Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccnc3)c(C)sc2n1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (100 mg, 0.232 mmol) (Example 61) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 3-Pyridinylboronic acid (42.7 mg, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 5% MeOH in DCM, was followed by further purification by MDAP (basic conditions), to afford the title compound (32.7 mg). LCMS (A) m/z: 430 [M+1]+, Rt 0.83 min (basic), Rt 0.85 min (acidic).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:19])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].C([O-])([O-])=O.[K+].[K+].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28].C[N:34]([CH:36]=O)[CH3:35]>>[CH3:31][O:30][C:27](=[O:29])[C:28]1[CH:17]=[CH:9][CH:8]=[CH:7][C:36]=1[NH:34][CH:35]1[CH2:18][CH2:6][N:5]([CH2:2][C:3](=[O:4])[NH:5][C:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:19])[C:11]4[C:16]([C:17]=3[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(CCl)Nc1ccc2c(c1)-c1ccccc1C2=O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccccc1NC1CCN(CC(=O)Nc2ccc3c(c2)-c2ccccc2C3=O)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 2-(Piperidine-4-yl-amino)-methyl benzoate (1100 mg, 4.70 mmol), 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide (1358 mg, 5 mmol) and K2CO3 (1380 mg, 10 mmol) in DMF (40 mL) was stirred at 10° C. for 2 hours and then at room temperature overnight. The reaction mixture was added to 50 mL water and 100 mL ethyl acetate, the organic phase was decanted and washed with water (3×50 mL), dried over sodium sulfate and a 2.8 M hydrogen chloride solution in absolute ethanol (1.80 mL) was added, to precipitate the hydrochloride, which was filtered off and washed with ethyl acetate. 1840 mg of a white solid were obtained. Yield: 77%.
Reaction SMILES: O1C2C=CC=C[C:4]=2[CH:3]=N1.[OH:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1)[CH3:4]
Reactant: c1ccc2oncc2c1
Reactant: COc1ccc2c(O)noc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1noc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzisoxazole from part (b) (193 mg, 1.17 mmol), ethanol (750, 1.29 mmol) and triphenylphosphine (460 mg, 1.75 mmol) were dissolved in anhydrous THF (4 ml) and cooled)(0°. Diisopropylazodicarboxylate (345 μl, 1.75 mmol) was added slowly and after 10-15 min the reaction flask was removed from the ice bath and the reaction mixture was stirred at room temperature overnight under an argon atmosphere. The solution was evaporated to dryness and the residue pre-absorbed onto silica, and chromatographed on silica (19 g); eluent: hexane (300 ml), 10-30% ethyl acetate/hexane to give 3-ethoxy-6-methoxy-1,2-benzisoxazole (101 mg, 44%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12](O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[O:16]1[CH2:33][CH:17]1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-:35].[K+].[K+]>C(#N)C>[OH:35][CH:17]([CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:24]1)[CH2:33][O:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: c1ccc(OCC2CCN(CC3CO3)CC2)cc1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1OCC(O)CN1CCC(COc2ccccc2)CC1

Procedure:
A mixture of 0.9 g. 2-ethoxycarbonyl-4-hydroxyindole, 1.7 g. N-(2,3-epoxypropyl)-4-phenoxymethylpiperidine, 1.2 g. potassium carbonate and 50 ml. acetonitrile is heated under reflux for 10 hours. The reaction mixture is then filtered while still hot and the filtrate left to cool overnight. 0.3 g. (15% of theory) 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-2-ethoxycarbonylindole crystallize out; m.p. 168°-170° C.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[CH:11][C:10]2=[C:14]3[C:3]=1[O:4][CH2:5][CH:6]([CH3:17])[N:7]3C(=O)[C:9]2=[O:15].[OH:18]O>[OH-].[Na+]>[F:13][C:12]1[C:2]([F:1])=[C:3]2[O:4][CH2:5][CH:6]([CH3:17])[NH:7][C:14]2=[C:10]([C:9]([OH:15])=[O:18])[CH:11]=1
Reactant: OO
Reactant: CC1COc2c(F)c(F)cc3c2N1C(=O)C3=O
Agent: [Na+]
Agent: [OH-]
Product: CC1COc2c(F)c(F)cc(C(=O)O)c2N1
Temperature: 5 °C

Procedure:
A suspension of 6.9 g (28.8 mmol) of 6,7-difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1,2-dione (Example 30) in 250 mL of 4.5% aqueous sodium hydroxide is treated dropwise with 16.4 mL of 30% hydrogen peroxide over 1 hour. The reaction is filtered to remove a trace of insoluble material and the filtrate is acidified to pH 4.5 with acetic acid. After cooling to 5° C., the precipitate is removed by filtration, washed with water and dried in vacuo to give 5.5 g of the title compound, mp 200-202° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=2[CH2:19]1)=O)C.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](O)=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=O)(C)(C)C>>[OH:3][CH2:4][CH2:6][N:7]([CH2:54][C:51]1[CH:50]=[CH:49][C:48]([CH:45]2[CH2:44][CH2:43][N:42]([CH3:40])[CH2:47][CH2:46]2)=[CH:53][CH:52]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=2[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc([C@@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)cc1OC
Yield: 56.7 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4,5-dimethoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (39 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (38 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (25 mg) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:31](=[O:32])[CH2:30][O:29][CH3:28])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH2:6][CH2:5]1
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Reactant: COCC(=O)Cl
Product: COCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
1.5 g of 11β,17,21-trihydroxy-6α-methyl-4-pregnene-3,20-dione is reacted analogously to Example 1(a) with methoxyacetic acid chloride, worked up, and chromatographed, thus isolating 1.6 g of 11β,17-dihydroxy-21-methoxyacetoxy-6α-methyl-4-pregnene-3,20-dione.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:12]([C:20]([F:23])([F:22])[F:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C@H:29]1[C:37]2[C:32](=[CH:33][C:34](O)=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:34]3[CH:33]=[C:32]4[C:37](=[CH:36][CH:35]=3)[C@H:29]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:39])[CH2:30][CH2:31]4)[C:12]([C:20]([F:21])([F:23])[F:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
To a solution of 3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 316) (0.34 g, 1.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.18 g, 0.84 mmol) in THF (8.50 mL) was added PPh3 (0.29 g, 1.09 mmol) and ADDP (0.28 g, 1.09 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.33 g, 74%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.72 (d, 1H), 7.25 (d, 2H), 7.12 (d, 1H), 7.01 (d, 1H), 6.76 (d, 1H), 6.68 (dd, 1H), 4.15 (q, 2H), 4.08 (t, 2H), 3.82 (t, 2H), 3.45 (qt, 1H), 2.90-2.68 (m, 5H), 2.42-2.28 (m, 2H), 2.16 (qt, 2H), 1.78-1.68 (m, 1H), 1.30-1.24 (m, 6H).
Reaction SMILES: [NH3:1].CC(O)C.[F:6][C:7]([F:41])([CH2:13][C:14]1([OH:40])[C:27]2[CH:26]=[C:25]([O:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][C:17]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)=[CH:18][CH:19]=2)[C:8]([O:10]CC)=O>>[F:41][C:7]([F:6])([CH2:13][C:14]1([OH:40])[C:27]2[CH:26]=[C:25]([O:28][CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][C:17]([C:34]1[CH:39]=[N:38][CH:37]=[N:36][CH:35]=1)=[CH:18][CH:19]=2)[C:8]([NH2:1])=[O:10]
Reactant: N
Reactant: CCOC(=O)C(F)(F)CC1(O)c2cc(OCC(C)(C)C)ccc2Oc2ccc(-c3cncnc3)cc21
Solvent: CC(C)O
Product: CC(C)(C)COc1ccc2c(c1)C(O)(CC(F)(F)C(N)=O)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ammonia, as a 2 M solution in iPrOH (15 mL, 30.0 mmol), was added to ethyl 2,2-difluoro-3-(9-hydroxy-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-yl)propanoate (0.100 g, 0.201 mmol) at room temperature. After 30 minutes of stirring at RT the solution was concentrated to afford 2,2-difluoro-3-(9-hydroxy-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-yl)propanamide. M=470.3 [M+H].
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:16][F:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:14]/[OH:15])=[CH:12][C:4]1=2.C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[C:28]=1[Cl:40].Cl>CN(C=O)C.O>[F:17][CH2:16][C:3]1([CH2:2][F:1])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([C:13]3[CH2:34][C:33]([C:31]4[CH:30]=[C:29]([Cl:39])[C:28]([Cl:40])=[C:27]([Cl:26])[CH:32]=4)([C:35]([F:38])([F:37])[F:36])[O:15][N:14]=3)=[CH:12][C:4]1=2
Reactant: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: OB1OC(CF)(CF)c2cc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of (E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (440 mg, 1.83 mmol) in DMF (10 mL) at rt was added NCS (294 mg, 2.19 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (577 mg, 2.10 mmol) and TEA (403 mg, 4.0 mmol) in DMF (10 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, then stirred at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, 16%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 7.96-7.80 (m, 5H), 4.89-4.80 (m, 2H), 4.73-4.64 (m, 2H), 4.46 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H) ppm; HPLC purity: 95.3% at 214 nm; MS: m/z=516 (M+1, ESI+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:48][C:39]([CH3:41])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reaction time: 0.08 h
Yield: 97.2 %

Procedure:
3-Phenoxybenzoic acid (3.00 g, 14.0 mmol) was dissolved in DMF (45 mL), and the solution was added with EDCI (4.03 g, 21.0 mmol) and HOBT monohydrate (1.07 g, 7.00 mmol) under ice-cooling, followed by stirring at the same temperature for 5 minutes. Then, the mixture was added with cumylamine (4.03 mL, 28.0 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane to obtain 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.51 g, yield 97%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.1 g, 10 mmol), o-tolylboronic acid (1.5 g, 1.1 eq), tetrakis(triphenyl-phosphine)palladium (575 mg, 0.05 eq), and sodium carbonate (5.5 g, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-o-tolylquinoline-3-carbaldehyde was obtained as white solid. 1H-NMR (CDCl3) 9.96 (s, 1H), 8.83 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.3 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.36-7.46 (m, 4H), 2.84 (s, 3H), δ 2.30 (s, 3H). Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])([CH3:28])[CH3:27])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
Sodium hydride (0.664 g, 26.28 mmol) was added to a solution of 4-hydroxy-benzoic acid benzyl ester (5.0 g, 21.90 mmol) and 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) in DMF (50 mL). The resulting mixture was warmed up to 80° C. and stirred for 1 h before additional 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) and sodium hydride (0.664 g, 26.28 mmol) was added. After 18 h at 80° C. about 50% product could be detected by LC-MS. The reaction mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (MgSO4) and evaporated and the desired product was isolated from the remaining mixture by HPLC. The title compound was obtained as an oil (2.5 g, 30.8%). 1H NMR (500 MHz, CDCl3): δ 7.96 (d, 2H), 7.43 (d, 2H), 7.37 (t, 2H), 7.33 (d, 1H), 6.82 (d, 2H), 5.32 (s, 2H), 1.60 (s, 6H), 1.40 (s, 9H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[F:27][C:28]1[C:33]([CH:34]=[O:35])=[CH:32][CH:31]=[C:30]([NH:36][C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[N:29]=1.O>O1CCCC1>[F:27][C:28]1[C:33]([CH:34]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)[OH:35])=[CH:32][CH:31]=[C:30]([NH:36][C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[N:29]=1
Reactant: COc1ccc(Nc2ccc(C=O)c(F)n2)cn1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: 5 °C
Yield: 92.4 %

Procedure:
To a solution of 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1.02 g, 2.461 mmol) in 6.0 mL of tetrahydrofuran at −50° C. under nitrogen, isopropylmagnesium chloride (1.23 mL, 2.00 M in tetrahydrofuran, 2.46 mmol) is added slowly. The reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C., followed by addition of 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde (56, 0.165 g, 0.667 mmol) in 2.0 mL of tetrahydrofuran. The reaction is allowed to warm to room temperature over an hour, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (68, 330 mg). MS (ESI) [M+H+]+=536.2.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].Cl.[C:9]([NH2:13])(=[NH:12])[CH2:10][CH3:11].C(Cl)Cl>O>[CH3:5][O:4][C:2]([NH:13][C:9](=[NH:12])[CH2:10][CH3:11])=[O:3]
Reactant: CCC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC(=N)NC(=O)OC
Yield: 91 %

Procedure:
298.6 parts of methyl chloroformate and 472.8 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 298 parts of propionamidine hydrochloride in 1,300 parts of methylene chloride and 200 parts of water, at from 20° to 25° C., in the course of 25 minutes, while stirring. The reaction mixture is stirred at 25° C. for three hours and diluted with 300 parts of water, and the phases are separated. The aqueous phase is extracted once with 200 parts of methyl chloride and the solvent is stripped off from the organic extract to give 325 parts (=91% of theory) of N-methoxycarbonylpropionamidine of melting point 87°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[C:22]2[C:27]([N:28]=[C:29]3[C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][CH:23]=2>>[C:17]([O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=2[C:21]2[C:22]3[C:27]([N:28]=[C:29]4[C:34]=2[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9][CH2:10]1)(=[O:19])[CH3:18]
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Reactant: CC(=O)OCCN1CCN(c2ccc(N)cc2)CC1
Product: CC(=O)OCCN1CCN(c2ccc(N)cc2-c2c3c(nc4ccccc24)CCCC3)CC1
Yield: 47 %

Procedure:
0.14 ml (2.0 mmol) of 2-bromoethanol and 0.17 ml (2.4 mmol) of acetyl chloride were dissolved in 2 ml of dichloromethane. 0.28 ml (2.0 mmol) of triethylamine was added, and the reaction mixture was stirred at room temperature. After 1 h 50 ml of dichloromethane was added to the reaction mixture, which was then washed with a sodium bicarbonate (sat.) solution, a 10% citric acid solution and water. The organic phase was dried over sodium sulfate and evaporated to obtain 0.241 g (72%) of 2-bromoethylacetate. Following the procedure outlined in Step 1 of Example 1, but substituting 2-bromoethylacetate for methyl iodide, afforded 2-[4-(4-nitrophenyl)piperazin-1-yl]ethylacetate (64%), which was reduced according to the procedure of Step 2 in Example 1 to give the corresponding amine 2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate in quantitative yield. 2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate was reacted with 9-chloro-1,2,3,4-tetrahydroacridine (according to the procedure of Step 4 in Example 1) to obtain 2-{4-[4-amino-(1,2,3,4-tetrahydroacridin-9-yl)phenyl]piperazin-1-yl}ethyl acetate with 47% yield. Treating the ester with 4 equivalents of lithium hydroxide in a dioxane/water solution overnight, afforded the title compound with 60% yield (overall yield 20%).