Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.C([NH+](CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 85 %

Procedure:
Pd(OH)2/C (6.60 g, 5.3 mmol) was flushed with nitrogen, (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 22) dissolved in methanol (164 mL) was added followed by the addition of triethylammonium formate (28.4 g, 188.0 mmol). The reaction mixture was refluxed for 1 h, cooled down to room temperature, filtered through a celite pad and the filtrate was concentrated under vacuum. the residue was recrystallized with methyl tert-butyl ether (200 mL) and heptanes (50 mL) to provide (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a beige solid (25.7 g, 85% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>O>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-pyridinamine hydrochloride (300 mg) was added portionwise to concentrated sulfuric acid (1.96 mL) at 4° C. To the mixture was added fuming nitric acid (0.1 mL) dropwise at 4° C. The mixture was stirred at ambient temperature for 3 hours. To the solution was added water and the mixture was extracted with EtOAc. The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-3-nitro-2-pyridinamine (125 mg) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:24])[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:3][C:4]=2[F:24])[O:22][CH3:23])=[CH:15][CH:16]=1)#[N:21]
Reactant: OB(O)c1ccccc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2)cc1F
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a solution of (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 69.1, 247 mg) in 1,2-dimethoxyethane (5 ml) was added tetrakis(triphenylphosphine) palladium (0) (73 mg). A solution of phenylboronic acid (118 mg) in EtOH (2.1 ml) and a solution of sodium carbonate (563 mg) in water (3 ml) were added. The mixture was stirred for 1.5 h at 85° C. The solids were filtered off and the filtrate was evaporated. The product was purified by flash chromatography (cyclohexane/EtOAc 2:1=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-biphenyl-4-yl)-2-methoxy-acetamide (172 mg). Off-white solid. MS 393.1 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]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]>[CH3:15][C:8]([C:6]1[CH:7]=[C:2]([B:17]([OH:21])[OH:18])[CH:3]=[N:4][CH:5]=1)([CH3:16])[CH2:9][O:10][C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)(COC(F)(F)F)c1cncc(Br)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: CC(C)(COC(F)(F)F)c1cncc(B(O)O)c1
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 64 Step B (80 mg, 0.27 mmol), bis(pinacolato)diboron (136 mg, 0.537 mmol), tris(dibenzylideneacetone)dipalladium (0) (49.1 mg, 0.054 mmol), tricyclohexylphosphine (30.1 mg, 0.107 mmol) and potassium acetate (79 mg, 0.805 mmol) in 1,4-dioxane (1.3 mL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then cooled to room temperature and passed through a syringe filter. The resulting solution was then concentrated under reduced pressure to afford the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[CH3:26][C:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:41])[N:29]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:28]=1>>[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:31]3[C:27]([CH3:26])=[N:28][N:29]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:30]=3[CH3:41])=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3c(C)nn(C(=O)OC(C)(C)C)c3C)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (92 mg, 0.25 mmol) was reacted with tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (120 mg, 0.37 mmol) to afford crude product (100 mg) as a brown solid which was carried forward without any purification: ESI MS m/z 521 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][CH:34]=[C:33]5[CH3:39])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A mixture of 7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquinazoline (4.6 g), 5-hydroxy-3-methylindole (2 g), (Journal of Organic Chemistry 1993, 58, 3757), potassium carbonate (3.1 g) and DMF (20 ml) was stirred and heated to 90° C. for 2 hours. The solid was removed by filtration washed with acetonitrile and the combined filtrates concentrated to dryness under vacuum. The product so obtained was triturated under ether/petroleum ether (8/2), collected by filtration and dried to give 7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (5.8 g).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:10]([CH3:29])=[N:9][CH:8]=1)=[O:6]>CO.C1COCC1.O>[NH2:4][C:5]([C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:10]([CH3:29])=[N:9][CH:8]=1)=[O:6]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(N)=O)cnc3C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ncc(C(N)=O)nc1-c1ccc([C@H]2CC[C@H](C(=O)O)CC2)cc1

Procedure:
Lithium hydroxide monohydrate (42 mg, 1.00 mmol) was added to a stirred solution of methyl trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate (Example 65, 71 mg, 0.20 mmol) in MeOH (2 mL), THF (1 mL) and water (0.5 mL). After 16 h the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC (150 mm×21 mm Phenomenex Column packed with Luna 10u C18 silica, eluting with 5-95% acetonitrile/water) to give the title compound as a yellow solid (6 mg, 9%); 1H NMR δ 9.01 (1H, s), 8.08 (1H, s), 7.73 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 2.70-2.50 (1H, m), 2.65 (3H, s), 2.37-2.25 (1H, m), 2.10-2.00 (2H, m), 1.95-1.85 (2H, m), 1.65-1.40 (4H, m); MS 340.
Reaction SMILES: [CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Pt]=O>[CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(C(c2ccncc2)C2CCCCC2)cc1
Agent: O=[Pt]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Product: Fc1ccc(C(C2CCCCC2)C2CCNCC2)cc1
Yield: 50 %

Procedure:
A mixture of 4-[(cyclohexyl)(4-fluorophenyl)methyl]pyridine (10.42 g, 0.039 mole), platinum oxide (1.5 g), and 10 drops of concentrated hydrochloric acid in 200 ml of glacial acetic was subjected to hydrogenation at 80° C. and 300 p.s.i. overnight, after which NMR analysis showed 50% desired product and 50% starting material. The reaction was repeated using 5% platinum on carbon at 85° C. and 1400 p.s.i. overnight. The reaction mixture was then cooled to room temperature and filtered. Solvent was removed by rotary evaporator. The oil obtained was dissolved in chloroform and extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give 9.94 g of brown oil. NMR analysis showed a 75%-25% mixture of product and starting material. The 9.94 g of oil obtained was dissolved in methanol and subjected to flash chromatography on silica gel using methanol and ammonium hydroxidemethanol for elution. Fractions of similar purity were combined and solvent removed. The clear oil obtained was dried in vacuo overnight at 80° C., to give 5.86 g (59.6% yield) of title compound as a clear oil.
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[O:6]1[CH2:7][CH2:8][C:3]2([O:9][C:13]3[C:14]4[C:19]([C:10](=[O:21])[C:11](=[O:20])[C:12]=3[S:1][CH2:2]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][CH2:5]1
Reactant: OC1(CS)CCOCC1
Reactant: O=C1C=Cc2ccccc2C1=O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCOCC1)O2

Procedure:
The crude 4-(mercaptomethyl)tetrahydro-2H-pyran-4-ol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione. The crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product as a purple solid. M.p.=195-197° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.6 1.0 Hz, 1H), 7.79 (dd, J=7.6 0.8 Hz, 1H), 7.67 (td, J=8.0 1.6 Hz 1H), 7.50 (td, J=8.0 1.2 Hz, 1H), 3.96-3.83 (m, 4H), 2.97 (s, 2H), 2.10-2.05 (m, 2H), 1.95-1.87 (m, 2H); LCMS: 303 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(Cc2cccc(Br)n2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccc(F)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(4-fluoro-benzyl)-pyridine.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][C:6](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[C:5]1=[O:9]
Reactant: CC1(C)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
100 ml of a 10% aqueous solution of sodium hydroxide were added to a mixture of 10 g of 2,2-dimethylcyclopentanone and 13.8 g of 4-chlorobenzaldehyde in 100 ml of ethanol at 0° C. After 30 minutes, a thick slurry was filtered off and the solid washed and then dried. 12.5 g of 2,2-dimethyl-5-(4-chlorobenzylidene)-1-cyclopentanone with a melting point of 120° C. were obtained. This compound, dissolved in 50 ml of THF, was added to a solution formed in the following manner: 1.9 g of sodium hydride (80% dispersion in mineral oil) in 50 ml of anhydrous DMSO were heated to 80° C. until complete dissolution of the solid. The solution was then diluted with 100 ml of THF, then cooled to -10° C. A solution of 11.5 g of trimethylsulphonium iodide in 80 ml of dimethyl sulphoxide were added to the mixture in the course of ten minutes and the mixture was stirred for 15 minutes at -10° C. A solution of 11.8 g of 2,2-dimethyl-4-chloro-5-(4-chlorobenzylidene)-1-cyclopentanone was then added in 100 ml of THF.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:21]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:2]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Reactant: O=Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cn2cc(Cc3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-((1H-indol-1-yl)methyl)benzoate 1 (0.250 g, 0.94 mmol) and benzaldehyde (96 μL, 0.94 mmol) in DCM (10 mL) at 0° C. was added SiEt3H (0.45 mL, 2.83 mmol) followed by trifluoroacetic acid (0.14 mL, 1.88 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was then adjusted to pH 10 with 2 N NaOH and the organic products were extracted with DCM (3×15 mL). The combined organic fractions were washed with brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The title compound was isolated using automated column chromatography method 1 (0.262 g, 78%). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.32-7.27 (m, 4H), 7.23-7.10 (m, 6H), 6.87 (s, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8, 143.0, 141.2, 136.8, 130.1, 129.5, 128.7, 128.4, 128.3, 126.6, 126.5, 126.0, 122.1, 119.5, 119.3, 115.4, 109.6, 52.2, 49.7, 31.6.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.S(Cl)(Cl)=O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:8][C:7]([CH:6]1[CH2:5][CH2:4][N:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[C:2]1=[O:1])=[O:9])[CH3:25]
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 57.5 °C
Yield: 65 %

Procedure:
A mixture of 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid obtained in step 1 (0.7 g, 2.56 mmol), thionyl chloride (0.36 g, 3.0 mmol), and ethanol (10 ml) were heated at 55-60° C. for 2 hours. The mixture was cooled and solvent was removed. The residue was dissolved in ethyl acetate (20 ml). The organic layer was washed with sat. NaHCO3 and saturated brine solution, dried over Na2SO4 and evaporated to obtain 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester as a yellow oil (0.5 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:10]([CH:21](C)[NH:22][CH2:23]C1C=CC=CC=1)[CH2:9][CH2:8]2)=[O:4].Cl>[Pd].CO>[C:15]1([CH:11]2[C:12]3[C:7](=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=3)[CH2:8][CH2:9][CH:10]2[CH2:21][NH:22][CH3:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)CCC(C(C)NCc1ccccc1)=C2c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCC1CCc2cc(C(=O)OC)ccc2C1c1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
To a mixture of 1-phenyl-2-[methyl(phenylmethyl)aminomethyl]-3,4-dihydronaphthalene-6-carboxylic acid methyl ester (4.20 g), methyl alcohol (120 cm3) and hydrochloric acid (5 M, 2.4 cm3) was added palladium on charcoal (5%, 500 mg). The resulting suspension was stirred at 50° C. under a hydrogen atmosphere (5 atm) for 18 h. Upon cooling the mixture was filtered through a pad of Dicalite® and the solvent was evaporated under reduced pressure to afford the title compound (3.49 g, 95%) as a white powder.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[N:1]1([C:7]([CH:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1coc2ccccc12)N1CCCCC1
Solvent: CO
Product: O=C(C1COc2ccccc21)N1CCCCC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 3-(1-piperidylcarbonyl)benzofuran (6.7 g) in methanol (150 ml) kept at 35°-50° C. were added small portions (in total 3 g) of Mg turnings during 5 hours. After stirring for another hour at 50° C. the mixture was poured onto an aqueous solution of NH4 Cl. The aqueous solution was extracted with dichloromethane (2×200 ml). The combined organic phases were worked-up yielding 6.7 g of the title 2,3-dihydrobenzofuran derivative as an oil.
Reaction SMILES: [CH3:1][C:2]([CH2:20][CH:21]=[CH2:22])([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3]([OH:5])=O.Cl.[O:24]=[C:25]1[CH2:30][CH2:29][C:28]([NH2:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[O:24]=[C:25]1[CH2:26][CH2:27][C:28]([NH:37][C:3](=[O:5])[C:2]([CH3:1])([CH2:20][CH:21]=[CH2:22])[C:6]2[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: C=CCC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Product: C=CCC(C)(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 10) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 3) according to the method of Description 11. 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.71 (2H, s), 7.35-7.27 (5H, m), 5.58 (1H, br s), 5.57-5.45 (1H, m), 5.09-5.03 (2H, m), 2.81-2.73 (2H, m), 2.66-2.60 (2H, m), 2.48-2.30 (6H, m), and 1.63 (3H, s).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[C@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([O:23][NH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:2]1.[C:25]([NH:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=O)[C:51]([OH:53])=[O:52])[N:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:25]([NH:44][C:45]1[S:46][CH:47]=[C:48](/[C:50](=[N:24]/[O:23][CH:6]([C:7]([O:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:8])[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)/[C:51]([OH:53])=[O:52])[N:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NOC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccsc1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: O=C(O)/C(=N\OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccsc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Diphenylmethyl 2-(3-thienyl)-2-aminooxyacetate (140 mg) was dissolved in methanol (14 ml), and 2-(2-tritylaminothiazol-4-yl)-2-oxoacetic acid (171 mg) was added. After stirring the mixture for 1 hr. at the room temperature, and further stirring for 30 min. under ice-cooling to obtain a crystal, the crystal thus obtained was filtered off to give (Z)-2-(2-tritylamino-4-thiazolyl)-2-[(diphenylmethyloxycarbonyl)(3-thienyl)methyl]oxyiminoacetic acid (210 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[CH2:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:13][CH3:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[S:16][C:15]([CH2:12][CH2:13][CH3:14])=[CH:19][CH:18]=2)[CH:10]=1
Reactant: CCCc1cccs1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCCc1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
5-Bromo-2-chlorobenzoic acid and 2-n-propylthiophene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[P:16]([OH:18])[OH:17]
Reactant: OP(O)C(NC(c1ccccc1)c1ccccc1)c1ccc2c(c1)OCO2
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(c1ccc2c(c1)OCO2)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(3,4-methylenedioxyphenyl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(3,4-methylenedioxyphenyl)-methanephosphonous acid, melting point 235°-236°.