Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 80.9 %

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred for dissolution. 30 g of esomeprazole was taken into a separate round bottom flask and dissolved in 150 ml of toluene and this solution was added to the above sodium hydroxide solution. The combined mixture was stirred for 1.5 hours, and distilled completely at 55° C. The residue was then co-distilled with 450 ml of toluene in three equal lots. The residue was dissolved in 60 ml of toluene and stirred at 29° C. for 1 hour, 20 minutes and filtered. The solid was dried at 34° C. for 9 hours to yield 25.8 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:23]1[CH:24]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=1[CH:31]([CH3:33])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 2-iodo-1-isopropyl-4-(methylsulfonyl)benzene (Intermediate 91), the title compound was obtained as a brown solid in 74% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.CO.CCOC(C)=O>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: O=C(Cc1nccs1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2nccs2)cc([N+](=O)[O-])c1O
Yield: 3.4 %

Procedure:
To a mixture of 1-phenyl-2-(thiazol-2-yl)ethanone (Intermediate 3) (170 mg, 0.84 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (212 mg, 1.00 mmol), and urea (151 mg, 2.52 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 30% of the starting materials were consumed, the reaction mixture was concentrated, and the crude product was purified by column chromatography and preparative HPLC to afford Compound 12 as a yellow solid (12.5 mg, yield: 3.4%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.25 (s, 1H), 9.25 (s, 1H), 7.82 (s, 1H), 7.50-7.56 (m, 4H), 7.48 (s, 1H), 7.36-7.40 (m, 3H), 7.22 (d, J=3.6 Hz, 1H), 5.68 (d, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); MS (ESI): m/z 439.1 [M+1]+.
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[CH3:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=1[O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Reactant: Cc1cccc(S(C)(=O)=O)c1F
Product: Cc1cccc(S(C)(=O)=O)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1

Procedure:
The compound of Example 156 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-fluoro-1-methyl-3-(methylsulfonyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH2:14][C:15]([CH2:53][F:54])([OH:52])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1>O.C(OCC)(=O)C>[F:13][CH2:14][C:15]([CH2:53][F:54])([OH:52])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CF)CF)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CF)CF)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogen carbonate (0.47 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.16 g) was added, and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 34 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.055 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N+:23]([O-])[CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC.[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][SH:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][S:46][C:24]1[C:25]2[C:20](=[CH:19][C:18]([S:15]([N:11]3[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH3:29])(=[O:17])=[O:16])=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c[n+]([O-])ccc2c1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c(SCCNC(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
320 mg of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide was dissolved in dichloromethane, and 0.1 mL of ethyl chlorocarbonate, 0.42 mL of 2-(N-tert-butoxycarbonylamino)ethanethiol, and 0.21 mL of triethylamine were added at 0° C. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:acetone=4:1) to obtain 223 mg of the compound of interest as a colorless oil (51%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:15]([O:18][C:19](=O)C)(=O)C>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([C:6](=[CH:15][O:18][CH3:19])[C:7]#[N:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Product: COC=C(C#N)C(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 150 °C
Yield: 98.8 %

Procedure:
A mixture of 21 g of 2,4-dichloro-5-fluoro-benzoyl-acetonitrile, 19.2 g of methyl o-formate and 23.1 g of acetic anhydride is refluxed at a bath temperature of 150° C. for 3 hours. The volatile constituents are then distilled off under a waterpump vacuum and finally under a fine vacuum at a bath temperature of 120° C. 24.5 g (99%) of 2-(2,4-dichloro-5-fluoro-benzoyl)-3-methoxy-acrylonitrile are obtained. A sample recrystallized from toluene gives colorless crystals of melting point 159° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:27]#[N:28].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: COc1ccc(C#N)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 90 °C
Yield: 65.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 3-bromo-4-methoxybenzonitrile (0.20 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) in toluene (5 ml) and ethanol (2 ml), with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.17 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: COCCOc1ccc(F)c(F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccc(F)c(F)c1C(=O)O
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a suspension of 3,4-difluorophenol (2 g) and cesium carbonate (7.51 g) in N,N-dimethylformamide (15 mL) was added 2-methoxyethyl bromide (2.14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3,4-difluoro-1-(2-methoxyethoxy)-benzene (2.49 g). To the solution of the obtained 3,4-difluoro-1-(2-methoxyethoxy)benzene (1.47 g) in tetrahydrofuran (39 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (10 g), and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:23])[C:16]2[N:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH3:2].C(O)C.[OH-].[Na+].ClCCl>O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:14][C:15](=[O:23])[C:16]3[N:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cccnc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Yield: 72.3 %

Procedure:
A stirred mixture of 2-(2-ethoxy-5-nitrophenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (Example 19; 1.1 g, 0.00353 mol), stannous chloride dehydrate (4.0 g, 0.0177 mol) and ethanol (15 ml) was heated under reflux for 4 hours. The resulting mixture was allowed to cool, diluted with water (15 ml), adjusted to pH 8 with 2N aqueous sodium hydroxide solution, vigorously shaken with dichloromethane (30 ml), and then this mixture filtered. The aqueous phase was separated and extracted further with dichloromethane (2×30 ml), and the organic extracts were then combined, dried (MgSO4) and evaporated under vacuum. Crystallisation of the product from acetonitrile gave the title compound as a hydrated yellow solid (0.72 g, 72%), m.p. 208°-210° C. Found: C,62.88; H,4.88; N,19.67. C15H14N4O2 ;0.25H2O requires C,62.81; H,5.10; N,19.54%.
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:14][N:13]([CH3:15])[C:9](=[O:10])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:26][CH2:27]1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(Nc2nc3cncnc3n2Cc2ccccn2)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 3.46 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 80° C. after cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.1 parts (71%) of N,N-dimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide; mp. 191.6° C. (compound 122).
Reaction SMILES: [O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:37]([Si:39](Cl)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38].O>CN(C)C=O>[O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:39]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:37][CH3:38])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C)OC(=O)OCC(Cl)(Cl)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)OC(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of tert-butyl (3S,7R,8S)-5-oxo-3-hydroxy-4,4,8-trimethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.7 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17]>C(O)C>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:6]/[C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)/[C:16]#[N:17]
Reactant: Cc1ccccc1CC#N
Reactant: O=Cc1ccc[nH]1
Solvent: CCO
Product: Cc1ccccc1/C(C#N)=C/c1ccc[nH]1
Temperature: 90 °C
Yield: 30.5 %

Procedure:
A thick walled tube was charged with 1H-pyrrole-2-carbaldehyde (2.0 g, 21.0 mmol), 2-methylphenylacetonitrile (2.5 g, 18.9 mmol, 0.9 equivalents), ethanol (75 ml), and 40% aqueous Triton B (4.0 ml, 3.3 mmol). The tube was sealed and heated to 90° C. for 4 days. Removal of the solvent, followed by chromatography on silica gel using dichloromethane/petroleum spirits (20:80) as eluant afforded a yellow solid (1.2 g). This is Compound 16 in Table 8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.C[C:19]([N:21](C)C)=O>>[C:19]([C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1)#[N:21]
Reactant: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Reactant: CC(=O)N(C)C
Product: Cc1nc2ccc3ccc(C#N)cc3c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
A solution of 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one (0.50 g, 1.7 mmol) and cuprous cyanide (0.46 g, 5.1 mmol) in dimethylacetamide (10 ml) under nitrogen was heated under reflux for 2 hours, cuprous cyanide (0.16 g, 1.8 mmol) added and refluxing continued for 18 hours. The solvent was removed under high vacuum to give crude 9-cyano-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended in sulphuric acid (2M, 300 ml), the suspension stirred at reflux under nitrogen for 40 hours, cooled and adjusted to pH 8.5 with sodium hydroxide (21 g) and saturated sodium bicarbonate solution. The resulting suspension was filtered to give the partially purified nitrile which was subjected to refluxing 2N hydrochloric acid in 95% ethanol for 24 hours. The solution was made basic with NaOH, filtered, the filtrate adjusted to neutral and filtered. The resulting filtrate was adjusted to pH 1.5 and the precipitate filtered and dried under high vacuum to give a 2:1 mixture of carboxylic acid to nitrile (225 mg). A solution of the mixture (0.22 g), N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (0.32 g, 1.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.19 g, 1.0 mmol) in dimethylformamide (25 ml) was stirred overnight, more 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g, 1.0 mmol) added, the reaction mixture stirred for another 4 hours, then concentrated in vacuo onto silica gel (2 g). Purification by chromatography on silica gel (150 g) eluting with methanol:methylene chloride (3:97 to 1.:19) and filtration of the resulting solid from, methanol gave, after drying under high vacuum, diethyl (N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl-L-glutamate (0.027 g). 1NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, ester CH3), 1.20 (t, J=7 Hz, ester CH3), 1.95-2.20 (m, 2H, gluCH2), 2.46 (s, 3H, 3-CH3 and t, J=7 Hz, 2H, gluCH2). 4.06 (q, J=7 Hz, 2H, ester CH2), 4.12 (q, J=6.5 Hz, 2H, ester CH2), 4.39-4.49 (m, 1H, gluCH), 7.75 (d, J=9 Hz, 1H, Ar), 7.93 (s, 4H, Ar), 8.12 (dd, J=8.5, 1.5 Hz, 1H, Ar), 8.19 (d, J=8.5 Hz, 1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 8.67 (d, J=7.5 Hz, 1H, gluNH), 10.37 (s, 1H, Ar), 10.76 (s, 1H, CONHAr), 12.72 (s, 1H, N2H). Exact mass spectrum calculated for (C30H30N4O7)+ : 559.2193. Found: 559.2191.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCNC5)cc4C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 78.6 %

Procedure:
The crude methyl 2-((S)-6-((2′,6′-dimethyl-4′-((S)-pyrrolidin-3-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8a (45 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of methanesulfonyl chloride (13 mg, 0.11 mmol) and triethylamine (18 mg, 0.18 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8b (40 mg, yield 77.0%) as a colorless oil.