Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C(=O)(O)[O-].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3cccs3)cc2)[nH]c2cc(Cl)ccc12
Yield: 82.2 %

Procedure:
A mixture of methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206, 0.40 g, 0.98 mmol), thiophene-2-boronic acid (0.14 g, 1.08 mmol), saturated aqueous sodium bicarbonate (4 ml), and dichlorobis(triphenylphosphine)palladium(II) (70 mg, 0.098 mmol) in DME (15 ml) was refluxed for 3 h. The mixture was poured into water (30 ml), and extracted with ethyl acetate (50 ml×2). The combined extracts were washed with brine (50 ml), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1:6) to afford 0.33 g (83%) of the title compound as yellow solids.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15].O.[CH3:40]N(C)C=O>>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([CH3:40])=[C:12]([Cl:13])[CH:11]=[C:5]2[C:6]1=[O:7])=[O:20])([O-:16])=[O:15]
Reactant: O=C1NC(=O)c2cc(Cl)c(Cl)cc21
Reactant: CN(C)C=O
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: O
Product: Cc1cc2c(cc1Cl)C(=O)N(C(=O)c1cc(Oc3ccc(C(F)(F)F)cc3C#N)ccc1[N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-chloro-5-chlorophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl]-4-methyl-5-chlorophthalimide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH3:25])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)c(F)c(C(=O)OCC)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Dissolve 6-fluoro-5-methanesulfonylamino-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.160 g, 0.444 mmol) in DMF (1.0 mL). Add potassium carbonate (44.4 mg, 0.32 mmol), iodomethane (41.5 μL, 0.67 mmol) and tetrabutylammonium bromide (14.3 mg, 0.04 mmol) to the solution. Stir the resulting slurry at room temperature for 16 h. Quench with saturated aqueous sodium sulfate solution (10 mL) and extract with ethyl acetate (3=30 mL). Combine the organic layers and dry (magnesium sulfate). Azeotrope the residue with xylenes to remove residual DMF. Purify (silica gel chromatography, eluting with 40:60 ethyl acetate:dichloromethane) to give the title compound as a solid (111 mg, 67%).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:15]=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:22]1>>[F:11][C:12]1[CH:13]=[C:14]([CH:15]([C:3]2[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=2[OH:1])[C:22]2[NH:21][C:29]3[C:24]([C:23]=2[CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(C(C)C)NC2=O)c2cc(F)cc(F)c2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with 3,5-difluoro-benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a yellow solid. MS: 468.0 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.[H-].[Na+].[H][H].[CH3:36]I>O1CCCC1>[CH3:36][O:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:16])=[CH:18][C:19]=2[CH3:31])=[C:24]1[CH3:30]
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCCC(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)=C1C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-((3R)-3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 41 (0.125 g, 0.303 mmol) was dissolved in anhydrous tetrahydrofuran (3.0 mL) followed by addition of sodium hydride (0.008 g, 0.333 mmol). After hydrogen gas evolution ceased (5 minutes), methyl iodide (0.038 mL, 0.606 mmol) was added and the reaction stirred for 30 minutes. Additional sodium hydride (0.008 g, 0.333 mmol) was added and stirring continued overnight. The reaction was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue by flash column chromatography, eluting with 30% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.120 g) as white crystals, m.p. 127–128° C.; [α]D=+45.65 (c=1.0, chloroform). Single crystal X-ray crystallography established the absolute configuration as the (R)-isomer.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[F:10].[CH3:47][S:48](Cl)(=[O:50])=[O:49].Cl>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([NH:33][C@:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([CH2:3][NH:2][S:48]([CH3:47])(=[O:50])=[O:49])[CH:5]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:46])=[CH:36][C:37]=1[C:42]([F:45])([F:44])[F:43]
Reactant: NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)—N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide hydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt was added TEA (6.8 μL, 0.05 mmol) followed by methanesulfonyl chloride (3.4 μL, 0.04 mmol). The reaction mixture was stirred at rt for 1 h and then poured into 1 N HCl. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO column chromatography (4 g, 0-40% EtOAc/hexane) to yield (R)-4-fluoro-N-(1-(4-fluoro-3-(methylsulfonamidomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 271) as a clear, colorless film (12 mg, 41%). 1H NMR (400 MHz, CDCl3) 7.95 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (m, 1H), 7.22 (m, 7H), 7.07 (t, J=8.97 Hz, 1H), 6.93 (m, 3H), 6.71 (m, 3H), 5.88 (m, 1H), 4.55 (t, J=6.32 Hz, 1H), 4.30 (t, J=5.81 Hz, 2H), 3.97 (m, 1H), 3.83 (m, 1H), 2.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:22](=[O:23])[C:21]3[C:20]([OH:24])=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[N:18]4)=[C:13]([OH:25])[C:12]=3[C:11]2=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:29]([O:31][C:32](Cl)=[O:33])[CH3:30].[C:35]1([CH:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N+]#N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1.ClCCl.O>[CH2:29]([O:31][C:32](=[O:33])[O:25][C:13]1[C:12]2[C:11](=[O:26])[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:22](=[O:23])[C:21]=2[C:20]([O:24][CH:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: O=C1c2c(c(O)c3ncccc3c2O)C(=O)N1CCc1ccc(F)cc1
Reactant: N#[N+]C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(CCc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
7-[2-(4-Fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 310 (250 mg, 0.71 mmol).was dissolved in dioxane (3.6 ml) and H2O (2.4 ml) and cooled to 0° C. After 1.0 M NaOH (1.42 ml, 1.42 mmol) and ethylchloroformate (84.6 mg, 0.78 mmol) were added, the reaction was stirred at 0° C. for one hour. The reaction mixture was quenched with the addition of acetic acid (0.6 ml) and concentrated in vacuo. The crude mixture was diluted with ethyl acetate and washed once with 5% Citric Acid (aqueous), twice with water, once with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dissolved in 1,2-dichloroethane (4.0 ml) and to this was added diphenyl-methanediazonium 38 (252 mg, 1.3 mmol). The reaction mixture was then stirred overnight at room temperature. Following dilution with dichloromethane, the reaction mixture was washed with once with water, once with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was then purified by silica gel chromatography (1/1—hexane/ethyl acetate) to afford carbonic acid 9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester ethyl ester 311 (251 mg, 0.425 mmol, 65%). 1H NMR (d-DMSO) δ 9.19 (dd, 1H), 8.52 (dd, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.54 (m, 4H), 7.20 (m, 8H), 7.02 (t, 2H), 4.24 (q, 2H), 3.79 (t, 2H), 2.90 (t, 2H), 1.25 (t, 3H). MS: 599.2 (M+23).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=CC=1C(O)=O.C(N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>CCOC(C)=O>[N-:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[CH2:4]([OH:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: CCOC(C)=O
Product: OCc1ccccc1
Product: c1c[n-]cn1

Procedure:
The carboxylic acid functionality in the quinolinecarboxylic acid (A) is protected using standard carboxylic acid protection procedures well known in the art, e.g., by formation of the corresponding ester, to give compound (B). For example, the benzyl ester (R21 is benzyl in (B)) may be prepared by treating a solution of compound (A) in EtOAc at room temperature with 1,1′-carbonyldiimidazole to produce the activated, imidazolide derivative of (A, then adding benzyl alcohol to the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.Br[CH2:27][O:28][C:29](=[O:31])[CH3:30].O>CN(C)C=O>[CH3:27][O:28][C:29](=[O:31])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CC(=O)OCBr
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (60 mg, 0.17 mmol, Example 59) and bromomethylacetate (60 mg, 0.39 mmol, Aldrich) in dimethylformamide (1.5 mL) was stirred at room temperature for 6 hours. The solution was poured into water and extracted into methylene chloride (2×). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin- 1-yl]-acetic acid methyl ester as a white solid. HRMS, observed: 418.1888; Calcd for M+: 418.1885.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:14]([CH3:13])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: CN(c1ccccc1)c1ncnc2cc(Cl)ccc12
Product: Cl
Yield: 52 %

Procedure:
A solution of 3.0 g of 4,7-dichloroquinazoline and 1.7 g of N-methylaniline in 10 ml of ethanol was heated for 10 minutes. After completion of the reaction, the ethanol was distilled off and the resulting crystals were recrystallized from a small amount of ethanol to give 2.4 g (yield 46%) of the desired Compound No. 56 in the form of pale yellow granules melting at 230°-233° C. (with decomposition).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:18]([CH3:31])[CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO>[CH3:31][C:18]1[CH:17]=[C:16]([CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:30]=[CH:29][C:19]=1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.6 %

Procedure:
Convert 3-phenyl piperidine hydrochloride (0.652 g, 3.30 mmol) to the free base using ion exchange chromatography (methanol→2 M ammonia/methanol) and concentrate. Combine the free base with 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (from step 1 above) (0.748 g, 3.29 mmol), sodium triacetoxyborohydride (1.05 g, 4.95 mmol), and acetic acid (0.30 mL, 5.24 mmol) in 1,2-dichloroethane (33 mL) and stir at ambient temperature. After 17 h, wash reaction mixture with saturated sodium bicarbonate (aq) (2× 50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→2:1 hexanes:ethyl acetate) to provide 0.878 g (70%) of the title compound as a white foam: 1H NMR (CDCl3): 8.46 (d, 1H, J=2.9 Hz), 7.91 (dd, 1H, J=2.9, 8.8 Hz), 7.34-7.19 (m, 7H), 6.99 (d, 2H, J=8.8 Hz), 3.52 (s, 2H), 3.06-2.94 (m, 2H), 2.86 (tt, 1H, J=3.9, 11.7 Hz), 2.13 (s, 3H), 2.10-1.91 (m, 3H), 1.84-1.68 (m, 2H), 1.48 (dq, 1H, J=4.9, 12.2 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]([OH:14])=O)=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:7]2[C:8]3[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=3[CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cccc2c1CCCC2=O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (430 mg, 2.26 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (464 mg, 2.26 mmol), HATU (1 g, 2.70 mmol) in anhydrous DMF (20 mL) is added DIPEA (446 μL, 2.70 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (65) as white solid (828 mg, 97%).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH:45]1[CH2:50][CH2:49][CH2:48][C@@H:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:46]1>C(#N)C>[C:54]([O:53][C:52](=[O:58])[NH:51][C@@H:47]1[CH2:48][CH2:49][CH2:50][N:45]([C:21]([N:7]2[C@H:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=3[S:17]([CH3:20])(=[O:19])=[O:18])[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[C:6]2=[O:33])=[O:22])[CH2:46]1)([CH3:55])([CH3:57])[CH3:56]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
4-Nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (Example 6A; 100 mg, 0.16 mmol) was dissolved in acetonitrile (1.25 ml), and tert-butyl (3R)-piperidin-3-ylcarbamate (96.1 mg, 0.48 mmol) was added with stirring. The mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). The product fractions were combined and concentrated under reduced pressure. This gave 81 mg (74% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[C:4](=[CH2:13])[NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-DL-serine methyl ester {5.48 g, Reference Example 15(a)} in tetrahydrofuran (60 mL) was treated with triethylamine (3.48 mL) followed by carbonyldiilmidazole (4.05 g). The mixture was stirred at room temperature overnight and then evaporated. The residue was extracted several times with tert-butyl methyl ether. The combined extracts were evaporated to give a colourless oil which was subjected to flash chromatography on silica eluting with toluene to give the title compound (3.64 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[C:12]1([CH:18]2[NH:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH3:41])[CH:33]=1>>[CH3:39][O:38][C:36]1[CH:37]=[C:32]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([N:20]4[CH2:21][CH2:22][NH:23][CH:18]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:19]4)=[N:7][CH:6]=[CH:5][N:4]3[N:8]=2)[CH:33]=[C:34]([O:40][CH3:41])[CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: Nc1nc2c(Cl)nccn2n1
Reactant: COc1cc(Cl)cc(OC)c1
Product: COc1cc(Nc2nc3c(N4CCNC(c5ccccc5)C4)nccn3n2)cc(OC)c1

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and tert-butyl 3-phenyl-piperazine-1-carboxylate were coupled according general procedure 3. The intermediate was isolated and Buchwald Hartwig Amination following general procedure 2 with 1-chloro-3,5-dimethoxy-benzene gave the title compound as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>O>[OH:8][CH2:7][C@H:5]([NH:6][C:11]([O:13][CH3:14])=[O:12])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](CO)C(=O)OC
Yield: 91.9 %

Procedure:
To a solution of 72.03 g L-serine-methylester hydrochloride in 400 ml of water were added at 0° C. 49.5 g of methyl chioroformate. The pH was kept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After 2½ h at 0° C. the mixture was extracted with 6 portions of ethyl acetate, the combined extracts were dried and evaporated to give 75.39 g (92%) of pure methyl 3-hydroxy-(S)-2-methoxycarbonylamino-propionate. IR (neat): 3380 m (NH, OH), 1720s, br. (C═O), 1535s (amide II). MS (EI): 178/20 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18].C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: ClCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCCc2c1ccn2CCCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,5,6,7-tetrahydroindol-4-one (10.0 g) in DMSO (100 mL) was added powdered sodium hydroxide (3.26 g) and the mixture was stirred at ambient temperature for 0.25 hours. 1-Bromo-4-chlorobutane (9.38 mL) was then added and the resulting mixture stirred at ambient temperature for 7 hours after which time TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (250 mL) and stirred for 0.5 hours. An oil separated and was isolated with a separatory funnel. The aqueous layer was extracted with dichloromethane (50 mL). The oil was dissolved with dichloromethane (25 mL) and the combined organics were dried with sodium sulfate, filtered and the solvent removed under vacuum. Flash chromatography (ethyl acetate:hexane, 1:1 to 2:1) yielded an oil (6.0 g) as the titled compound.