Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][CH:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:35][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:21]([Cl:20])[C:22]([O:24][CH3:25])=[O:23])=[CH:32][CH:31]=2)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C(Cl)Cc1ccc(CCO)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Triphenylphosphine (2.4 g, 9 mmol) was added to a solution of methyl 2-chloro-3-[4-(2-hydroxyethyl)phenyl]propanoate (2.1 g, 8.5 mmol) and 4-(benzyloxy)phenol (1.7 g, 8 mmol) in 20 ml toluene under nitrogen atmosphere. The solution was warmed to 55° C. and diisopropyl azodicarboxylate (1.8 g, 9 mmol) was added. The reaction mixture was stirred at 55° C. overnight. The mixture was allowed to cool and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a 80:20 mixture of heptane and EtOAc as eluent to yield 2.28 g of the desired product (yield 61%) as colourless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([N:46]([CH3:45])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccccc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCOCc1ccccc1
Temperature: 105 °C
Yield: 91 %

Procedure:
A solution of 4-(2-benzyloxy-ethyl)-2-(4-bromo-phenyl)-5-methyl-oxazole (200 mg, 0.538 mmol) in toluene (5.0 mL) in a seal tube under nitrogen gas flow was treated with Pd(OAc)2 (50 mg), 2-(di-t-butylphosphino)biphenyl (20 mg), N-methyl aniline (115 mg, 1.08 mmol), and sodium t-butoxide (104 mg, 1.08 mmol). The tube was sealed and heated at 105° C. for 14 h. The mixture was cooled and purified directly by silica gel column chromatography (30-50% EtOAc/hexanes) to yield the title compound (195 mg, 91%). MS (ESI) m/z 399.3 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].Cl.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23])[C:12]1[O:13][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: CNc1ccccc1I
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc2ccccc2c(=O)o1)c1ccccc1I

Procedure:
A solution of 2-methoxycarbonylphenyl isocyanate (1.0 g, 5.6 mmol), N-methyl-2-iodoaniline, hydrochloride (1.6 g, 5.9 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.3 mmol) in 100 mL of toluene was refluxed under N2 for 72 hours. The sample was concentrated, and partitioned between chloroform and 10% HCl. The chloroform was dried (MgSO4), filtered, concentrated and chromatographed (silica gel, methylene chloride) to give the title compound as a yellow solid, mp 144°-148° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][CH:13]=[CH:12][C:11]2=O>>[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[C:11]2[Cl:3]
Reactant: O=S(Cl)Cl
Reactant: O=c1cc[nH]c2c(Br)cccc12
Product: Clc1ccnc2c(Br)cccc12

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Thionyl chloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9.0 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid. The obtained 8-bromo-4-chloroquinoline (0.050 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.045 g), 8-quinolinol (0.0045 g), copper(I) oxide (0.0015 g), PEG (Mn=3400) (0.010 g), and cesium carbonate (0.17 g) were suspended in DMSO (2.1 ml). The suspension was purged with nitrogen, then sealed in the tube, and stirred at 110° C. for 2 hours. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate to obtain 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline as a pale yellow solid (0.073 g). Compound (119) was obtained as a pale yellow solid (yield based on 6 steps: 17%) according to Example 1(5) using the obtained 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline instead of compound (1d).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1
Reactant: O=C(c1sccc1Cl)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCN(Cc3sccc3Cl)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
A suspension of 29.7 mg of 1-[1-[1-(3-Chloro-2-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one and 7 mg of lithium aluminum hydride in 1 ml of THF was stirred at 0° C. for 2 h and then quenched with Na2SO4—10H2O. The mixture was stirred overnight and the insoluble material was removed by filtration. The filtrate was concentrated and purified with PTLC (CHCl3/MeOH/28% aqueous NH3=120/10/1) to give 11.0 mg of the target compound as a colorless solid.
Reaction SMILES: O[CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C(Cl)Cl>[O:27]1[CH2:28][CH2:29][N:24]([CH:2]2[C:12]3[C:13]4[C:5](=[C:6]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[NH:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH2:4][CH2:3]2)[CH2:25][CH2:26]1
Reactant: OC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: c1ccc(-c2[nH]c3cccc4c3c2CCC4N2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A portion (0.47 g) of the compound obtained in Example 256 was suspended in anhydrous methylene chloride (15 ml) and to the suspension was added dropwise a solution of thionyl chloride (0.15 ml) in anhydrous methylene chloride (5 ml) under cooling with ice. After stirring for 30 minutes, a solution (10 ml) of morpholine (1.65 ml) in anhydrous methylene chloride was added dropwise and the mixture was stirred for 3 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was washed with diethyl ether and methanol to yield 0.38 g (63%) of the titled compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:7][NH:6][CH2:5]1)[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Br:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]2)[C:12]([F:32])=[CH:11][C:10]=1[F:33].CN1CCCC1.C(OC(C)C)(C)C>CS(C)=O>[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([N:6]4[CH2:7][CH:4]([NH:3][CH2:1][CH3:2])[CH2:5]4)[C:23]=3[Br:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]2)[C:12]([F:32])=[CH:11][C:10]=1[F:33]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reactant: CCNC1CNC1
Agent: CN1CCCC1
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: CCNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
3-Ethylaminoazetidine (700 mg), 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.5 g), N-methyl-pyrrolidine (2.0 g)and dimethylsulfoxide (4.5 g) were combined, and the mixture was heated under stirring at 40° C. for 24 hours. After the mixture was allowed to cool down, isopropyl ether (10 mL) was added, the mixture was stirred, and a clear layer at the top of the mixture was removed. The same procedure was repeated once more, and the residue was concentrated under reduced pressure. Ethanol (5 mL) was added, and the mixture was heated under stirring at 70° C. for 30 minutes. The precipitated solid was collected by filtration. The title compound (1.38 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([O:18][CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)Cc2ccc(OCC3CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.626 mmol) 6-cyclopropylmethoxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLIII.1) in 3 mL THF are added 30 mg (0.69 mmol) NaH (55%) and stirred at r.t. for 30 min. Then 35 μL (0.56 mmol) methyl iodide are added and the reaction mixture is stirred at 80° C. over night. The reaction mixture is quenched by the addition of water and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: C1CO[C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:26])[C@H:15]([CH3:25])[CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:26][C@@H:14]1[C@H:15]([CH3:25])[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C:20](=[O:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:3](=[O:2])[CH3:4])[CH2:13]1
Reactant: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 51.9 %

Procedure:
A solution of 20,20-ethylenedioxy-3α-hydroxy-2α-methyl-5α-pregnane-11-one (0.38 g.) and toluene-p-sulphonic acid (30 mg.) in acetone (20 ml.) was kept at room temperature for 11/2 hr. The reaction mixture was then evaporated to low bulk and an aqueous solution of sodium hydrogen carbonate was added. The precipitated solid (0.32 g.) was collected and purified by preparative t.l.c. and crystallised from methyl acetate/petrol (b.p. 60°-80°) to give the title compound (0.175 g.), m.p. 179°-180°, [α]D + 125°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].[CH3:13]I.O>CC(C)=O>[CH3:13][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc2ccccc2n1C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To 10 grams of 2-methyl benzimidazole (75 mM), crushed 25 grams of crushed KOH (450 mM) in 300 ml acetone, methyl iodide (15 grams, 105 mM) was added at a continuous drip for 0.5 hours, at room temperature. Following additional 0.5 hour, water was added, the reaction extracted with dichloromethane, evaporated and chromatographed on silica gel to yield 6 grams (54%) of 1,2-dimethyl benzimidazole as a white solid having a melting point of 102° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:30]=[O:31])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=3[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:30]([CH:1]2[CH2:3][CH2:2]2)[OH:31])=[CH:9][CH:8]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Solvent: C1CCOC1
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.33 mL, 0.33 mmol) was added to a stirred solution of 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (111 mg, 0.299 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:13])/[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:13])/[C:10]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: C/C(=C\c1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)cc1
Yield: 84.6 %

Procedure:
A mixture of Example 1B (16.1 g, 89.4 mmol), N,O-dimethylhydroxylamine hydrochloride (9.15 g, 93.9 mmol), 1-hydroxybenzotriazole hydrate (12.7 g, 93.9 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (17.9 g, 93.9 mmol), and diisopropylethyl amine (47.4 g, 370 mmol) was stirred in DMF (400 mL) at ambient temperature overnight. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, 1N HCl, water, brine, dried over Na2SO4, and evaporated in vacuo. The resulting material was chromatographed (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield the title compound (16.89 g, 58% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (dd, J=8.82, 5.43 Hz, 2H), 7.00-7.14 (m, 2H), 6.79 (s, 1H), 3.70 (s, 3H), 3.29 (s, 3H), 2.11 (s, 3H). MS (DCI+) 224 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.ClCCl.O.C(#N)C>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[C:3]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Clc1ncnc2c1oc1ccccc12
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2ncnc3c2oc2ccccc23)c1
Yield: 74 %

Procedure:
First, 4.02 g of 4-chlorobenzofuro[3,2-d]pyrimidine, 4.52 g of 3,5-dimethylphenylboronic acid, 3.21 g of sodium carbonate, 0.17 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to microwave irradiation (2.45 GHz, 100 W) for 60 minutes. Further, 0.75 g of 3,5-dimethylphenylboronic acid, 0.53 g of sodium carbonate, and 0.043 g of Pd(PPh3)2Cl2 were added to the mixture, and the reaction container was heated again by 60-minute microwave irradiation (2.45 GHz, 100 W). After that, water was added to this solution and extraction with dichloromethane was carried out. The obtained solution of the extract was washed with water and saturated brine and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using a developing solvent in which the ratio of dichloromethane to ethyl acetate was 10:1, so that Hdmpbfpm, which was the pyrimidine derivative to be produced, was obtained as a white powder in a yield of 74%. Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is illustrated in (e-1) below.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C[N:15](C=O)C.N>ClCCl>[CH:1]1([CH2:6][C:7]([NH2:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: CN(C)C=O
Agent: N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
Cyclopentylacetic acid (5.2 g, 41 mmol) and thionyl chloride (10 mL) were combined then DMF (0.2 mL) was added and the solution was stirred 1.5 h at R.T. Dichloromethane (10 mL) was added and the solution cooled in an ice bath whereupon 25% aqueous ammonia (30 mL) was added and the mixture stirred for 0.5 h. The solution was extracted with CH2Cl2 (3×) and the combined extracts washed with 1N HCl, dried over MgSO4, and concentrated to give cyclopentylacetamide (2.699 g, 52%). [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and naphthalen-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C22H22O5 [M+NH4]+: 389.3.
Reaction SMILES: [CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13](=[O:23])[CH2:14][C:15]2[CH:16]=C([CH:20]=[CH:21][CH:22]=2)C#N)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[C:27]([OH:30])(=[O:29])[CH3:28]>O>[CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13](=[O:23])[CH2:14][C:15]2[CH:16]=[C:28]([CH:20]=[CH:21][CH:22]=2)[C:27]([OH:30])=[O:29])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)O
Reactant: CCCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Agent: Cl
Solvent: O
Product: CCCCCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1

Procedure:
The acid chloride prepared from 3-cyanophenylacetic acid (5 g) as described in Example 18 is added at once to 1-phenyloctane (5.9 g, 0.03 moles) in methylene chloride (20 ml). Anhydrous aluminium chloride (4.96 g, 0.037 moles) is added in 1 portion and the resulting mixture heated under reflux for 2 hours. The reaction mixture is cooled and poured into a mixture of ice water (200 ml) and concentrated hydrochloric acid (20 ml). The mixture is extracted with ether (3×50 ml) and the combined extracts dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica gel (hexane: ether; 70:30) to yield 3-(4-n-octylphenacyl)benzonitrile (3.12 g, m.p. 59°-64° C). This nitrile is heated under reflux in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) for 48 hours. The reaction mixture is diluted with water (60 ml) and extracted with ether (3×50 ml). The combined ether extracts are washed with water (50 ml) then dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane and again from aqueous ethanol to provide 3-(4-octyl-phenacyl)benzoic acid (1.5 g), m.p. 103°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:70]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([C:25](=[O:26])[NH:78][CH2:77][CH2:76][N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCN2CCCCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-piperidin-1-yl-ethylamine (24 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).