Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8]O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1c(F)c(F)c(CBr)c(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of phosphorus tribromide (2.1 g) and toluene (1 cm3) was added dropwise to a solution of 2,3,4,5,6-pentafluorobenzylalcohol (3.4 g) and pyridine (0.21 g) in toluene (10 cm3) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, then at the ambient temperature (ca. 20° C.) for 75 minutes, and was then added to an excess of saturated sodium bicarbonate solution. The products were extracted into diethyl ether, and the combined ether layers dried and concentrated by evaporation under reduced pressure. The residual solution (still containing toluene) was passed through a plug of silica gel.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C[O-].[Na+]>CO>[NH2:24][C:23]1[N:25]=[C:11]2[CH2:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13][CH:12]2[C:15](=[O:17])[N:22]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A suspension of ethyl N-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride (2.98 g, 10 mmol) and guanidine hydrochloride (1.15 g, 12 mmol) in a solution of sodium methoxide in methanol (11.5 mL, 25% wt) was stirred at 100° C. in a sealed tube overnight before solvent was removed in vacuo. Residue was dissolved in water (10 mL) and was extracted by CHCl3 and i-PrOH (3:1, 5×80 mL), dried over sodium sulfate. Solvent was removed in vacuo, and the product was obtained as a light yellow powder (2.45 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To s solution of PPh3 (2.6 g, 10.0 mmol) in dry DCM (60 mL) was added I2 (2.6 g, 10.0 mmol). After I2 was dissolved completely, TEA (3.5 mL, 25.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-4-oxobutylcarbamate (2.4 g, 5.0 mmol) was added. The mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (250 mL) was added, and the solution was filtrated to remove POPh3. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (gradient elution 0˜40% EtOAc/petroleum ether) to afford tert-butyl 3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)propylcarbamate (2.0 g, 86%) as a white solid. ESI-MS (EI+, m/z): 458 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9].I[CH2:21][CH2:22][OH:23].C(OCC)(=O)C.C(OC(=O)C)C.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][N:15]([CH2:21][CH2:22][OH:23])[CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: OCCI
Reactant: Clc1ccc(OC2CNCc3occc32)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4-(3,4-Dichlorophenyloxy)-4,5,6,7-tetrahydrofuro-[2,3-c]pyridine hydrochloride (Example 119) (50 mg) was dissolved in 5 mL of dehydrated ethanol and then 220 mg of 2-iodoethanol was dropped thereinto. The reaction solution was heated with stirring at 80° C. overnight and concentrated in vacuo to evaporate the solvent and excess 2-iodoethanol. The residue was purified by silica gel column chromatography and the resulting free substance of the objective compound was dissolved in 5 mL of ethyl acetate. Into this ethyl acetate solution was dropped a solution of one equivalent of hydrochloric acid ethyl acetate and the resulting mixed solution was concentrated to give 18 mg of the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-])=O)[CH3:2].Cl.[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[NH2:14])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1ccc(OC)cc1N
Yield: 79.3 %

Procedure:
A solution of (4-methoxy-2-nitrophenyl)carbamic acid ethyl ester (7.3 g; 0.03 mol) in 95% EtOH (500 ml), was hydrogenated at room temperature and pressure in the presence of 10% aqueous HCl (13 ml) and 10% Pd/C (0.35 g). When the theoretical amount of hydrogen was taken up, the catalyst was filtered off and the solution was evaporated to dryness to give the title compound (5 g) after crystallization from Et2O/EtOH (85:15). The compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7][OH:8].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>O1CCOCC1>[CH3:36][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34](=[O:35])[O:8][CH2:7][C:6]2[N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=3[Cl:22])[C:4]([CH3:23])=[N:3][C:2]=2[Cl:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CO)c(Cl)c1
Solvent: C1COCCO1
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2COC(=O)NS(=O)(=O)c2ccc(C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (150 mg) was dissolved in 1,4-dioxane (1.5 ml) and p-toluenesulfonyl isocyanate (99 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. To the residue was added ethanol (5 ml) and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate (2 ml), and hexane (13 ml) was added on an oil bath at 70° C. The mixture was allowed to cool and the precipitated crystals were collected by filtration. The crystals were dried by heating under reduced pressure to give (4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazol-5-yl)methyl N-(4-methylbenzenesulfonyl)carbamate (176 mg) as colorless crystals.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][CH:15]([NH2:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:24]([CH:15]([CH3:14])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: CC(N)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CCc1ccccc1)N1Cc2cccc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 1-methyl 3-phenyl-propylamine (0.065 g, 0.4 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(1-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.098 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.94 (m, 2H), 2.54-2.78 (m, 2H), 4.21 (dd, 2H), 4.64 (q, 1H), 7.12-7.24 (m, 6H), 7.41 (d, 1H), 7.88 (d, 1H). GC-MS: m/z 391 (M)+.
Reaction SMILES: C(OC([NH:11][C@:12]1([C:34]([O:36][CH3:37])=[O:35])[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[CH:19][CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:11][C@:12]1([C:34]([O:36][CH3:37])=[O:35])[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[CH:21][CH:22]=2)[CH2:13]1
Reactant: COC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC[C@@H](c2ccc(CCOc3cccc(OC)c3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(CCOc3cccc(OC)c3)cc2)C1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-(2-(3-methoxyphenoxy)ethyl)phenyl)cyclopentanecarboxylate (0.266 g, 0.528 mmol) in EtOH (2.0 ml) was added to a slurry of Pearlman's Catalyst (0.019 g, 0.026 mmol) in EtOH (5.28 ml). Hydrogen gas was then bubbled through the reaction mixture for 2-3 minutes. The resulting mixture was stirred under the atmosphere of hydrogen overnight. The crude mixture was filtered through Celite® and the filtrate was concentrated in vacuo to yield (1R,3R)-methyl 1-amino-3-(4-(2-(3-methoxyphenoxy)ethyl) phenyl)cyclopentanecarboxylate (157 mg, 0.425 mmol) as colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[ClH:33]>CO>[ClH:33].[ClH:33].[ClH:33].[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5scnc5c4)ncnc3[nH]2)CC1
Agent: Cl
Solvent: CO
Product: C1=C(c2cc3c(Nc4ccc5scnc5c4)ncnc3[nH]2)CCNC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-[4-(benzothiazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (28.3 mg, 0.063 mmol) in MeOH (3 mL) was added 4 N HCl (aq) (3 mL). The mixture was stirred at 60° C. for 8 h. Solvents were removed under reduced pressure to afford the title compound as yellow solid, which was used directly in the next step without purification. 1H-NMR (DMSO-d6, 400 MHz): δ=2.70 (m, 2H), 3.83 (m, 2H), 6.45 (s, 1H), 6.99 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.36 (s, 1H), 8.68 (s, 1H), 9.07 (s, 1H), 9.44 (s, 1H), 10.32 (s, br, 1H), 12.51 (s, 1H). MS (ES+): m/z 349.06 [MH+]. HPLC: tR=1.73 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1C
Temperature: 25 °C
Yield: 20.7 %

Procedure:
Intermediate 11 (3.0 g, 9.83 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.00 g, 30.76 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless liquid (0.700 g, 20% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.73 (d, J=2.5 Hz, 1H), 7.63 (dd, J=8.7, 2.5 Hz, 1H), 7.34 (t, J=4.8 Hz, 1H), 7.22-7.14 (m, 4H), 2.63 (q, J=7.5 Hz, 2H), 0.94 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>[Ni].[Pt]=O.CO>[CH2:15]([C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Agent: O=[Pt]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCCCCc1cccc(O)c1
Reaction time: 3 h

Procedure:
100 g of cardanol in solvents (100 cm3) such as ethyl acetate, methanol and the like was hydrogenated in a parr hydrogenator at 30-60 psi pressure by using catalysts (50 mg) such as palladised carbon, platinum oxide, raney nickel and the like. at 30-100° C. The hydrogenation was carried out for 2-4 hrs. The solution was filtered to remove the catalyst and methanol stripped off. The crude 3-pentadecyl phenol was distilled under vacuum (4 mm of Hg). The fraction which distilled at 200° C. to 210° C. was collected. The white solid obtained was recrystallised from hexane twice to obtain pure 3-pentadecyl phenol.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[B:28]1[O:32]C(C)(C)[C:30](C)(C)[O:29]1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)[N:8]=1)=O.[BH4-].[Na+].Cl>CO>[OH:32][B:28]1[C:27]2[CH:26]=[CH:25][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([O:15][CH2:16][CH2:17][OH:18])[N:8]=3)=[CH:4][C:3]=2[CH2:30][O:29]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OCCOC4CCCCO4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2.5 g, 5.15 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.38 g, 10.32 mmol). After 1 h at rt, the solution was cooled in an ice bath and 2M HCl was added until pH reached to 3˜4. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 30 min. The solvent was removed under reduced pressure purification was accomplished by reverse phase prep HPLC using CH3CN/H2O (0.1% AcOH) as the eluent to yield the title compound D99 (1.0 g, 40%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.97 (s, 2H), 4.82 (t, 1H), 4.12 (t, J=4.9 Hz, 2H), 3.73-3.50 (m, 2H); MS (ES) m/z: 313 (M+1)+; HPLC purity 98.78% (Maxplot), 98.58% (220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cnc(C#Cc2ccccc2)cn1
Temperature: 60 °C
Yield: 23.5 %

Procedure:
To a solution of 2-bromo-5-iodopyrazine (500 mg, 1.76 mmol), phenylacetylene (224 mg, 241 μL, 2.19 mmol, 1.25 equiv.), triethylamine (533 mg, 734 μL, 5.27 mmol, 3 equiv.), bis(triphenylphosphine)palladium (II) chloride (73.9 mg, 0.105 mmol, 0.06 equiv.) and triphenyl-phosphine (13.8 mg, 0.053 mmol, 0.03 equiv.) in 10 ml of THF was added under an Argon atmosphere copper (I) iodide (10.0 mg, 0.053 mmol, 0.03 equiv.). The suspension was warmed to 60° C. overnight, taken up in 5 ml of ethyl acetate and adsorbed on 4 g of silica. Purification by flash chromatography on silicagel using a 2:1 ethyl acetate/heptane mixture yielded the title compound as a light brown solid (107 mg, 23% yield). The material was directly used in the next step without further characterization.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[NH4+:23]>COCCOC>[NH2:23][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CCc1ccccc1)c1cccc(C(F)(F)F)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 1-(2-fluoro-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.8 g, 16.2 mmol) and ammonium hydroxide (150 ml of 30% solution) in DME (50 ml) was heated to 140° C. in a steel pressure reactor. After 3 hr, the reaction was cooled to 0° C., the steel pressure reactor was opened and the reaction was partitioned between water and EtOAc. The organic layer was dried (MgSO4) and concentrated to give 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one as a yellow oil (4.3 g). MS (ES) m/z 293.9.
Reaction SMILES: [CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([O:14]C1CCCCO1)[CH2:12]2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C(O)=O>CO>[CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:14])[CH2:12]2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC=CC1C2CC(OC3CCCCO3)CC12
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCCCCC=CC1C2CC(O)CC12

Procedure:
A solution of 8.5 g. of 6-(1-heptenyl)-3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane (from Example 12) and 700 mg. of oxalic acid in 350 ml. of methanol is stirred at room temperature (about 25° C.) for 7 days. The solution is then evaporated and the residue extracted with diethyl ether. Evaporation of the ether solution gives a quantitative yield of 6-(1-heptenyl)bicyclo[3.1.0]hexan-3-ol; γ 3375, 3050, 3025, 1625, 1070, 1020, 960, 850 and 725 cm-1.; γ max 197 mmu (heptane), γ 5.2, 4.8 p.p.m. Thin layer chromatographic analysis shows four spots (silica gel, developed with benzene-ether 5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:33]=[CH:32][C:24]([C:25](/[N:27]=[CH:28]/[N:29](C)C)=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:38]N>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:33]=[CH:32][C:24]([C:25]3[NH:38][N:29]=[CH:28][N:27]=3)=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(-c2ccccc2)nc(-c2ccc(-c3ncn[nH]3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of the crude product of Step 1, 2 mL of acetic acid and 0.15 mL of anhydrous hydrazine was stirred at 90° C. for 30 min. The reaction mixture was diluted with MeOH and was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 8.08 (s, 1H), 8.05 (m, 4H), 7.73 (m, 2H), 7.58 (m, 3H), 7.35 (d, 2H), 7.11 (d, 2H), 3.68 (s, 3H), 1.61 (s, 6H). LCMS: m/z 421 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][CH:8]=2)[CH2:3][O:2]1.[NH2:19][C:20]1[C:25]([F:26])=[C:24](Cl)[N:23]=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:21]=1[Cl:32].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:20]1[C:25]([F:26])=[C:24]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][O:2][CH2:3]3)[N:23]=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:21]=1[Cl:32]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)COC3)c(F)c(N)c1Cl
Temperature: 85 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
To the crude 2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (estimated to be 570 mg, 2.3 mmol, 1.1 equiv) was added methyl 4-amino-3,6-dichloro-5-fluoropicolinate (500 mg, 2.1 mmol, 1.0 equiv), dichloro[bis(triphenylphosphino)]-palladium(II) (150 mg, 0.21 mmol, 0.10 equiv), and sodium carbonate (240 mg, 2.3 mmol, 1.1 equiv) followed by a 1:1 mixture of water:acetonitrile (7.0 mL) at 23° C. The resulting dark orange/brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×70 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to yield the title compound as an orange powder (150 mg, 22%): mp 153-156° C.; IR (neat film) 3468 (m), 3334 (s), 3205 (m), 2952 (m), 2856 (m), 1735 (s), 1623 (s), 1579 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81-7.86 (m, 2H), 7.33 (d, J=8 Hz, 1H), 5.16 (br d, J=4 Hz, 1H), 4.89 (br s, 2H), 3.97 (s, 3H); ESIMS m/z 323 [(M+H)+].
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].O=C1C[C:23]2[C:18](=[CH:19][C:20](C(O)=O)=C[CH:22]=2)N1.NC1C=CC=CC=1>>[O:14]=[C:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([NH:2][C:1]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[O:4])[CH:6]=2)[NH:10]1
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Solvent: Nc1ccccc1
Product: O=C1Cc2cc(C(=O)Nc3ccccc3)ccc2N1

Procedure:
The title compound was synthesized according to the method described for N-methyl-2-oxoindoline-5-carboxamide from 2-oxoindoline-6-carboxylic acid (89 mg, 0.500 mmol) and aniline (0.14 mL, 1.50 mmol) to obtain 45 mg, 36%. 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.36 (t, J=7.9 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.34 (s, 2H); MS ESI 253.0 [M+H]+, calcd for [C15H12N2O2+H]+ 253.10.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]=2[S:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25]O>>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:25][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[N:7]=[C:6]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccncc2)c2scc(Br)c12
Reactant: OCCc1ccccn1
Product: O=c1c2c(Br)csc2c(-c2ccncc2)nn1CCc1ccccn1
Yield: 70 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.4 starting from 3-bromo-7-pyridin-4-yl-5H-thieno[2,3-d]pyridazin-4-one and 2-pyridin-2-yl-ethanol. Yield: 70%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=O)[NH:9]2)([CH3:3])[CH3:2].Cl.Cl.Cl.[N:20]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:14]([C:8]3[NH:9][C:10]4[C:6]([CH:7]=3)=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:13]=[CH:12][CH:11]=4)=[O:16])[CH2:33][CH2:34]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: CC(C)Oc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see below) and amine 5.