Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH:10]=[O:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1c(C=O)cnn1CCO
Solvent: c1ccncc1
Product: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a solution of 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (40.2 g) in pyridine (400 ml) was added triphenylmethyl chloride (86.7 g) at room temperature. The mixture was stirred at 60° C. for 5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (3:2) to give 5-amino-1-(2-triphenylmethyloxyethyl)-1H-pyrazole-4-carbaldehyde (62.8 g).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:31][CH2:8][C:7]([C:5]1[S:6][C:2]([F:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(F)s1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)c1ccc(F)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
To a stirred clear amber solution of 1-(5-fluorothiophen-2-yl)ethanone (9.70 g, 67.3 mmol) in dichloromethane (224 mL) at 0° C. under nitrogen is added diisopropylethylamine (14.7 mL, 84.1 mmol) followed by the drop wise addition of trimethylsilyl trifluoromethanesulfonate (13.8 mL, 74.0 mmol) over 10 minutes while maintaining the internal temperature below 5° C. The resulting solution is stirred at 0° C. for 90 minutes. N-bromosuccinimide (13.17 g, 74.0 mmol) is added in one portion and the resulting orange solution is stirred at 0° C. for 1 hour. Dilute aqueous sodium bicarbonate (200 mL of a 1:1 water/saturated aqueous sodium bicarbonate solution) and dichloromethane (50 mL) are added. The phases are separated and the aqueous phase is re-extracted with dichloromethane (150 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a red oily/amorphous residue. The residue is diluted with hexanes (50 mL) and dichloromethane (5 mL) and filtered to remove solids. The solids are washed with a solution of hexanes/dichloromethane (˜50 mL, 7:3). The combined filtrates are concentrated under reduced pressure and the residue is purified by silica gel chromatography eluting with hexanes/dichloromethane (two-step gradient from 70:30 to 60:40 to 50:50) to give the title compound (13.33 g, 89%). 1H NMR (CDCl3) δ 4.27 (s, 2H), 6.58 (dd, J=1.3, 4.4 Hz, 1H), 7.52 (dd, J=1.5, 4.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:20])=[O:13])=[CH:5][CH:4]=1
Reactant: N
Reactant: CSc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ccc(C=CC(N)=O)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.00 g (25.7 mmol) 3-(4-methylsulfanyl-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 4.90 ml (38.6 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 20 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 100 ml of a 25% aqueous ammonia solution. After evaporation of the organic solvent, 200 ml water were added and the solution cooled. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 4.46 g (90%) 3-(4-methylsulfanyl-phenyl)-acrylamide as an off-white solid melting at 193° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1[CH2:23][O:22][CH:19]([CH2:20]Br)[CH:18]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:16]1[CH2:23][O:22][CH:19]([CH2:20][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH:18]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:17]1
Reactant: COc1ccc(C2OCCOC2CBr)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCOC2CN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 77.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylaminomethyl)piperidine (9.70 g) in toluene (160 ml) were added 3-ethylenedioxy-3-(4-methoxyphenyl)propyl bromide (13.0 g) and potassium carbonate (18.8 g), and the resulting mixture was stirred at 80° C. for 16.5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 14.7 g of 1-(3-ethylenedioxy-3-(4-methoxyphenyl)propyl)-4-(tert-butoxycarbonylaminomethyl)piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Yield: 19 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 4-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 19% yield (21 mg).
Reaction SMILES: C(O)(C)C.C(O)(=O)C.[N+:9]([C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O.[Fe].C(OCC)(=O)C>[NH2:9][C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1
Reactant: O=[N+]([O-])c1c(OCCCN2CCN(c3ccccc3)CC2)ccc2c1CCCC2
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Nc1c(OCCCN2CCN(c3ccccc3)CC2)ccc2c1CCCC2
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Iron powder (15 g, 0.27 mol), isopropyl alcohol (45 ml), water (11 ml), and acetic acid (1.5 ml, 26.2 mmol) were added to 5,6,7,8-tetrahydro-1-nitro-2-[3-(4-phenyl-1-piperazinyl)propoxy]naphthalene (5.5g, 13.9 mmol) and stirred for 2 hours under reflux. After cooling the reaction mixture, the mixture was added with potassium carbonate (10 g) that was dissolved in a small volume of water. After stirring for several minutes, ethyl acetate was added to the reaction mixture and the precipitates were removed by filtration. The filtrate was concentrated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 1-amino-5,6,7,8-tetrahydro-2-[3-(4-phenyl-1-piperazinyl)propoxy]naphthalene (4.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1>C(CN)O.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Solvent: NCCO
Solvent: O
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Temperature: 180 °C
Reaction time: 15 h
Yield: 171.9 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,γ,γ,γ-pentafluoropropyloxypyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in ethanolamine(5.0 ml), then stirred at 180° C. for 15 hours in the pressure tube. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to obtain 560 mg of desired compound as solid in 89% of yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.CCN(CC)CC.[NH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et3N (72 μL, 0.52 mmol), and CH2Cl2 (300 μL) under N2, was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 98% CH2Cl2/2% MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>CS(C)=O.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A solution of 3,4-methylenedioxyphenol (7.0 g, 50.7 mmol) in anhydrous DMSO (20 mL) was added dropwise over 30 minutes to a stirred suspension of 60% oil dispersion sodium hydride (2.02 g, 50 mmol) in anhydrous DMSO (40 mL) under a nitrogen atmosphere. Upon completion of addition, a solution of p-fluorobenzaldehyde (6.2 g, 50 mmol) in DMSO (10 mL) was added, and the temperature was slowly raised to 150° C. The reaction mixture was maintained at 130°-160° C. for one hour and then allowed to cool to ambient temperature. After 12 hours at ambient temperature, the reaction mixture was poured onto crushed ice and water, made slightly acidic with concentrated hydrochloric acid and extracted with ether. The combined organic extracts were washed with successively with cold dilute aqueous sodium hydroxide, cold dilute hydrochloric acid, ice-cold water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to give a red liquid which solidified. The solid was triturated with boiling n-pentane, filtered and washed with boiling pentane to give 8.2 g (67%) of the title compound. m.p. 67°-70° C. 1H NMR (CDCl3, 300MHz) δ 6.0 (s, 2H), S.6 (m, 2H), 6.8 (d, 1H), 7.04 (m, 2H), 7.84 (m, 2H), 9.92 (s, 1H). MS (DCl/NH3) m/e 243 (M+H)+.
Reaction SMILES: C([N+:8]12[CH2:14][C:11]([C:15]([O-:17])=[O:16])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)C1C=CC=CC=1.[CH3:18]O>[Pd].[C]>[N:8]12[CH2:14][C:11]([C:15]([O:17][CH3:18])=[O:16])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: O=C([O-])C12CC[N+](Cc3ccccc3)(CC1)C2
Reactant: CO
Agent: [Pd]
Product: COC(=O)C12CCN(CC1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) in MeOH was added 10% Pd carbon with a 50% hydration (650 mg), followed by stirring at room temperature for 5 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in MeOH and added with sulfuric acid (3 mL), followed by heating under reflux for 1 hour. The reaction mixture was neutralized with an aqueous K2CO3 solution and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3: MeOH: 28% aqueous ammonia) to obtain methyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (890 mg) as a colorless oily substance.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9](N)[S:10][CH:11]=1)=[O:6])[CH3:3].C([O-])(O)=O.[Na+].[Na+].[Cl-:19].N([O-])=O.[Na+]>O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([Cl:19])[S:10][CH:11]=1)=[O:6])[CH3:3]
Reactant: [Cl-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cu+2]
Agent: Br
Agent: O=C([O-])O
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: 0 °C

Procedure:
2-Amino-thiazole-4-carboxylic acid ethyl ester hydrobromide (34.46 g, 0.137 mol) was basified with a saturated solution of NaHCO3 (aq) (300 mL) and extracted with EtOAc (8×300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated in vacuo to liberate the free base. To a well stirred suspension of the free base in 9M H2SO4 (aq) (500 mL) at 0° C. to −5° C., CuSO4 (63.34 g, 0.397 mol) and NaCl (30.39 g, 0.520 mol) were added, followed by the dropwise addition of a solution of NaNO2 (10.39 g, 0.151 mol) in H2O (150 mL), over 45 min. The mixture was maintained at 0° C. for 1 h then warmed to RT. After 1 h at RT the reaction mixture was diluted with H2O (2 L) and extracted with Et2O (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated in vacuo to yield the title compound as a pale yellow amorphous solid (sufficiently pure to be used directly in the next step). MS m/z: 192.0 (M+H). Calc'd. for C6H6ClNO2S-191.64.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:53](=[O:54])[C:52]([C:55](O)=[O:56])=[CH:51][CH:50]=[N:49]2)=[CH:44][CH:43]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:55]([C:52]2[C:53](=[O:54])[N:48]([C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)[N:49]=[CH:50][CH:51]=2)=[O:56])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=3)[N:9]=[C:10]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (84.3 mg, 0.1539 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (108.1 mg, 0.4618 mmol, prepared according to Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (147.6 mg, 0.7697 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (104.0 mg, 0.7697 mmol), N-ethyl-N-isopropylpropan-2-amine (199.0 mg, 1.539 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (108.3 mg, 92.11%). LRMS (APCI pos): m/e 664 (M−99).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:12][C:13](OC(C)=O)=[O:14]>C(O)(=O)C>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:14])[CH3:12]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of 3-amino-4-methylbenzoic acid (375 g, 2.48 mol) in glacial acetic acid (2500 mL) was added dropwise Ac2O (1547.7 g, 15.2 mol). After the addition, the reaction mixture was stirred at room temperature overnight. The solid formed was collected by filtration, and washed with acetic acid (500 mL×2) and ether (500 mL×2). Then the solid was dried in vacuo to give the title compound (420 g, 87.6%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:28][CH2:27][C:13]2([C:29]3[CH:34]=[C:33](Br)[C:32]([F:36])=[CH:31][C:30]=3[F:37])[N:14]=[C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH2:17][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:28][CH2:27][C:13]2([C:29]3[CH:34]=[C:33]([C:38]#[N:39])[C:32]([F:36])=[CH:31][C:30]=3[F:37])[N:14]=[C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH2:17][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3cc(Br)c(F)cc3F)CO[C@@H](COCc3ccccc3)CC2CS1)c1ccccc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C23CO[C@@H](COCc4ccccc4)CC2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Temperature: 80 °C

Procedure:
C9 (300 mg, 0.511 mmol), zinc cyanide (72.0 mg, 0.613 mmol), tetrakis(triphenylphosphine)palladium(0) (342 mg, 0.296 mmol) and N,N-dimethylformamide (9 mL) were added to a 16 ml Emry microwave vial. The vial was sealed and purged with nitrogen for 10 minutes while stirring. The reaction was heated at 80° C. in a Biotage microwave for 120 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (1×200 mL), dried over sodium sulfate, filtered, and absorbed on silica gel. The obtained solid after removal of solvent was subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the desired product as a yellow solid. Yield: 269 mg, 0.503 mmol, 98%. LCMS m/z 534.3 [M+H+].
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)[CH3:2].C[Al](C)C.CO[C:17]([C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[C@@H:21]([CH3:37])[CH2:20]1)=[O:18]>C1(C)C=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[C:17]([C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:30])[C@@H:21]([CH3:37])[CH2:20]2)=[O:18])=[CH:5][CH:6]=1
Reactant: CCNc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccncc2)c2ccccc21
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccncc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 11 %

Procedure:
To a solution of N-ethyl-4-chloroaniline (650 mg, 4.18 mmol) in anhydrous toluene at 10° C. was slowly added a 2M solution of trimethylaluminium in hexanes (2.1 mL, 4.18 mmol). The reaction mixture was stirred at room temperature until gas evolution stopped. A second round bottom flask was charged with cis-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (370 mg, 1.19 mmol) and the preformed aluminum amide was added. The resulting reaction mixture was refluxed for 20 hours. The reaction was concentrated, quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!), basified with 1M aqueous sodium hydroxide, and extracted with ethyl acetate. The resulting organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride) followed by HPLC to provide (±)-trans-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (11%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.60-1.70 (m, 1H), 2.45-2.55 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 4.98-5.10 (m, 1H), 6.40 (d, 1H), 6.90 (m, 2H), 7.00 (t, 1H), 7.30 (m, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 8.55 (d, 2H). MS m/z: 434/436 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([O:15]C)[C:12]([O:17]C)=[C:11]([Cl:19])[C:10]=2[Cl:20])=[O:8])=[CH:5][CH:4]=[N:3]1.Br>>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:17])=[C:11]([Cl:19])[C:10]=2[Cl:20])=[O:8])=[CH:5][CH:4]=[N:3]1
Reactant: COc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OC
Agent: Br
Product: Cn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Yield: 83.8 %

Procedure:
A mixture of 6.25 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanone and 70 ml of aqueous 47% hydrobromic acid is refluxed for 3 hours and the reaction mixture is evaporated to remove solvent. The residue is dissolved in aqueous 10% sodium hydroxide solution and the solution is adjusted to pH 3 -4 by addition of acetic acid. The mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent under reduced pressure. The residue is crystalized from isopropyl ether and the crystals are collected by filtration to give 4.77 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)m ethanone. Yield: 84%