Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH2:2].[C:18]([CH2:24][C:25]#[N:26])(=O)[C:19]([CH3:22])([CH3:21])[CH3:20].Cl.CCO>CCO>[NH2:26][C:25]1[N:1]([C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[N:2]=[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccc(CCNC(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CCNC(=O)C(F)(F)F)c2)n1
Temperature: 77.5 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a stirring solution of N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide (0.18 g, 0.73 mmol) in absolute EtOH (5 ml) at RT was added pivaloylacetonitrile (0.11 g, 0.87 mmol) and saturated HCl/EtOH (3 drops from a pipet). The resulting solution was stirred at 75-80° C. overnight, then cooled to RT and concentrated. The residue was dissolved in Et2O and washed with saturated. NaHCO3. The aqueous was extracted with Et2O (1×). The combined organics were washed with brine (1×), dried (MgSO4), filtered, concentrated and purified via flash chromatography to provide N-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenethyl]-2,2,2-trifluoroacetamide as an orange glass (0.18 g, 70% yield). 1H NMR (300 MHz, CDCl3): δ 7.47-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.14-7.12 (m, 1H), 5.51 (s, 1H), 3.67 (q, J=6.6 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 355.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:41]1[CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>ClCCl>[N:41]1([CH2:19][C:18]([CH3:21])([CH3:22])[O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: C1CNC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)C=O)cn2)c1=O
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: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CN3CCC3)cn2)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A pressure flask containing 2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionaldehyde (188 mg, 0.582 mmol) was taken up in dichloromethane (2.5 ml). Sodium triacetoxyborohydride (309 mg, 1.46 mmol) and acetic acid (0.1 ml, 1.75 mmol) were added and the flask was next cooled in an ice bath under nitrogen atmosphere. Azetidine (0.24 ml, 3.49 mmol) was added and the flask was sealed. The flask was placed in an oil bath heated to 50° C. and stirred for 16 hours. The mixture was cooled to ambient and taken up in dichloromethane (50 ml) and a saturated solution of aqueous sodium bicarbonate (50 ml). The material was transferred to a separatory funnel and shaken. The organic phase was collected and washed with a solution of 50% diluted brine (50 ml). The dichloromethane phase was collected and the aqueous phases were back extracted with methylene chloride (2×40 ml). The combined organic phase was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was loaded onto two preparatory TLC plates and eluted with 8% methanol/dichloromethane. The product band was collected to provide the desired product as a light white-brown powder (139 mg). (M+H)+=364 m/e.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:27][C:26]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([F:23])[CH:25]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 54.6 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 25 mg, 0.08 mmol), tetrabutylammonium iodide (30 mg, 0.08 mmol) and 3-fluoro-5-trifluoromethyl-benzyl bromide (75 mg, 0.29 mmol) in dimethylformamide (1 mL) was heated at 100° C. overnight. The reaction mixture was diluted with dichloromethane (50 mL) and the solution was washed with water/brine (1:1; 20 mL), water (2×20 mL), sodium thiosulfate (20 mL) and brine (20 mL). The solution was dried (magnesium sulfate), filtered, concentrated and purified by chromatography, eluting with 50% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(3-fluoro-5-trifluoromethyl-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (21 mg, 53%) as an off-white solid. APCI(+)-MS (M+H) 481.
Reaction SMILES: [CH:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(O)[CH:7](C(=O)C2C=CC=CC=2)[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCC(C)N1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
When proceeding as described in Example 2, but replacing 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine (used as starting material in said example) by 1-secondary butyl-3-benzoyl-4-phenyl-4-hydroxypiperidine and reacting 25 g. thereof with benzene in the presence of aluminum chloride, 17 g. of the crude base 1-secondary butyl-4,4-diphenylpiperidine are obtained. The crude base is not purified by distillation in a high vacuum but by adding ether saturated with hydrogen chloride to its solution in acetic acid ethyl ester. Thereby, the crystalline hydrochloride is precipitated. It melts at 242° to 245° C. (with decomposition) after recrystallization from acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (20.64 g) and ethyl 2-chloroisonicotinate (19.06 g) were suspended in a mixed solvent of toluene (200 mL) and THF (100 mL), and to the suspension 2 M sodium carbonate (200 mL) and tetrakis(triphenylphosphine)palladium(0) (5.93 g) were added. The mixture was stirred overnight at 90° C. under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
In a 100 ml round bottom flask was added 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.122 g, 0.391 mmol) from Example XXIV, step (1a), 4-amino-N-methylbenzenesulfonamide (0.080 g, 0.430 mmol), and THF (3.9 ml, 0.1 M). Potassium tert-butoxide (0.976 mL, 0.976 mmol) was added drop-wise and the reaction was stirred at 25° C. overnight. The mixture was concentrated and diluted with ethyl acetate and water. The layers were separated and the organic was washed water (20 ml), then brine (10 ml), dried over Na2SO4, filtered and concentrated to provide 4-(3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulfonamide (0.090 g, 55.3% yield) as a brownish solid. m/z=(417, M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]=[C:17]2[N:21]3[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][C@H:20]3[CH2:19][S:18]2)[S:14][CH:15]=1)=[O:6].[ClH:30].C(OCC)C>C(O)C>[ClH:30].[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]=[C:17]2[N:21]3[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][C@H:20]3[CH2:19][S:18]2)[S:14][CH:15]=1)([OH:6])=[O:4]
Reactant: COC(=O)CCCCc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)CCCCc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Temperature: 20 °C

Procedure:
5 N Aqueous sodium hydroxide (20 cc) is added to a solution of (S)-3-{[4-(4-methoxycarbonylbutyl)-thiazol-2-yl]imino}-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (7.4 g) in ethanol (60 cc). The mixture is heated under reflux for 2 hours. After cooling to 20° C., it is acidified by adding 12 N hydrochloric acid (d=1.19; 10 cc). Diethyl ether (30 cc) is added and the mixture is cooled to 0° C. The resulting precipitate is filtered off, washed with water (4×15 cc), ethanol (2×10 cc) and diethyl ether (2×30 cc) and crystallised by dissolving it in boiling propan-2-ol (200 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with propan-2-ol (20 cc) and diethyl ether (50 cc) and dried at 45° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-{[4-(4-carboxybutyl)thiazol-2-yl]imino}-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline hydrochloride (4.9 g), m.p.=214° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH2:22][O:23][C:24]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])([CH2:7][O:8][C:9]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1.O>[CH:59]1[C:60]2[CH:48]([CH2:47][O:46][C:44]([NH:1][CH2:2][C:3]([CH2:7][O:8][C:9]([C:10]([F:13])([F:12])[F:11])([C:14]([F:17])([F:16])[F:15])[C:18]([F:19])([F:21])[F:20])([CH2:22][O:23][C:24]([C:29]([F:30])([F:31])[F:32])([C:25]([F:26])([F:27])[F:28])[C:33]([F:34])([F:35])[F:36])[C:4]([OH:6])=[O:5])=[O:45])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:55]=2[CH:56]=[CH:57][CH:58]=1
Reactant: NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a stirred solution of amino acid 1 (10.1 g, 17.2 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium carbonate (4.6 g, 42.9 mmol). After all the sodium carbonate was dissolved, the resulting mixture was cooled to 0° C. and 9-fluorenylmethyl chloroformate (6.7 g, 25.9 mol) was added in three portions. The resulted reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=5/1) to give the acid 2 as a white solid (13.3 g, 96%). mp. 104-105° C.; 1H NMR (400 MHz, CD3OD) δ 3.45 (s, 2H), 4.16 (m), 4.27 (m, 4H), 4.46 (d, J=8.8 Hz, 2H) 7.26 (t, J=7.2 Hz, 2H), 7.35 (t, J=7.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.74 (d, J=7.2 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.00 (s); 13C NMR (100.7 MHz, CD3OD) δ 36.9, 42.8, 53.7, 68.2, 69.0, 80.9 (m), 120.9, 121.7 (q, J=292.6 Hz), 126.2, 128.1, 128.8, 142.6, 145.2, 158.8, 174.4; MS (CI) m/z 808 (M++1, 100); HRMS (CI) Calcd for C28H20F18NO6: 808.1003, Found: 808.1010.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30]>>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of 1-methylpiperazine (7 ml) and 7-(2-bromoethoxy)-6-methoxy4-phenoxyquinazoline (1.0 g, 2.67 mmol), (prepared as described for the starting material in Example 22), was stirred at ambient temperature for 5 hours. The excess 1-methylpiperazine was removed by evaporation and the residue was partitioned between aqueous sodium hydrogen carbonate and methylene chloride. The organic phase was separated, passed through phase separating paper and the volatiles removed by evaporation to give 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-phenoxyquinazoline (970 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=O)[CH:3]=1.O.[NH2:13][NH2:14]>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:13][NH2:14])=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)on1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)NN)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of ethyl 5-methylisoxazole-3-carboxylate (3.0 g, 19 mmol) in methanol (30 ml) at 0° C. under nitrogen was added hydrazine hydrate (3.04 g, 95 mmol) over 0.3 h. The reaction was stirred at 0° C. for 0.25 h and at RT for 1 h. The white precipitate was filtered off and washed with methanol to give the title-compound (0.78 g, 29%) as a white solid, 1H NMR (250 MHz, CDCl3) δ 2.41 (3H, d, J=0.8 Hz, CH3), 4.07 (2H, br s, NH2), 6.44 (1H, q, J=0.8 Hz, Ar—H), 7.99 (1H, br s, N—H); MS (ES+) m/e 142 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]([CH3:15])[CH3:14])=[C:7]([NH2:16])[CH:6]=1)[CH3:2]>CN(C=O)C.[Cu]I>[CH:13]([C:12]1[NH:16][C:7]2[C:8]([CH:11]=1)=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:6]=2)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(C#CC(C)C)c(N)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(C)C)[nH]c2c1
Temperature: 160 °C

Procedure:
To a solution of ethyl3-amino-4-(3-methylbut-1-ynyl)benzoate (Compound 32, 5.30 g, 22.9 mmol) in DMF (50 ml) at 25° C. under argon then added CuI (218 mg, 11.5 mmol). The reaction was heated for 2 h at 160° C., filtered off black solid, and then rinsed solid with EtOAc, organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-]>CO.[Pd]>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[N:7][CH:8]=1
Reactant: CC(N=[N+]=[N-])c1ccc(F)cn1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1ccc(F)cn1
Yield: 98.6 %

Procedure:
2-(1-Azidoethyl)-5-fluoropyridine (Method 3; 7.7 g, 46.3 mmol) and Pd (10 wt. %, dry basis, on activated carbon, 2.47 g, 2.32 mmol) in methanol (20 ml) was placed under H2 for 4 hours. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated to give the title compound as pale yellow oil (6.40 g, 99%). 1H NMR (400 MHz) 8.45 (d, J=2.8 Hz, 1H), 7.67 (ddd, J=2.8, 2.8 and 2.8 Hz, 1H), 7.54 (m, 1H), 4.01 (q, J=6.8 Hz, 1H), 1.97 (b, 2H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35].Cl>CS(C)=O.O>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])=[O:35]
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1ccco1)C1C(=O)N(C(=O)Nc2ccc(F)cc2F)c2ccccc21
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 682 mg (3.0 mmole) of 3-(2-furoyl)-2-oxindole in 8 ml of dimethyl sulfoxide was added 668 mg (6.6 mmole) of triethylamine followed by 512 mg (3.3 mmole) of 2,4-difluorophenyl isocyanate. Stirring was continued for 1 hour, and then the reaction mixture was poured into 60 ml of water. The resulting mixture was acidified with 3N hydrochloric acid and then it was cooled in an ice-bath. The solid was removed by filtration and recrystallized from ca. 35 ml of acetic acid, to give 925 mg of the title compound as yellow crystals, mp 191°-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)[CH:10]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Product: O=C(Nc1cc(F)ccc1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-amino-4-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.0 (M−H−, 100%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[F:27][C:28]1[C:33]([CH2:34]O)=[C:32]([F:36])[C:31]([F:37])=[C:30]([F:38])[C:29]=1[F:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH2:34][C:33]1[C:32]([F:36])=[C:31]([F:37])[C:30]([F:38])=[C:29]([F:39])[C:28]=1[F:27])=[O:24]
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(F)c(F)c2F)C1(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 4.12 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride was added at 0° C. to a mixture of 3 g of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid, 30 ml of methylene chloride, 3.96 g of pentafluorobenzyl alcohol and 100 mg of 4-dimethylaminopyridine and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 hexane-ethyl acetate mixture yielded 4.78 g of pentafluorobenzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-23° (c=0.5% in chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH3:7])=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: CC(N)c1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(NCc1cccnc1)c1ccc(Br)cc1

Procedure:
A solution of 4-bromo-α-methylbenzylamine (1.5 g, 7.7 mmol), 3-pyridinecarboxaldehyde (0.8 g, 7.5 mmol), and sodium triacetoxyborohydride (2.25 g, 10.5 mmol) in 60 ml of 1,2-dichloroethane was stirred at room temperature for 18 h. The solution was diluted with dichloromethane and washed twice with a saturated sodium bicarbonate solution, once with water, and once with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 8.70 (m,2H), 7.85 (m,1H), 7.67 (d,2H,J=8 Hz), 7.45 (d,2H,J=8 Hz), 7.43 (m,1H), 3.95 (q,1H,J=8 Hz), 3.83 (q,ABX,2H), 1.57 (d,3H,J=8 Hz). MS calcd. 291.2; MS (M+1) 292.1.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C:10]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(CC)CC)C>ClCCl>[C:45]([O:43][CH2:42][C@:11]12[O:24][C@:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)([O:13][CH2:12]1)[C@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]2=[O:44])(=[O:47])[CH3:46]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of (1S,3R,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-one 28g (13.4 g, 21.8 mmol) in dichloromethane (40 mL) were added acetic anhydride (3.0 mL, 32.7 mmol) and triethylamine (6.0 mL, 43.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with water (100 mL). The resulting mixture was extracted with dichloromethane (100 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 28h as a pale yellow solid (12.1 g, 84.6%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.29 (m, 4H), 7.24 (m, 3H), 7.19 (s, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 6.99 (d, 2H), 6.76 (m, 2H), 6.68 (d, 2H), 4.94 (d, 1H), 4.58 (d, 1H), 4.47 (d, 1H), 4.37 (d, 1H), 4.31 (m, 2H), 4.07 (d, 1H), 3.95 (m, 3H), 3.88 (m, 5H), 1.97 (s, 3H), 1.31 (t, 3H).