Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](O)=[O:10]>>[CH:9]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: NCc1ccccn1
Reactant: O=CO
Product: O=CNCc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Aminomethylpyridine (60 g.) was refluxed with 180 ml. of formic acid for 4 hours and left to stir for approximately 16 hours at room temperature. The reaction mixture was concentrated to an oil and purified; 2-formamidomethylpyridine obtained by distillation (72.3 g., b.p. 117°-141° C./0.5 mm.)
Reaction SMILES: ClC1C=C(S([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=O)=O)C=CC=1.[CH2:34](OC(=O)C1C=CC(N)=CC=1)[CH3:35]>>[CH2:34]([O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][NH:11]3)=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:31][CH:30]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 487.29 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 4 was performed using 4-amino-benzoic acid ethyl ester, yielding 4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reacted with 3-chloro-benzenesulfonyl chloride in step 5, yielding 4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].[Na+].[I-:10]>CC(O)=O>[I:10]/[CH:3]=[CH:2]\[C:1]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: C#CC(=O)OC(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=O)/C=C\I
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a mixture of isopropyl propiolate (350 g, 3.1 moles) in AcOH (1300 mL) was added NaI (930 g, 6.2 moles) at 25° C. The reaction mixture was heated to 115° C. and stirred for 1.5 hrs. The reaction mixture was cooled to 25 to 30° C. and quenched with water followed by extraction with MTBE. The organic layer was washed with saturated bicarbonate, bisulfite and brine solution. The organic layer was dried over sodium sulfate and concentrated under vacuum to give the product (Z)-isopropyl 3-iodoacrylate (626 g; 83.5%). Product was confirmed by 1H NMR.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH:23]3[NH:26][C:27]3[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=3)[O:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>C(#N)C>[CH2:1]([N:26]([CH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)[CH:25]=2)[CH2:21][CH2:22]1)[C:27]1[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=1)[O:30][CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH3:2]
Reactant: CCI
Reactant: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(c1cccc(OCC(=O)OC(C)C)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Ethyl iodide (45 mg, 0.286 mmol) and potassium carbonate (8 mg, 0.057 mmol) were added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (12 mg, 0.029 mmol) and acetonitrile (2 mL) in a 50 mL round bottom flask at room temperature. The mixture was then heated to reflux and allowed to stir overnight. The solution was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 50% ethyl acetate/hexanes) to afford 7 mg (55%) of isopropyl 2-(3-(ethyl(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:31]=[C:30]2[C:26]([C:27](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCC(=O)O)c1C
Yield: 43.7 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (234 mg), 239 mg 6-(2-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by chromatography on a silica gel column eluting with ethyl acetate:hexane 1:1 containing 0.1% acetic acid to give 182 mg (44%) of the title compound as a brown solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:5]=1.O[Li].O.C(O)(=O)C>C1COCC1.CO.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[C:18]3[CH:19]=[N:20][CH:21]=[C:16]([C:14]([NH:13][C:10]4([C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:3]([OH:32])=[O:2])[CH2:12][CH2:11]4)=[O:15])[C:17]=3[CH:24]=[N:23]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Reaction time: 3 h

Procedure:
To a solution of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid methyl ester (0.650 g, 1.51 mmol) in a mixture of THF/methanol/water (22.5 mL, 3:1:1) is added LiOH.H2O (253 mg, 6.04 mmol). After 3 hours, the reaction mixture is neutralized with glacial acetic acid and concentrated in vacuo. The residue is dissolved in a solution of 20% methanol in methylene chloride (100 mL). Water (100 mL) is added and the mixture is acidified to pH 4 with 2M aqueous hydrochloric acid. Phases are separated, and the aqueous layer is extracted with 20% methanol in methylene chloride (9×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to approximately 50 mL. The resulting crystallized solids are filtered, washed with cold methanol (3×2 mL) and air dried to afford the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:8]=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:5][CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:16])[C:14]3[C:6]([C:7]=2[CH:8]=1)=[CH:5][CH:4]=[C:3]([CH2:2][O:20][C:18](=[O:21])[CH3:19])[CH:15]=3
Reactant: CC(=O)[O-]
Reactant: O=C1c2cc(CBr)ccc2-c2cc(Br)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
7-Bromomethyl-3-bromo-9-fluorenone (1.7 g) was suspended in DMF (25 ml). To this suspension was added potassium acetate (576 mg). The reaction mixture was stirred at 100° C. for one hour. It was then diluted with ethyl acetate, washed four times with water, twice with brine, dried and evaporated. The residue was chromatographed on silica gel using 2% ethyl acetate/methylene chloride and gave the desired product (1.18 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:44]=[C:43]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[O:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:44]=[C:43]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[O:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K11) according to the general procedure M. Obtained as a light yellow foam (774 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[CH3:22][O:23][C:24]1[C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=[C:26]([CH:33]=O)[CH:25]=1.[BH3-]C#N.[Na+]>CCOC(C)=O.O1CCCC1.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:33][C:26]2[CH:25]=[C:24]([O:23][CH3:22])[C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1cc(C=O)cc2c1OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc2c1OCO2
Reaction time: 4 h
Yield: 70.1 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 250 mg of 7-methoxy-1,3-benzodioxole-5-carboxaldehyde in place of the benzaldehyde, 0.2 ml of acetic acid and 0.4 ml of tetrahydrofuran and the reaction medium is left for 4 hours at ambient temperature. Then 100 mg of NaBH3CN is added and agitation is carried out at ambient temperature for approximately 3 hours. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of saturated aqueous solution of NaCl, followed by drying and evaporating the solvent and purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 90/10/1. In this way 311 mg of expected product is obtained in the form of beige crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:27]>O1CCCC1.C(OCC)C>[ClH:27].[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH:16]([NH2:18])[CH3:17]
Reactant: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CC(C)N)c(OC)c2ccccc12
Temperature: 0 °C

Procedure:
The product from Step B (0.5 g, 1.83 mmol) was dissolved in tetrahydrofuran (50 mL). This solution was cooled to 0° C. and then a 1 M solution of lithium aluminum hydride in tetrahydrofuran (9 mL) was added. The reaction mixture was allowed to warm to room temperature and then warmed at reflux for an additional 5 h. The excess lithium aluminum hydride was destroyed by the addition of ethyl acetate and water. The organic material was extracted with dichloromethane (3×50 mL). The combined extracts were dried (MgSO4) and concentrated to give an oil which was dissolved in dry ethyl ether. To this solution was added a 1.0 M solution of hydrogen chloride in diethyl ether (10 mL). A solid formed (200 mg) and was collected by filtration: 1H NMR (DMSO-d6) δ 1.15 (d, 3H, CH3), 2.97 (m, 2H, CH2), 3.60 (m, 1H), 3.82 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.85 (s, 1H, Ar—H), 7.96 (d, 2H, Ar—H), 8.12 (d, 2H, Ar—H), 8.15 (bs, NH3+); MS 246 (M+1). Analysis. Calcd. for C15H19NO2.HCl.2 H2O: C, 63.13; H, 7.20; N, 4.91. Found: C, 62.73; H, 7.03; N, 4.87.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[C:34]#[N:35].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[C:34]([C:33]1[CH:32]=[C:31]([NH:30][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]3[CH2:16][CH2:17][CH2:18][O:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: N#Cc1cccc(N)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2c(Nc3cccc(C#N)c3)cccc2c1CCCOc1cccc2ccccc12
Temperature: 100 °C

Procedure:
A mixture of ethyl 7-bromo-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (45.2 mg), 3-aminobenzonitrile (14.2 mg), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (Cy-map) (5.9 mg), tris(dibenzylideneacetone)dipalladium(0) (4.6 mg), and Cs2CO3 (46 mg) in dioxane (1 mL) was degassed via vacuum-nitrogen cycle three times. The reaction mixture was heated at 100° C. for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified with flash chromatography (1:9 EtOAc/Hex) to provide the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:35]([O-:40])(=[O:39])[C:36]([O-:38])=[O:37]>CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:3]=1.[C:35]([O-:40])(=[O:39])[C:36]([O-:38])=[O:37]
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CN1CCC(OC(c2cccc(-c3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 95 °C

Procedure:
A mixture of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200 mg), phenylboronic acid (70 mg), palladium acetate (4.8 mg) and 1,1-bis(diphenylphosphino)ferrocene is placed in a round-bottom flask and purged with argon. A 1M aqueous degassed solution of potassium carbonate (1.51 mL) and degassed tetrahydrofuran (2 mL) are introduced. The mixture is heated at 95° C. for 30 min, cooled back to room temperature and filtered over a celite pad. The cake is rinsed with ethyl acetate and water. The pooled phases are decanted. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (gradient dichloromethane/methanol from 98/2 to 90/10) to give the crude base which is then converted to the oxalate in acetone to give 2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate as a beige amorphous solid.
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:40]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[N:54]=[C:53]([CH2:55]Br)[CH:52]=[CH:51][C:49]=2[N:50]=1>>[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[N:54]=[C:53]([CH2:55][N:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:39][C:40]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]3=4)[CH:52]=[CH:51][C:49]=2[N:50]=1
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(CN3c4ccccc4Cc4ccccc43)ccc2n1

Procedure:
N-[(2,4-Diaminopyrido[3,2-d]pyrimidin-6-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminopyrido[3,2-d]pyrimidin-6-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[3,2-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[N:9]=2)=[O:7])[CH2:5][CH2:4]1.CO>C1COCC1.[Cl-].[NH4+]>[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[O:7])[CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(=O)C3CC3)c3cc([N+](=O)[O-])cnc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1n[nH]c2ncc([N+](=O)[O-])cc12)C1CC1
Yield: 85 %

Procedure:
NaOH (0.39 mL, 0.39 mmol) was added to cyclopropyl(5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (0.076 g, 0.20 mmol) in THF:MeOH (1 ml, 4:1). After the compound dissolved in about 5 minutes, the reaction was complete. The reaction mixture was diluted with aqueous ammonium chloride (8 mL) and extracted with EtOAc (3×4 mL). The combined organic layers were dried over sodium sulfate, decanted, and concentrated to provide cyclopropyl(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (0.040 g, 0.17 mmol, 88% yield).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][N:18]([CH2:2][CH:3]([OH:4])[CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[C:19](=[NH:20])[NH2:21]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Product: N=C(N)N(CCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O)CC(O)C(O)C(O)C(O)CO

Procedure:
The manufacture took place by reductive amination of D-glucose and L-(+)-arginine in the molar ratio 2:1 using Raney nickel or palladium/activated carbon (10%) as a catalyst in the temperature range from 50° to 70° C. As a reaction product a light-yellow resin was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH2:23]>CO.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=191-193° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>CN(C=O)C.N1C=CC=CC=1>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Reactant: Clc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(Cl)cccc32)nc(N2CCOCC2)cc1=S

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 158 mg of 4-chloro-2,3-dihydro-1H-indole.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:1]=[C:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[O:7][CH3:6])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCCC1Oc1cc(C(=O)OC)ccc1OC
Temperature: -40 °C

Procedure:
28.5 g of methyltriphenylphosphonium bromide are suspended under nitrogen in 300 ml of anhydrous THF and the mixture is cooled to -40° C. 50 ml of n-butyllithium (1.6M) in n-hexane are then added dropwise with stirring. After stirring at -20° to -10° for 30 min, a solution of 20 g of methyl 4-methoxy-3-(2-oxocyclopentyloxy)benzoate in 100 ml of abs. THF is added dropwise. The mixture is then allowed to warm to RT and is stirred for a further 1 h. It is poured onto water and extracted with ethyl acetate. The oil which remains after concentrating the organic phase is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 12.7 g of the title compound are obtained as a colorless oil.