL) was added, and the solution was again concentrated under reduced pressure to remove excess trifluoroacetic acid to give (+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1 H), 8.06 (d, J=8.4 Hz, 2 H), 7.84 (d, J=7.8 Hz, 1 H), 7.80-7.75 (m, 1 H), 7.75-7.69 (m, 1 H), 7.58 (d, J=8.4 Hz, 2 H), 7.55-7.48 (m, 1 H), 5.50 (dd, J=5.0, 9.5 Hz, 1 H), 2.56 (s, 3 H), 2.24-2.14 (m, 1 H), 1.92-1.75 (m, 2 H), 1.08 (d, J=6.4 Hz, 3 H), 1.05 (d, J=6.2 Hz, 3 H).
Reaction SMILES: C(O[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C1C=CC=CC=1.[CH3:28][N:29](CC1C=CC(C(OCC)=O)=CN=1)[CH3:30].Cl.C(OCC)(=O)C=C>O=[Pt]=O>[CH3:28][N:29]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:30]
Reactant: CCOC(=O)CCN1CC(C(=O)OCC)CCC1COCc1ccccc1
Reactant: CCOC(=O)c1ccc(CN(C)C)nc1
Agent: O=[Pt]=O
Agent: C=CC(=O)OCC
Agent: Cl
Product: CCOC(=O)CCN1CC(C(=O)OCC)CCC1CN(C)C
Yield: 51 %

Procedure:
Using the same procedure employed for the preparation of 15c and using 14e (335 mg, 1.6 mmol), 2 M ethereal HCl (6 mL), PtO2 (24 mg), and ethyl acrylate (1.7 mL, 16 mmol) gave 15e (259 mg, 51%) and 17 (52 mg, 12%) following PTLC purification (10% MeOH—CHCl3). Compound 15e: reddish yellow oil; Rf 0.37 (10% MeOH—CHCl3); IR (neat) 2945, 2818, 1731, 1457, 1376, 1182 cm−1; 1H NMR (CDCl3) δ 1.18 (t, J=7.2 Hz, 3H, CH2CH3), 1.19 (t, J=7.2 Hz, 3H, CH2CH3), 1.56-1.70 (m, 4H, C(3)H2, C(4)H2), 2.15 (s, 6H, N(CH3)2), 2.26-2.48 (m, 5H, C(5)H, NCH2CH2, (CH3)2NCH2), 2.69-2.91 (m, 5H, C(2)H, C(6)H2, NCH2CH2), 4.05 (q, J=7.2 Hz, 2H, CH2CH3), 4.07 (q, J=7.2 Hz, 2H, CH2CH3), the 1H NMR assignments were consistent with the COSY spectrum; 13C NMR (CDCl3) 14.0 (CH2CH3), 14.1 (CH2CH3), 22.8 (C(3)), 25.5 (C(4)), 33.5 (NCH2CH2), 40.1 (C(5)), 46.0 (N(CH3)2), 49.3 (C(6)), 49.7 (NCH2CH2), 55.4 (C(2)), 57.7 ((CH3)2NCH2), 60.1 (2C, CH2CH3), 172.6 (C(O)), 174.2 (C(O)) ppm, the assignments were consistent with the DEPT and HMQC spectra; MS (+CI) 315 [M+1]+; Mr (+CI) 315.229 49 [M+1]+ (calcd for C16H31N2O4 315.228 38). Compound 17 (cis- and trans-mixture): Rf 0.75 (10% MeOH—CHCl3); 1H NMR (CDCl3) δ 1.00 (d, J=6.6 Hz, 2H), 1.10 (d, J=6.6 Hz, 1H), 1.21-1.28 (m, 6H), 1.44-2.00 (m, 4H), 2.21-2.30 (m, 1H), 2.42-2.59 (m, 4H), 2.67-2.88 (m, 3H), 4.08-4.17 (m, 4H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1.[NH3:40]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:40][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3c(F)ccc(F)c3F)c3ncc(F)cc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4c(F)ccc(F)c4F)c4ncc(F)cc34)nnc21
Reaction time: 8 h
Yield: 70 %

Procedure:
15 ml of phosphoryl chloride were added to 1.50 g (3.149 mmol) of the compound from Example 82A, and the mixture was stirred overnight. The reaction mixture was then taken up in 222 ml of acetonitrile and, with ice cooling, stirred into 133 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. Ethanol and water were added to the residue. A precipitate formed, which was filtered off and then washed with diethyl ether. Drying under high vacuum gave 982 mg of the title compound (70% of theory).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])=[O:2].C(C=C)=O.COC(=O)C(Br)C(OC)=O.CO>C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:6]([O:8][CH3:9])=[O:7])[C:11]([O:13][CH3:14])=[O:12])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1C=O
Agent: C=CC=O
Agent: COC(=O)C(Br)C(=O)OC
Solvent: CO
Solvent: CCO
Product: COC(=O)C1(C(=O)OC)CC1C=O

Procedure:
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using equivalent amounts of dimethylbromomalonate and methanol instead of diethylbromomalonate and ethanol, respectively, the title compound, nmr (CDCl3) δ 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d, J = 4 cps, 1H), is obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH3:29][C:30]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH2:32].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:30]1([CH3:29])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH:32][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.4 %

Procedure:
After adding sodium triacetoxyborohydride (7.98 g, 37.6 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol), 2,4,6-trimethylaniline (3.56 g, 26.3 mmol) and acetic acid (2.9 mL, 50.2 mmol) in methylene chloride (50 mL), the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogencarbonate (150 mL) was added to the reaction mixture, which was then stirred until bubbling settled. The organic layer was separated and the aqueous layer was extracted with chloroform (100 mL). The organic layers were combined, washed with saturated brine (100 mL) and dried (Na2SO4), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g Merck Art. 9385, hexane:ethyl acetate=9: 1) to obtain the title compound as a brown oil (5.71 g) (71% yield).
Reaction SMILES: FC1C=C2C(C(C3C=NN(CC4CCNCC4)C=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1.[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:41]=1[F:42])[N:38]([S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH:37]=[C:36]2[C:52]1[CH:53]=[N:54][N:55]([CH2:57][CH:58]2[CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]2)[CH:56]=1>>[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:41]=1[F:42])[N:38]([S:43]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)(=[O:44])=[O:45])[CH:37]=[C:36]2[C:52]1[CH:53]=[N:54][N:55]([CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)c(F)cc34)cn2)CC1
Agent: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2cc(F)c(F)cc21
Yield: 308.2 %

Procedure:
Following the general method as outlined in Intermediate 21, starting from tert-butyl 4-((4-(5,6-difluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (Intermediate 45; 330 mg; 0.59 mmol), 830 mg (>100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15].[CH2:16]([N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH2:17][C:18]#[CH:19]>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[I:15][C:10]1[CH:11]=[CH:12][C:13]([C:19]#[C:18][CH2:17][CH2:16][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[CH:14][CH:9]=1
Reactant: Ic1ccccc1I
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution containing triethylamine (250 mL), copper (I) iodide (1.72 g, 9.09 mmol) and diiodobenzene (56) (20.00 g, 60.60 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was stirred at room temperature. The reaction flask was evacuated and then purged with nitrogen three times. The solution was treated with bis(triphenylphosphine) palladium(II) dichloride (4.20 g, 6.06 mmol) and continued to stir at room temperature for 30 min. A solution containing triethylamine (250 mL) and 2-but-3-ynylisoindole-1,3-dione (12.06 g, 60.06 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was added dropwise through an addition funnel over 12 hours. The reaction was allowed to stir at room temperature for 48 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 57 (12.5 g, 51%) as a brown solid: 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.60 (d, 2H), 7.04 (d, 2H), 3.92 (t, 2H), 2.79 (t, 2H); m/z (ESI) 402 [C18H12INO2+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:24])[C:13]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:39]([C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[OH:40])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:24])[C:13]1=[O:25])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Cl)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (383 mg, 1 mmol) in THF (4 mL) at −78° C. was added LDA (1.8N in THF, 2.7 mL, 4.86 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then 4-chlorobenzaldehyde (280 mg, 2 mmol) in THF (1 mL) was added dropwise. After stirring for 20 min the reaction was quenched with aq. NH4Cl (2 mL) then diluted with EA (5 mL) and water (2 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-((4-chlorophenyl)(hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (155 mg, 30% yield) as a white solid. LCMS: (M+-OH—H) 506 and TR=2.357 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=1.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:27]2[CH:32]=[N:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(O)cc1F)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of benzyl (2-fluoro-4-hydroxyphenyl)carbamate (79 g, 303 mmol) in dimethyl sulfoxide (480 mL) were added cesium carbonate (123 g, 378 mmol) and 5-chloro-2-nitropyridine (40 g, 252 mmol), and the mixture was stirred at room temperature for 6 hr. Water (1000 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=3/1) and collected by filtration to give the title compound (74 g, 77%).
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[CH:8]1[CH:17]=[C:16]2[C:18]([O:20][C:21](=O)[C:14]3=[C:15]2[C:10](=[C:11]([Br:23])[CH:12]=[CH:13]3)[CH:9]=1)=[O:19]>N1C=CC=CC=1>[Br:23][C:11]1[CH:12]=[CH:13][C:14]2[C:21](=[O:20])[N:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:18](=[O:19])[C:16]3[C:15]=2[C:10]=1[CH:9]=[CH:8][CH:17]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Yield: 94.1 %

Procedure:
O-tert-Butylhydroxylamine hydrochloride (3.0 g, 23.9 mmol) was added to 4-bromo-1,8-naphthalic anhydride (5.0 g, 18.0 mmol) in pyridine (30.0 mL). The mixture was refluxed for 4 hours, concentrated, and the residue suspended in water. The solid was filtered and dried to give 5.9 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:15]([O:18][C@@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:17])[CH3:16]>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([O:18][C@@H:19]([CH3:23])[C:20]([NH:14][NH:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]=[C:2]([Br:1])[C:6]=2[CH:7]=1)=[O:12])=[O:21])(=[O:17])[CH3:16]
Reactant: NNC(=O)c1ccc2occ(Br)c2c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](C)C(=O)NNC(=O)c1ccc2occ(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 3-bromo-1-benzofuran-5-carbohydrazide (2.64 g, 10.35 mmol) in N,N-dimethylacetamide (10 mL) was added dropwise (1S)-2-chloro-1-methyl-2-oxoethyl acetate (1.44 mL, 11.38 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (3.41 g, yield 89%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Reactant: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 4-chloro-6-[(1E)-3 ,3 -diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluoro-N-methoxy-N-methylbiphenyl-2-carboxamide (2.7 g, 6.6 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with 3 M of methylmagnesium chloride in tetrahydrofuran (6.6 mL, 20 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture still contained some starting material and was, therefore, cooled to 0° C., treated with additional 3 M of methylmagnesium chloride in tetrahydrofuran (2.2 mL, 6.6 mmol) dropwise, and stirred at 20° C. for 2 hours. The reaction mixture was cooled to 0° C., quenched with 1 M hydrogen chloride in water (26 mL, 26 mmol), poured into 0.1 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 20%) gave the desired product (2.3 g, 93%). LCMS for C20H20ClFN3O (M+H)+: m/z=372.1; Found: 371.9.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])(=[O:31])=[O:30])[CH2:8]1)=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Reaction time: 14 h
Yield: 86.4 %

Procedure:
To a solution of 3.87 g piperidine-3-carboxylic acid ethyl ester hydrochloride (commercially available) (20 mmol) in 40 mL DCM was added 10 mL of DIPEA (60 mmol). At room temperature 2.72 mL 2-chloro-benzenesulfonyl chloride (20 mmol) was added drop wise and stirred for 14 h. The mixture was diluted with 30 mL of DCM, washed with water (3×50 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography on silica eluting with 10% ethyl acetate in hexane to yield 5.73 g (86.3%) of the title compound. (MH+) 332.16.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[O:31][C:41](=[O:42])[NH:33][N:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2ccccc2[C@H]1c1cc(Cl)ccc1OCc1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-hydrazinocarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (137 mg, 0.29 mmol, 1.0 eq.) and NEt3 (82 μL, 0.59 mmol, 2.0 eq.) in THF (3 mL), 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The solvent was removed in vacuo. The residue, redissolved in DMF (2.4 mL), was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as a white foam.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[CH3:30])=[O:12])[C:7]=1[C:8](O)=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OC)(C)(C)C>[I:1][C:2]1[C:7]2[C:8](=[O:9])[O:12][C:11](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:26])([F:27])[F:28])[C:21]([F:23])([F:24])[F:22])=[CH:16][C:15]=3[CH3:30])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COC(C)(C)C
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N=C1OC(=O)c2c(I)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
In methyl t-butyl ether (60 ml) was suspended 5.47 g (10 mmol) of 6-iodo-N-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamic acid, and a solution of 3.15 g (15 mmol) of trifluoroacetic anhydride in methyl t-butyl ether was slowly dropped thereinto. The resulting mixture was stirred at room temperature for 3 hours and then poured into ice water, followed by three runs of extraction with ethyl acetate. The extract solution was washed twice with saturated aqueous sodium hydrogencarbonate solution and then once with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 5.0 g (yield 94%) of 1,3-dihydro-7-iodo-3-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoro-methyl)ethyl]phenylimino}-2-benzofuran-1-one.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].Cl[C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[C:23]([CH3:30])[CH:22]=3)[O:18][C:16]=2[N:17]=1>CC(N(C)C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:30])[C:24]([O:28][CH3:29])=[C:25]([CH3:27])[CH:26]=3)[O:18][C:16]=2[N:17]=1
Reactant: Oc1ccccc1F
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)nc3o2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1c(C)cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
149 mg of sodium hydride were added under an argon atmosphere to a solution of 418 mg of 2-fluoro-phenol in 15 ml dimethylacetamide. After stirring for 30 min at room temperature a solution of 900 mg of 5-chloro-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine in 20 ml dimethylacetamide was added slowly. The mixture was allowed to stir for 1.5 h at room temperature. Upon consumption of the starting oxazolo[5,4-d]pyrimidine an aqueous solution of citric acid (100 g/l) was added until the pH was neutral. The aqueous layer was extracted twice with 15 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were removed in vacuo. The title compound was isolated by silica gel chromatography (heptane/ethyl acetate gradient) as a white solid. Yield: 820 mg.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:30]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (250 mg, 1.03 mmol) was dissolved in acetonitrile (0.10 ml), and cooled to 0° C. Triethylamine (244 μl, 1.75 mmol) and cyclobutanecarbonyl chloride (177 μl, 1.55 mmol) were dropwise added to the solution, followed by stirring at room temperature for 1 hour. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under, reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate/hexane (1:4, v/v) gave the entitled compound (283 mg, 85%) as a white solid.