Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:34]([CH3:35])[CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, dimethylamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by dimethylamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide (26 mg, 0.059 mmol, 37%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[NH:24][CH:28]=[CH:27][N:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ncc[nH]3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.10 g, 0.32 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-imidazolecarbaldehyde (0.03 g, 0.31 mmol) was added followed by oxone (0.13 g, 0.21 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (15 mg, 12.1% yield) as light brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.N1C2C(=C(C3C=C(NC4C=NC=CC=4)C=C(OC)C=3)C=CC=2)C=C1>>[Br:10][C:4]1[CH:3]=[C:2]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: Nc1cccnc1
Agent: COc1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: COc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
(3-Bromo-5-methoxy-phenyl)-pyridin-3-yl-amine was prepared from 1,3-dibromo-5-methoxy-benzene and pyridin-3-ylamine as described for Example 36. This material was converted to [3-(1H-indol-4-yl)-5-methoxy-phenyl]-pyridin-3-yl-amine by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.44 (d, J=2.7 Hz, 1H), 8.34 (br s, 1H), 8.17 (dd, J=4.7, 1.2 Hz, 1H), 7.50 (ddd, J=8.2, 2.7, 1.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.27-7.23 (m, 2H), 7.19-7.15 (m, 2H), 6.98 (t, J=1.7 Hz, 1H), 6.89 (dd, J=2.2, 1.4 Hz, 1H), 6.73 (t, J=2.1 Hz, 1H), 6.64 (t, J=2.2 Hz, 1H), 5.81 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:21]([CH3:22])[C@H:20]4[N:17]([C:18](=[O:26])[C@@H:19]4[C@H:23]([OH:25])[CH3:24])[C:16]=3[C:27]([O:29]CC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[N:5][N:4]=[N:3]1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:25][C@@H:23]([C@H:19]1[C:18](=[O:26])[N:17]2[C@@H:20]1[C@@H:21]([CH3:22])[C:15]([S:14][C@@H:12]1[CH2:11][NH:10][C@H:9]([CH2:8][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:13]1)=[C:16]2[C:27]([OH:29])=[O:28])[CH3:24]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4nnnn4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSc4nnnn4C)C3)[C@H](C)[C@H]12
Yield: 49.3 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-6-[(1R)- 1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g), 20% palladium hydroxide on carbon (0.5 g), 0.05M phosphate buffer (pH 6.3, 30 ml) and tetrahydrofuran (30 ml) was stirred for 3 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filt-rate was concentrated under reduced pressure to remove the organic solvent. The residue was washed with ethyl acetate (30 ml×2) and evaporated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (60 ml) and 10% aqueous acetone solution (120 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-{(1-methyl-1H-tetrazol-5-yl)thiomethyl}pyrrolidin-4-ylthio]-7-oxo-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.23 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[C:23]([Cl:35])=[CH:22][N:21]=1>>[Cl:35][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Product: COc1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 23 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine to yield 5-Chloro-N*4*-(2-methoxy-phenyl)-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (34.40 mg, 23% yield) as a white powder. 1H-NMR (CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.37 (s, 1H), 7.23 (m, 1H), 7.05 (m, 2H), 6.92 (m, 3H), 3.94 (s, 3H), 3.24 (q, J=18.8, 9.4 Hz, 2H), 2.83 (m, 3H), 2.67 (m, 2H), 2.07 (m, 2H), 1.33 (m, 2H). LC/MS (ESI+)=492 (M+H). MP=182-183.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[C:30](=[O:31])[C:29]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]5[C:27]4=[O:36])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 56.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (4.0 g, 18 mmol), K2CO3 (2.7 g, 20 mmole), N-(2-bromoethyl)phthalimide (4.8 g, 19 mmole) and CH3CN (100 ml) was stirred at reflux under N2 for 4 hours. After standing at ambient temperature for 65 hours, the reaction was poured into H2O. The resultant solid was collected to yield 4.0 g of a yellow powder. The product was recrystallized twice from ethanol to yield 3.5 g (50%) of a beige powder m.p.=220°-223 ° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:8]=2)[N:3]=1.[NH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:21][C@H:22]2[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]2)[CH:11]=[CH:10]3)=[CH:15][CH:16]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Fc1ccc(COc2ccc3nc(Cl)ccc3c2)cc1
Product: Fc1ccc(COc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 130 °C
Yield: 5.9 %

Procedure:
A stirred mixture of 2-chloro-6-(4-fluoro-benzyloxy)-quinoline (0.08 g, 0.4 mmol) and (R)-1-aminoindane (0.107 g, 1.00 mmol) was heated in a sealed tube for 20 h at 130° C. Purification by flash chromatography on silica gel (ethyl acetate in heptane, 0→80%) yielded the title compound as a dark oil (9 mg, 8%), MS 385.6 [(M+H)+].
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:37]([O:34][C:31]1[CH:30]=[CH:29][C:28]([C:14]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]3[N:13]=2)=[CH:33][CH:32]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (21 μL, 0.24 mmol) and potassium carbonate (122 mg, 0.88 mmol). The mixture was heated at reflux for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (67 mg, 61%) as a yellow solid. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.73 (d, 1H), 7.53 (d, 2H), 7.24 (t, 1H), 6.95 (d, 2H), 6.28 (d, 1H), 6.08–5.96 (m, 3H), 5.41 (dd, 1H), 5.27 (dd, 1H), 5.10 (d, 1H), 4.56 (d, 2H), 4.32 (m, 1H), 3.95 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1); Anal. Calcd for C30H34N6O: C, 72.86; H, 6.93; N16.99. Found: C, 72.47; H, 7.05; N, 16.75.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Br:8].CN(C)C1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:10][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Br:20])=[C:7]([Br:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1cc(Br)c(N)c(Br)n1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Br)c(NC(=O)CBr)c(Br)n1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
3-Amino-2,4-dibromo-6-methylpyridine (1.16 g, 4.38 mmol) was dissolved in methylene chloride (10 mL). N,N-dimethylaniline (0.77 g, 6.35 mmol) was added to the solution and then a solution of bromoacetyl bromide (1.03 g, 5.12 mmol) in dichloromethane (2 mL) was added dropwise thereto over 5 minutes with stirring and cooling with ice. After completion of addition, the temperature of the mixture was elevated to room temperature and stirred for 12 hours. The resultant mixture was washed sequentially with water, an aqueous saturated sodium hydrogencarbonate solution, and saturated brine. Subsequently, the mixture was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was crystallized from hexane-acetone, to thereby yield 1.44 g of N-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide as colorless crystals (yield 85.3%).
Reaction SMILES: C(N1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.Cl.[NH2:18][C@H:19]([C:27]([NH2:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:7]1(=[O:16])[N:18]([C@@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]([NH2:29])=[O:28])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
By following the procedure of Example 19 but employing N-carbethoxyphthalimide and (S)-phenylalaninamide hydrochloride, there is obtained (S)-2-phthalimido-3-phenylpropionamide which can be recrystallized from ethanol to afford white crystals: mp 211°-215° C.; 1H NMR (DMSO-d6) δ 7.92 (s, 5 H, Ph), 7.72, 7.33 (2 s, 2 H), 7.2-7.0 (m, 4 H, Ar), 4.92 (dd, 1H, J=12,4.5 Hz), 3.52 (dd, 1 H, J=4.3, 13.9), 3.35 (dd, 1 H, J=12, 13.9); 13C NMR (DMSO-d6) δ 169.6, 167.4, 137.7, 134.3, 131.2, 128.5, 128.1, 126.3, 122.9, 54.2, 33.7.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:36])[CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A stirred suspension of 4-(4-Benzyloxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.34 mmol, 170 mg) and paraformaldehyde (6.1 mmol, 550 mg) in DCM was stirred for 20 min then sodiumtriacetoxyborohydride (6.1 mmol, 1.2 g) was added. Stirring was continued overnight. The solvent was evaporated and saturated NaHCO3 solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant product was purified by flash silica gel column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([NH:28][C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]([CH:25]2[CH2:26][CH2:27][C:22]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:23][CH2:24]2)[C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)[C@@H](C)NC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred mixture of 2,4-dichloro-5-nitropyrimidine (4, 12 g, 62.1 mmol), potassium carbonate (11.7 g, 84.78 mmol) in acetone (100 mL) was added methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (13.8 g, 62.1 mmol) at rt. The reaction mixture was stirred for 16 h at rt. The bulk of solvent was removed under reduced pressure to give a residue, which was diluted with ethyl acetate (100 mL), washed with water, dried over sodium sulfate. The solvent was evaporated to give a crude material, which was then purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to afforded the desired product (10.1 g). 1HNMR (300 MHz, CDCl3): δ 1.55-1.64 (m, 3H), 1.70-1.99 (m, 6H), 2.05-2.20 (m, 3H), 3.06-3.15 (m, 1H), 3.75 (s, 3H), 3.99 (t, 4H), 8.61 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroindole (3.5 g; 21.6 mmol) in DMF (100ml) was added Cs2CO3 (13.9 g; 42.6 mmol). The mixture thus obtained was stirred 1 h hour at room temperature then 1-bromo-2-methoxyethane (5.9 g; 42.6 mmol) was added dropwise. The resulting mixture was heated to 120° C. under stirring for 4 hours. After cooling, the mixture was poured into water (500 ml) and the crude product was filtered, dried under vacuum to give 1-(2-methoxyethyl)-5-nitro-1H-indole which was used in the following reaction without any further purification.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][NH:11][C:12]2=[O:17].N([O-])=[O:19].[Na+].B(O)(O)O>O>[OH:19][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][NH:11][C:12]2=[O:17]
Reactant: O=N[O-]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: O=S(=O)(O)O
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2c(O)cccc12
Yield: 97 %

Procedure:
Concentrated sulphuric acid (8 ml) was added to a stirred mixture of 5-amino-1(2H)-phthalazinone (9.4 g, 0.058 mole) and water (50 ml). The resultant stirred paste was cooled in ice and diazotised by the addition of sodium nitrite (4.15 g, 0.06 mole) in water (15 ml). The filtered diazonium sulphate solution was added over 1.5 hours to a stirred boiling solution of concentrated sulphuric acid (30 ml) and boric acid (5.42 g, 0.088 mole) in water (200 ml). The solution was heated for a further 30 minutes then cooled and the collected solid was washed with water to give 5-hydroxy-1(2H)-phthalazinone 9.12 g, 96% m.p. 351°-355°). 5-Hydroxy-1(2H)-phthalazinone was purified as the 5-acetoxy derivative m.p. 162° (ethanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[N:8]1([C:6]2[N:7]=[C:2]([C:33]3[CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[CH:30]=[CH:31][CH:32]=3)[CH:3]=[C:4]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(-c2cc(Nc3ccc(OC(F)(F)F)cc3)nc(N3CCOCC3)n2)c1
Temperature: 30 °C
Yield: 49.7 %

Procedure:
To a mixture of compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.3 g, 0.8 mmol) and 3-acetyl benzene boronic acid (0.13 g, 0.79 mmol) in DMF (10 mL) was added palladium tetrakis triphenyl phosphine (0.027 g, 0.023 mmol) and 2M Na2CO3 soln (0.67 g, 6.32 mmol) at room temperature. The reaction mixture was then heated for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C., diluted with water, extracted with ethyl acetate (3×10 mL). Combined organic layers were concentrated and the residue was purified by column chromatography using 15% ethylacetate in pet-ether to afford the desired compound (0.18 g, 49%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([C:25]#[C:26][CH2:27][CH2:28][CH2:29]O)[CH:22]=[CH:23][CH:24]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCCC#Cc1cccc(C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(C(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(3-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1CCCc2c(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cccc21
Yield: 72.1 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-chlorobenzyl)-piperazine; yield 72.1% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 239°C (decomposed);
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:23])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)CCl>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:15]1[CH3:23])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 22.5 g (0.15 mole) of phthalic anhydride and 61.0 g (0.30 mole) of 77.5 percent active 1-ethyl-2-methylindole in 120 ml of ethylene dichloride chilled to 0° to 5° C. by means of an ice bath, there was added in small portions 32.0 g (0.24 mole) of aluminum chloride. The mixture was maintained at 0°-5° C. for an additional 15 minutes, allowed to warm to room temperature and stirred overnight. Then, 240 ml of water was added to the reaction mixture and the ethylene dichloride layer was separated from the acidic aqueous layer. The organic layer was extracted with 600 ml of 3.5 percent aqueous sodium hydroxide. The alkaline extract was acidified with dilute hydrochloric acid and the separated solid collected, washed with water and dried to obtain 24.0 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =CH2CH3), a slightly pink solid having a melting point of 184°-185° C.