Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(Cl)CCl>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:34][S:35]([NH:38][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([CH2:15][N:5]([C@@H:6]3[CH2:8][C@H:7]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3](=[O:4])[C:2]([F:32])([F:1])[F:33])[CH2:21][CH2:20]2)=[CH:31][CH:30]=1)(=[O:37])=[O:36]
Reactant: O=C(O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
To a solution of 4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoic acid (150 mg, 0.326 mmol) in N,N-dimethylformamide (DMF) (2 mL) were added methanesulfonamide (37.2 mg, 0.391 mmol), EDC (74.9 mg, 0.391 mmol) and DMAP (39.8 mg, 0.326 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% NH4Cl aqueous solution and extracted with EtOAc(3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexaens) to give 82 mg of product as off-white solid. MS: (M+H)+=538.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.38-1.74 (m, 4H), 1.91-2.22 (m, 3H), 2.47 (m, 1H), 2.98-3.11 (m, 2H), 3.21 (d, J=6.82 Hz, 1H), 3.37-3.66 (m, 7H), 4.39 (s, 2H), 7.04-7.38 (m, 5H), 7.67 (d, J=8.34 Hz, 2H), 8.03 (d, J=8.08 Hz, 2H).
Reaction SMILES: CNN.Cl[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11](C=O)[CH2:10][C:9](=CO)[C:8]2=O.C(O)(=O)C>CO>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=CN1CC(=CO)C(=O)c2cc(Cl)ccc21
Agent: CNN
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2ncccc2c1
Reaction time: 1.5 h
Yield: 116 %

Procedure:
Methylhydrazine (52.5 g) was dropwise to a mixture of 6-chloro-1-formyl-3-hydroxymethylene-4-oxo-1,2,3,4-tetrahydroquinoline (276 g) and acetic acid (13 ml) in methanol (2.76 liters) at 10° C. to 12° C. over a period of 10 minutes. After being stirred for 1.5 hours at the same temperature, the resulting precipitate was collected by filtration, washed with methanol and dried to give 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H-pyrazolo 4,3-c]quinoline (174 g).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[N:15]=[C:14]3[CH:16]=[CH:17][N:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[C:20]#[N:21])[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:22][C:16]1[C:14]2=[N:15][C:10]([N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH3:9])=[C:11]([C:20]#[N:21])[CH:12]=[C:13]2[N:18]([CH3:19])[CH:17]=1
Reactant: CCN(CC1CCCC1)c1nc2ccn(C)c2cc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2c(Br)cn(C)c2cc1C#N
Reaction time: 0.5 h

Procedure:
To a mixture of 5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (105 mg, 0.37 mmol) in DMF (2 mL) is added N-bromosuccinimide (NBS, 66 mg, 0.37 mmol) at 0° C. After stirring for 30 min, H2O is added, and the reaction mixture is extracted with EtOAc. The organic layer is dried over sodium sulfate, concentrated and purified by silica-gel column chromatography to give 3-bromo-5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:48]([OH:50])=O)[CH2:46][OH:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:51]([O:55][C:56](=[O:61])[NH:57][CH2:58][CH2:59][NH2:60])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([CH2:46][OH:47])[C:48]([NH:60][CH2:59][CH2:58][NH:57][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:61])=[O:50])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.05 g (2.759 mmol) of HATU and 648.3 mg (5.016 mmol) of N,N-diisopropylethylamine are added to a solution of 600 mg (2.5 mmol) of N-[(benzyloxy)carbonyl]-L-serine in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 442.0 mg (2.76 mmol) of tert-butyl(2-aminoethyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=1.N.CO>[Ni]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CC#N)n1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cccc(CCN)n1
Yield: 83.9 %

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)acetonitrile (5.00 g, 33.75 mmol) in 2M ammonia/MeOH (84 mL, 168.73 mmol) was stirred in the presence of Raney-nickel (8 g, 136.30 mmol) [obtained by washing Kawaken NDHT-90 with 4N aqueous sodium hydroxide solution (40 mL), water (×5) and MeOH (×3)] at room temperature for 22 hr under hydrogen atmosphere (0.5 MPa). The catalyst was removed by decantation, and the reaction solution was concentrated under reduced pressure. To the obtained residue was added toluene (about 80 mL), and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, solvent gradient; 10→100% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanamine (4.30 g, 28.3 mmol, 84%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:30][C:29]3[CH:28]=[N:27][N:26]([CH3:31])[C:25]=3[NH:24][C:23]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:22]2=3)=[O:20])=[CH:15][C:14]=1[F:37].C1C(N=NC2C3C=CC(S([O-])(=O)=O)=CC=3C=CC=2O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+]>C1COCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:22]2[N:21]([C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][NH:11][CH2:10][CH2:9][OH:8])=[C:14]([F:37])[CH:15]=3)=[O:20])[CH2:30][C:29]3[CH:28]=[N:27][N:26]([CH3:31])[C:25]=3[NH:24][C:23]=2[CH:32]=1
Reactant: COC(=O)CNCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Agent: O=S(=O)([O-])c1ccc(N=Nc2c(O)ccc3cc(S(=O)(=O)[O-])ccc23)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNCCO)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Lithium aluminium hydride (14.5 mg, 0.38 mmol) was added to a solution of [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamino]-acetic acid methyl ester from example E110 (58.5 mg, 0.13 mmol) in THF (5 ml), and the mixture was stirred at room temperature for 30 min. Before being quenched with MeOH and extracted with EtOAc. The organic extract was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% di-chloromethane then 20% methanol:80% dichloromethane) to give a pale yellow solid identified as the title compound (15 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[C:17]([C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH:24]1[CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[C:17]([C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH:24]1[CH2:25][N:26]([C:7](=[O:9])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:27]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: CCOC(=O)CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Temperature: 25 °C
Yield: 90 %

Procedure:
To an ice-cold stirred solution of 4-ethoxy-4-oxobutanoic acid (0.42 g, 2.56 mmol) and DMF (0.03 ml) in THF (15 mL) was added oxalyl chloride (0.35 g, 2.72 mmol). After 1 h the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (5.0 mL) and the solution was added to an ice-cold solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol) and triethylamine (0.31 g, 3.06 mmol) in THF (30.0 ml) and the resulting reaction mixture was warmed to room temperature. After 16 h the reaction mixture was filtered, the filtrate was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoate (0.51 g, 90%) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:21][C:20]1[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Yield: 20 %

Procedure:
tert-butyl piperazine-1-carboxylate (1.0 g, 5.37 mmol) and 2,3-dichloropyridine (795 mg, 5.37 mmol) charged to a microwave vial was added with diisopropylethylamine (2.34 mL, 13.42 mmol) and DMF (1.0 mL). The reaction mixture was subject to microwave irradiation at 165° C. for 30 minutes. The reaction was repeated six times in order to scale up. Combined reaction mixture was partitioned between EtOAc and water, organic layer washed with brine and dried over MgSO4. The crude product obtained by solvent evaporation was purified via flash column chromatography. tert-butyl 4-(3-chloropyridin-2-yl)piperazine-1-carboxylate was obtained in 20% yield (1.9 g) as yellow oil.
Reaction SMILES: Cl.[CH2:2]1[O:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[O:3]1.[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33]Cl)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33][N:6]3[CH2:5][CH:4]4[O:3][CH2:2][O:9][CH:8]4[CH2:7]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: C1OC2CNCC2O1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN1CC2OCOC2C1
Yield: 69.8 %

Procedure:
3,4-methylenedioxypyrrolidine hydrochloride (87 mg) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.25 g; prepared as described in Example 43) and diisopropylethylamine (0.2 ml) in acetonitrile (10 ml) and the mixture heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/isopropanol/triethylamine (97/2/1) to (95/4/1). The fractions containing the expected product were evaporated under vacuum to give the title product as a yellow solid (0.203 g; 70%); 1H NMR Spectrum: (CDCl3) 1.92-222 (m, 4H), 2.54-2.61 (m, 2H), 3.05-3.15 (m, 2H), 3.26-3.38 (q, 2H), 3.42-3.47 (m, 1H), 3.58-3.65 (m, 1H), 4.00-4.10 (m, 4H), 4.47-4.55 (m, 3H), 4.65-4.72 (m, 1H), 4.84 (s, 1H), 5.02 (s, 1H), 7.11-7.22 (m, 2H), 7.24 (s, 1H), 7.96-8.02 (m, 1H), 8.38 (s, 1H), 8.61 (s, 1H), 8.63 (s, 1H); Mass Spectrum: (M+H)+ 558.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[N:12]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>CO.[Pd].[C]>[OH:1][CH:2]([CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(O)CCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(O)CCn1ccc(N)n1

Procedure:
A solution of the above crude ethyl 3-hydroxy-5-(3-nitropyrazol-1-yl)valerate (2.41 g.) in MeOH (250 ml.) was hydrogenated over 5% w/w Pd/carbon (0.3 g.) at atmospheric pressure over 2 hours. Uptake was 650 ml. The catalyst was filtered off and the filtrate was evaporated in vacuo to give ethyl 3-hydroxy-5-(3-aminopyrazol-1-yl)valerate as an oil (1.47 g.).
Reaction SMILES: ClCl.[C:3]([NH:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].C(NNC(=O)C1C=CC(C#N)=CC=1)(C)(C)C.C(NNC(=O)C1C(=CC=CC=1)N)(C)(C)C.[H][H]>>[C:3]([NH:7][NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Agent: CC(C)(C)NNC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)NNC(=O)c1ccccc1N
Agent: ClCl
Product: CC(C)(C)NNC(=O)c1ccccc1

Procedure:
The above reactions are illustrated below: ##STR15## wherein Q is halogen, preferably chlorine; R is tert-butyl or tert-amyl. Other compounds that can be prepared by the above procedure using the appropriately substituted benzoyl halide include: m-chlorobenzoic acid, 2-tert-butylhydrazide, mp 120°-123° C.; p-cyanobenzoic acid, 2-tert-butylhydrazide, mp 135°-136° C.; anthranilic acid, 2-tert-butylhydrazide, mp 165°-167° C.; tert-butyl or isopropyl; and X is hydrogen, halogen, C1 -C3 alkyl, methoxy, methylamino, NH2, nitro or CF3.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1)[CH:24]=O)[CH3:19]>CO>[CH2:30]([O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH2:18][CH3:19])[CH:28]=1)[CH2:24][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4])[CH3:31]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1
Solvent: CO
Product: CCOc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
Borane-pyridine complex (155 μL, 1.46 mmol) was added to a methanol solution (3.3 mL) of an amine (3) (127 mg, 0.486 mmol) and 3,5-diethoxybenzaldehyde (123 mg, 0.632 mmol) at 40° C. and the mixture was stirred for 2.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (9) as a yellow solid (114 mg, yield 54%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[C:13](Cl)(=[O:15])[CH3:14]>ClCCCl>[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a stirred suspension of aluminum chloride (42 g, 312 mmol) in 1,2-dichloroethane (100 ml) was added 3-fluorophenol (31 g, 276 mmol) dropwise at 0° C. After addition, acetyl chloride (24 g, 306 mmol) was added dropwise and then the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, and poured into ice. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with hexane to give title compound (3.57 g, 8% yield).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][C@H:31]([OH:38])[C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C:28]2=[O:39])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:54]([CH3:57])([CH3:56])[CH3:55])(=O)=O>CCOCC>[Si:1]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][C@H:31]([O:38][Si:54]([CH3:57])([CH3:56])[CH3:55])[C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C:28]2=[O:39])[CH2:20]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O[Si](C)(C)C)[C@]2(C)C(=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3α-tert-butyldiphenylsilyloxy-12α-hydroxy-5β-androstan-17-one (14.6 g) in ether (75 ml) is cooled to 0° C. and 2,6-lutidine (4.2 ml), trimethylsilyl trifluoromethanesulfonate (4.6 ml) are added and the mixture allowed to warm to room temperature, stirred for about 15 minutes, then diluted with ether. The organic solution was washed with dilute aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude product purified by flash chromatography in 15% ether in hexane to give the desired product.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][C:5]=1[CH3:14].O.[OH-].[Li+].C(OCC)(=O)C.Cl>CO.O>[CH3:14][C:5]1[N:6]=[C:7]([C:10]([F:13])([F:11])[F:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
6.68 g (0.0305 mol) of 2-methyl-6-trifluoromethyl-nicotinic acid methyl ester (prepared in the manner described in Heterocycles, 46, 129 (1997)) are dissolved in 250 ml of methanol/water (3:1 mixture) and 1.92 g (0.046 mol) of lithium hydroxide hydrate are added in portions at a temperature of 22° C. After 4 hours at 22° C., the reaction mixture is added to ethyl acetate and 2N hydrochloric acid; the organic phase is washed three times with water, dried over sodium sulfate and concentrated by evaporation, and the residue is triturated with a small amount of hexane. After filtering, 5.69 g (90% of theory) of the expected 2-methyl-6-trifluoromethyl-nicotinic acid having a melting point of 147-149° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:31]([C:32]3[CH:47]=[CH:46][C:35]([CH2:36][NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:34][CH:33]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:20]=[CH:19][N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.ClCCl.CO>[NH2:1][C:2]1[C:7]([C:8]2[N:31]([C:32]3[CH:47]=[CH:46][C:35]([CH2:36][NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:34][CH:33]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:20]=[CH:19][NH:18][CH:17]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)nc(-c2cccnc2N)n3-c2ccc(CNC(=O)c3ccccc3)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ncccc1-c1nc2cc(-c3cc[nH]c3)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-(2-(2-aminopyridin-3-yl)-6-(1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide was synthesized according to General Procedure A followed by General Procedures I, B and C and subsequent TBAF-deprotection. TBAF-deprotection: To a solution of N-(4-(2-(2-aminopyridin-3-yl)-6-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide (5.2 g) in anhydrous tetrahydrofuran (100 ml) was added 1.0 M tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (3 ml). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (300 ml), dichloromethane (200 ml) and methanol (50 ml) and stirred for 1 hour. The organics were separated and the aqueous was washed with dichloromethane (1×200 ml). The organics were combined, washed with water (2×200 ml), brine (1×100 ml), dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (30% ethyl acetate in dichloromethane to 5% methanol/25% ethyl acetate in dichloromethane) gave the product as a yellow solid. Further trituration with ether and hexanes gave a light yellow solid (1.2 g, 41%). 400 M Hz 1H NMR (DMSO-d6) δ: 11.02 (s, 1H), 9.17-9.11 (m, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.00-7.96 (m, 1H), 7.93 (d, J=7.6 Hz, 2H), 7.58-7.33 (m, 8H), 7.21 (d, J=7.6 Hz, 1H), 7.04 (s, 2H), 6.85 (s, 1H), 6.56 (s, 1H), 6.40 (t, J=6.0 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H); LCMS: 486 [M+H]. Calc. for C29H23N7O 0.18 water 0.02 ethyl acetate 0.08 dichloromethane: C, 70.42; H, 4.80; N, 19.71. Found C, 70.41; H, 4.78; N, 19.71.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:26]#[N:27])=[C:21](B(O)O)[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:26]#[N:27])=[C:21]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=[C:4]([O:14][CH3:15])[CH:3]=2)[CH:22]=1
Reactant: COc1cc(I)c(OCC(F)(F)F)cn1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(OCC(F)(F)F)cn1

Procedure:
500 mg (purity 94%, 1.41 mmol) of 4-iodo-2-methoxy-5-(2,2,2-trifluoroethoxy)pyridine and 282 mg (1.55 mmol, 1.1 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 168 mg (33% of theory)
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([CH3:24])=[N:20][O:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl[Pd](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>[CH3:24][C:19]1[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cc1noc(C)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)noc3C)c(C)nc12
Yield: 23.1 %

Procedure:
Using the procedure analogous to Example 242, from 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90 mmol), 4-bromo-3,5-dimethyl isoxazole (Alfa, 320 mg, 1.8 mmol), cesium carbonate (880 mg, 2.70 mmol) and PdCl2(PPh3)2 (25 mg) in DMF (5 ml), heated at 130 for 4 hrs, then overnight at ambient temperature gives the title compound (65 mg, 23% yield). ES-MS (m/z): calc'd for C18H24N4O: 312.4; found 313.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 6.68 (s, 1H), 3.32 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 1.82 (m, 4H), 0.87 (m, 6H).