Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Li+].CC([N-]C(C)C)C.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27]Cl.O>C1COCC1>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH:5]1[CH2:6][CH2:7][NH:3][C:4]1=[O:8]
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Yield: 66.6 %

Procedure:
Charge a flask with 1-trimethylsilanyl-pyrrolidin-2-one (5.0 g, 32 mmol), dissolve in THF (150 mL) and cool to −78° C. under nitrogen. Add LDA (2M, 19 mL, 38 mmol) and stir at −78° C. for 10 minutes. Add 2,4-dichloro-1-chloromethyl-benzene (8.1 g, 41 mmol) and warm to room temperature. Pour into water after 2 hours and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify the residue over silica gel (1:1 hexanes:ethylacetate to 100% ethyl acetate) to afford 5.2 g (67%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.38 (d, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 6.01 (bs, 1H), 3.31 (m, 3H), 2.75 (m, 2H), 2.13 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([NH:6][C:7]1[S:8][C:9]2[CH2:20][CH2:19][CH2:18][CH2:17][C:10]=2[C:11]=1[C:12]([O:14]CC)=O)=[O:5])[CH3:2].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:12]([C:11]1[C:10]2[CH2:17][CH2:18][CH2:19][CH2:20][C:9]=2[S:8][C:7]=1[NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[O:14]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1c(NC(=O)C(CC)CC)sc2c1CCCC2
Product: CCC(CC)C(=O)Nc1sc2c(c1C(=O)NCCN(C)C)CCCC2

Procedure:
The product of Example 14 and N,N-dimethylethylenediamine were processed as in Examples 29A, 29B and 5B to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.92 (t, J=7.5 Hz, 6H), 1.54-1.72 (m, 4H), 1.80-1.89 (m, 4H), 2.19-2.30 (m, 1H), 2.36 (s, 3H), 2.64-2.78 (m, 4H), 3.00 (s, 6H), 3.38 (t, J=5.9 Hz, 2H), 3.75 (t, J=5.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.65-7.72 (m, 2H); MS (DCI/NH3) m/z 366 (M+H)+; anal. calculated for C19H31N3O2S.C7H8O3S—H2O: C, 56.19; H, 7.44; N, 7.56. Found: C, 56.43; H, 7.61; N, 7.61.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Fc1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(F)cc1)OC
Reaction time: 36 h

Procedure:
A mixture of 4-fluorobenzyl bromide (4.86 g, 0.026 M) and trimethylphosphite (10 mL, 0.085 M) is heated at the reflux temperature for 48 hours. The solution is cooled and excess trimethylphosphite is removed under reduced pressure. The crude product is chromatographed over silica gel (40-63 mμ, 400 g, 45 mL fractions, ethyl acetate), eluting with ethyl acetate. Fractions 41-80 are combined, concentrated, and placed under vacuum for 36 hours. The product (4.52 g) is a colorless oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[CH:23]2)[CH:17]=1)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[C:26]([NH2:47])[C:25]=3[N:24]=[CH:23]2)[CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: [NH4+]
Reactant: CCCCc1cc(Cn2cnc3cnc4ccccc4c32)no1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(Cn2cnc3c(N)nc4ccccc4c32)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (930 mg of 77% pure material, 4.2 mmol) was added to a solution of 1-[(5-butylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.06 g, 3.46 mmol) in chloroform (40 mL), and the solution was stirred for 1.5 hours at room temperature. p-Toluenesulfonyl chloride (726 g, 3.81 mmol) and concentrated ammonium hydroxide (15 mL) were then added, and the mixture was stirred vigorously for three hours at room temperature. Saturated aqueous sodium bicarbonate was added, and the aqueous layer was separated and extracted several times with chloroform. The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was purified by flash column chromatography on silica gel (eluting with 4% to 8% methanol in dichloromethane) to provide 0.92 g of 1-[(5-butylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 201-203° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:12])[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCC1(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OC1C=CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a suspension of 5,5-diphenyl-2-cyclopenten-1-one (5.0 g) in toluene (25 ml) was added dropwise diisobutylaluminum hydride (15 ml, 1.5M solution in toluene) for 10 minutes at -78° C. to -50° C. After 30 minutes, ethyl acetate (5 ml) was added to the resultant yellow solution. The solution was acidified to pH 1 with 6N hydrochloric acid (20 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent and further purified by bulb to bulb distillation to give 5,5-diphenyl-2-cyclopenten-1-ol (2.46 g).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)C.Cl.CC([O-])=O.[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]2[CH2:40][CH2:39][NH:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36].C([BH3-])#N.[Na+]>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]2[CH2:40][CH2:39][N:38]2[CH2:4][CH2:5][CH2:6][NH:7][C:8]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CCOC(CCNc1cc(OC)c2ccccc2n1)OCC
Reactant: Clc1ccc(C2CCN2)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: COc1cc(NCCCN2CCC2c2ccc(Cl)c(Cl)c2)nc2ccccc12
Yield: 80.9 %

Procedure:
2-[3,3-Diethoxypropylamino]-4-methoxyquinoline (0.046 g, 0.15 mmol) in THF (4 ml) was treated with 0.5M HCl (2 ml) for 10 min. The reaction mixture was evaporated to dryness and to the residue in methanol/HOAc (1 ml/0.018 ml) was added NaOAc (0.024 g, 0.3 mmol), 2-(3,4-dichlorophenyl)azetidine (0.03 g) and sodium cyanoborohydride (0.009 g, 0.15 mmol). After reaction for 40 min at 20° C., the reaction was evaporated to dryness under reduced pressure, and the residue partitioned between ethyl acetate and sat. sodium bicarbonate. The organic layer was dried, evaporated to dryness under reduced pressure and purified by chromatography on silica gel eluting with 1-3% (9:1 MeOH/NH3) in dichloromethane to give the title compound as a colourless gum (50 mg, 80%); δH (CD3OD) 1.55 (2H, m), 2.0 (1H, m), 2.25 (1H, m), 2.45-2.7 (2H, m), 2.8 (1H, m), 3.2-3.4 (4H, m), 3.9 (3H, s), 3.95 (1H, t), 6.0 (1H, s), 7.05 (1H, t), 7.15-7.5 (5H, m), 7.8 (1H, d); MS (ES+) 416/418 (47/32%, MH+), 244 (50), 201 (100).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:16]=1[C:17](O)=[O:18])([O-:14])=[O:13]>[N+](C1C=CC=C([N+]([O-])=O)C=1C(Cl)=O)([O-])=O>[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:16]=1[C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])([O-:14])=[O:13]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: NCC(=O)O
Agent: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
The reaction of 2,6-dinitrobenzoyl chloride (prepared from 2,6-dinitrobenzoic acid, 1.2 g and SOCl2, 20 mL) with glycine (530 mg, 7.075 mmol) in the presence of Na2CO3 (749 mg, 7.075 mmol) as described in intermediate 2 gave the title compound as an off-white color solid (1.2 g, 80%), mp 210-212° C. 1H NMR (400 MHz, DMSO-d6): δ 12.76 (1H, s), 9.22 (1H, t, J=5.0 Hz), 8.45 (2H, d, J=8.4 Hz), 7.93 (1H, t, J=8.4 Hz), 3.98 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 268 (M−H)−.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[CH:32][N:31]=1)CCC>CN(C=O)C.[Cu]I.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>[CH3:17][S:16][C:13]1[S:12][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]3[C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:33]=[CH:32][N:31]=2)=[N:15][N:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(N2CCOCC2)n1
Reactant: CSc1nnc(-c2ccc3c(c2)c(I)cn3C(=O)OC(C)(C)C)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3c(c2)c(-c2nccc(N4CCOCC4)n2)cn3C(=O)OC(C)(C)C)s1
Temperature: 90 °C
Yield: 20 %

Procedure:
To a solution of tert-butyl 3-iodo-5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (1.2 g, 2.5 mmol) and 4-(2-(tributylstannyl)pyrimidin-4-yl)morpholine (1.38 g, 4.0 mmol) in DMF (10 mL) was added CuI (0.62 g, 3.2 mmol) and Pd(PPh3)4 (0.29 g, 0.25 mmol). The mixture was purged with Ar for 5 min then heated at 90° C. for 1 h. The mixture was poured into H2O and the aqueous layer was extracted with Et2O. The combined organic layers were dried, filtered and concentrated. The residue was purified with flash chromatography to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(4-morpholinopyrimidin-2-yl)-1H-indole-1-carboxylate (255 mg, 20%). MS (ESI, pos. ion) m/z: 511.1 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 9.12 (1H, d), 8.39 (2H, brs), 8.25 (1H, d), 7.9 (1H, dd), 6.79 (1H, d). 3.7-3.85 (8H, brs), 2.85 (3H, s), 1.65 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:7]=1.[B:12]1(B2OC(C)(C)C(C)(C)O2)[O:16]C(C)(C)C(C)(C)[O:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:10]1[CH2:11][CH:8]([C:6]2[CH:7]=[C:2]([B:12]([OH:16])[OH:13])[CH:3]=[N:4][CH:5]=2)[CH2:9]1
Reactant: Brc1cncc(C2COC2)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1cncc(C2COC2)c1
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 63 Step A (45 mg, 0.21 mmol), bis(pinacolato)diboron (107 mg, 0.420 mmol), tris(dibenzylideneacetone)dipalladium (0) (38.5 mg, 0.042 mmol), tricyclohexylphosphine (23.6 mg, 0.084 mmol) and potassium acetate (61.9 mg, 0.631 mmol) in dioxane (1.0 mL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then passed through a syringe filter and concentrated under reduced pressure to provide the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C@H:16]2[CH2:20][C@@H:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[NH:18][CH2:17]2)[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])[CH2:4][CH2:3]1.[C:30]([N:37]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@H:39]([C:49](O)=[O:50])[CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:30]([N:37]1[CH2:38][C@@H:39]([C:49]([N:18]2[CH2:17][C@@H:16]([N:8]([C@H:5]3[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]([C@@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)=[O:10])[CH2:20][C@H:19]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])=[O:50])[C@H:40]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:41]1)([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
(2S)—N-(cis-4-methylcyclohexyl)-N-{(3S,5S)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-3-yl}tetrahydrofuran-2-carboxamide (0.76 g, 1.87 mmol) obtained in Step E of Example 16 and (3S,4R)-1-BOC-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid obtained in Preparation 14 were reacted according to the same procedure as in the Step F of Example 1 to give the title compound (1.18 g, 88%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[C:21]([CH2:26]Br)[CH:20]=1>>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[C:21]([CH2:26][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:20]=1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Product: COC(=O)c1ccc(Br)c(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Yield: 45.9 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.39 g (1.3 mmol) 4-bromo-3-bromomethyl-benzoic acid methyl ester. After ionic exchange purification, 0.196 g (46% of yield) of 4-bromo-3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:6]=1[O:7][CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:54][O:55][C:56](=[O:62])[C@@H:57]1[CH2:61][CH2:60][CH2:59][NH:58]1>ClCCl.C(#N)C>[CH3:54][O:55][C:56]([CH:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:5]=1[C:1]([CH3:2])([CH3:4])[CH3:3])=[O:62]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1CCCN1CCOc1cc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 2-(2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin4-ylamino]-phenoxy}-ethanol (24 mg, 0.05 mmol) and triethyl amine (6 mg, 0.06 mmol) in dichloromethane 1 ml and add methanesulfonyl chloride (6 mg, 0.05 mmol). Stir the solution at room temperature for 1 hour and evaporate to dryness. Re-dissolve the residue in acetonitrile (2 ml), transfer to a sealed tube, add potassium carbonate (13 mg, 0.1 mmol) and L-proline methyl ester (13 mg, 0.1 mmol) and heat the mixture at 80° C. for 8 hours. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure. Purify the residue by flash chromatography on silica gel (ethyl acetate) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]4[C:38](=[CH:39][CH:40]=3)[C:18]3[NH:19][C:20]([C@@H:22]5[CH2:26][CH2:25][CH2:24][N:23]5[C:27](=[O:37])[C@@H:28]([NH:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]([CH3:31])[CH3:30])=[N:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:41][C:42]([C@@H:44]1[CH2:48][C@H:47]([S:49][CH3:50])[CH2:46][N:45]1[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=O>C(O)(=O)C>[CH3:36][O:35][C:33]([NH:32][C@H:28]([C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C:20]1[NH:19][C:18]2[C:38]3[C:14]([CH:15]=[CH:16][C:17]=2[N:21]=1)=[CH:13][C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]1[NH:1][C:42]([C@@H:44]4[CH2:48][C@H:47]([S:49][CH3:50])[CH2:46][N:45]4[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:41][C:3]=1[CH:4]=[CH:5]2)=[CH:40][CH:39]=3)=[O:37])[CH:29]([CH3:30])[CH3:31])=[O:34]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(N)c(NC(=O)[C@@H]6C[C@H](SC)CN6C(=O)OC(C)(C)C)ccc5c4)ccc3c2[nH]1)C(C)C
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7C[C@H](SC)CN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Yield: 53.7 %

Procedure:
To (2S,4S)-tert-butyl 2-(1-amino-6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl) naphthalen-2-ylcarbamoyl)-4-(methylthio)pyrrolidine-1-carboxylate (95 mg, 0.12 mmol) in acetic acid (4 mL) and the reaction mixture stirred for 16 hours. Concentrated in vacuo and diluted with EtOAc, washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide tert-butyl (2S,4S)-2-(2′-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methylsulfanyl)pyrrolidine-1-carboxylate (50 mg, 54%). MS (ESI) m/z 777 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:11][N:10]=1
Reactant: C(=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)\c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=c1cc(CCc2ccccc2)[nH]nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
To a solution (8 mL) of 3,4-bis(benzyloxy)-6-[(E)-2-phenylvinyl]pyridazine (272 mg) in ethanol was added 10% palladium-carbon (90 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate-chloroform, and the resulting solid was collected by filtration and dried under reduced pressure to give 3-hydroxy-6-(2-phenylethyl)pyridazin-4(1H)-one (60 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CC(N(C)C)=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([NH:1][CH2:12][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10 mmol), 4formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride (304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10 mL) and DMA (10 ml) was stirred overnight. at room temperature. After solvents removal, the crude residue was dissolved in ethyl acetate (100 ml) and then washed with saturated aqueous solution of NaHCO3 (50 ml×3). The combined aqueous layers were acidified with 6% of NaHSO4 to pH=4. The resulting white suspension was filtrated and then the filter cake was washed with water (5 ml×3). The cake was dried over freeze dryer to afford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]([O:19]C)=[O:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1>[OH-].[Na+].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(-c2ccc(F)cc2)nn2ccccc12

Procedure:
A solution of methyl 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5 mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL) was heated at reflux for about 3 hours. The mixture was filtered and the filtrate was washed with diethyl ether (20 mL) and then concentrated under reduced pressure to about half the original volume. Concentrated hydrochloric acid was added to adjust the pH to about 2 and the resulting solid was collected by filtration and washed with water and dried under vacuum to give the title compound as a white solid, 4.8 g (ca. 100%). 1H NMR (d6 DMSO) δ 12.43 (br s, 1 h), 8.84 (d, 1H, J=6.9 Hz), 8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H, J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257 (100), (MH+).