Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.[C:22]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:32][CH:33]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)Oc1ccc(N)cc1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Product: CC(C)(C)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(-c3cncnc3)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 170 using (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1) and 4-tert-butoxyaniline to afford an off-white foam. HPLC (Condition 4) tR=4.31 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=434.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 9H) 1.67-1.77 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=3.91 Hz, 1H) 3.14-3.25 (m, 2H) 3.30-3.45 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 6.88-7.00 (m, 2H) 7.56-7.66 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 8.87 (d, J=0.78 Hz, 2H) 9.17 (s, 1H) 9.92 (s, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3([C:19]#[N:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
NaH (14.6 g, 0.61 mol) was suspended in DMF (100 mL). [4-(3-Pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (25.5 g, 0.10 mol) was dissolved in DMF (100 mL) and added dropwise to the ice-cooled suspension of NaH. The reaction mixture was stirred at room temperature for 30 min followed by dropwise addition of 2-bromoethylether (36.2 g, 0.16 mol) in DMF (200 mL) in ice-cold condition. The reaction mixture was poured into ice-cold water. The solid was filtered, washed with water, dried and the resulting solid was washed with 5% EtOAc in hexane to give the title compound (22 g, 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([O:17][CH2:18][CH2:19][OH:20])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:21])=[CH:4][N:3]=1.Cl.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:21][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([O:17][CH2:18][CH2:19][OH:20])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:29][C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: OCCOC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(OCCO)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a suspension of 2-((6-((2,5-dichloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)oxy)ethanol (0.18 g, 0.54 mmol) in n-BuOH (5 mL) were added 1-methylpyrazol-4-amine hydrochloride (0.15 g, 1.10 mmol) and DIPEA (0.28 g, 2.18 mmol). The mixture was stirred in a sealed tube at 150° C. overnight and then concentrated in vacuo. The residue was purified by a silica chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as brown sticky liquid (42 mg, 20%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]([O:14][CH3:15])[O:9][CH:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][CH:2]=1>CCO.CCOC(C)=O.[Pd]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH:7]2[CH2:11][CH:10]([O:12][CH3:13])[O:9][CH:8]2[O:14][CH3:15])=[CH:5][CH:6]=1
Reactant: COC1C=C(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reaction time: 1.75 h
Yield: 96.1 %

Procedure:
A mixture of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran (1.00 g, 3.55 mmol) and 5% Pd/C (300 mg) in EtOH:EtOAc (1:2) was stirred under H2 atmosphere for 1.75 hours. The catalyst was filtered onto Celite. The filtrate was concentrated to provide 0.97 g (97%) of a diastereomeric mixture of 3-biphenyl4-yl-2,5-dimethoxy-tetrahydro-furan as a colorless oil which was typically used without purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C[Si](Cl)(C)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:25])[CH3:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CN(C1C=CN=CC=1)C.CO.N1C=CC=CC=1.O1CCCC1.CN(C)C=O>[CH2:23]([NH:25][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: CCN
Reactant: O=C(O)C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)C(O)c1ccccc1
Yield: 82.9 %

Procedure:
According to Reference Example 8-56, 2-hydroxy-2-phenylacetic acid (500 mg, 3.29 mmol) was dissolved in dichloromethane (7.5 mL), and the solution was stirred with pyridine (0.532 mL, 6.58 mmol), DMAP (40 mg, 0.33 mmol), trimethylsilyl chloride (0.835 mL, 6.58 mmol), N,N-dimethylformamide (0.050 mL), oxalyl chloride (0.301 mL, 3.45 mmol), a solution containing a 2 mol/L tetrahydrofuran solution of ethylamine (1.81 mL, 3.62 mmol) and pyridine (0.878 mL), and a solution containing a methanol (5 mL) and citric acid (695 mg, 3.62 mmol). Thus, N-ethyl-2-hydroxy-2-phenylacetamide (Compound EF) (489 mg, yield: 83%) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-])=O)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pt]>[NH2:31][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:20][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate (4.84 g, 10.1 mmol) was dissolved in 150 mL of toluene and the solution was placed in a pressure bottle. Platinum on carbon (5%, 680 mg) was then added and the reaction mixture was shaken under H2 at 52 PSI (3.6×105 Pa). After 8 hours, the reaction mixture was then filtered through a pad of CELITE filter agent. The pad was rinsed with 2-propanol and the combined filtrates were concentrated under reduced pressure to give tert-butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (4.51 g) as a brown foam.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>>[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:35][CH:34]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CSc1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Product: CSc1ccc(COCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 4-(methylthio)phenylmethane chloride are treated aa described in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:19]([F:22])([F:21])[F:20])=[N:13][C:14]([C:15]([O:17]C)=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[Na+].Cl>O1CCCC1.CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:19]([F:20])([F:21])[F:22])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 34 %

Procedure:
Methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (30 mg, 0.057 mmol) was dissolved in 1.5 mL of a mixed solvent of tetrahydrofuran, methanol and water (V N N=1:1:1), followed by addition of sodium hydroxide (10 mg, 0.25 mmol). After stirring for 12 hours, concentrated hydrochloric acid was added dropwise to the reaction mixture until the pH was 2. The reaction mixture was extracted with dichloromethane (15 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 8 (10 mg, yield 34.4%) as a light yellow solid.
Reaction SMILES: [O-]CC.[Na+].[C:5](#[N:8])[CH:6]=[CH2:7].[CH2:9]([O:12][P:13]([CH:15]([O:20][CH2:21][CH2:22][CH3:23])[O:16][CH2:17][CH2:18][CH3:19])[OH:14])[CH2:10]C.C(O)(=O)C>C(O)C>[C:5]([CH2:6][CH2:7][P:13]([CH:15]([O:16][CH2:17][CH2:18][CH3:19])[O:20][CH2:21][CH2:22][CH3:23])(=[O:14])[O:12][CH2:9][CH3:10])#[N:8]
Reactant: CCCOC(OCCC)P(O)OCCC
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOC(OCCC)P(=O)(CCC#N)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium ethoxide in absolute ethanol (0.48 g of sodium metal in 15 ml of absolute ethanol) is cooled to 0° under nitrogen or argon. A solution of 2.72 g of acrylonitrile and 12.2 g of di-n-propyloxymethylphosphonous acid n-propylester in 50 ml of absolute ethanol is added at such a rate that the temperature does not exceed 5°. After the addition is completed, the solution is allowed to warm to room temperature and stirred overnight. After addition of 1.22 g of glacial acetic acid, the reaction mixture is concentrated in vacuo. The residue is partitioned between ethyl acetate and water and the organic phase separated. After drying over anhydrous magnesium sulphate the solvent is evaporated in vacuo to afford an oil. Chromatography on silica-gel yields ethyl 2-cyanoethyl(di-n-propyloxymethyl)phosphinate as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([O-])([O-])OCC>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:13]=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: CCOC([O-])[O-]
Product: O=S1(=O)N=CNc2ccc(Cl)cc21
Temperature: 110 °C

Procedure:
40 ml of ethyl orthoformate are added to 4.75 g of 2-amino-5-chlorobenzenesulphonamide, the preparation of which is described in the journal J. Chem. Soc. Perkin I 1979, 1043-1047. The mixture is heated at 110° C. for 30 minutes in an open vessel. Dissolution is observed, and then the appearance of a precipitate.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH2:29][C@H:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:33][C@H:30]([CH2:31][OH:32])[CH2:29][CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC[C@H](O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC[C@@H](O)CCOc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 78.2 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(3S)-(3,4-dihydroxybutan-1-yl)oxy]quinazoline (2.00 g) in methanol (40 ml) is added 10% palladium/carbon (300 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 21.5 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is washed with acetone to give 4-[(3S)-(3,4-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.10 g) as crystals.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[C:8]([F:9])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[N:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([C:6]3[CH:7]=[C:8]([F:9])[C:3]([CH:2]([F:1])[F:21])=[CH:4][C:5]=3[O:19][CH3:20])=[N:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1
Reactant: Clc1ncnc2cc(Br)ccc12
Reactant: COc1cc(C(F)F)c(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.101 g, 0.123 mmol), 2-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate SSSSS; 1.365 g, 4.52 mmol), 7-bromo-4-chloroquinazoline (Synnovator, 1.000 g, 4.11 mmol), and potassium carbonate (2.270 g, 16.43 mmol) in 12 mL dioxane was treated with 4 mL water and was allowed to stir at room temperature overnight. LC/MS showed mostly product, so the reaction mixture was diluted with DCM and filtered through a plug of Celite. The aqueous layer was removed and the organics concentrated. The crude residue was carried on to step 2 without purification. (M+H)+=384.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:18])([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[CH3:7])=[O:5])[CH3:2].CN.Cl.[CH3:22][N:23](C)CCCN=C=NCC>C(Cl)Cl.C(O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:5])[C:6]([CH3:18])([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:13])[NH:23][CH3:22])[CH:10]=1)[CH3:7])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
1.0 g (4.0 mmol) of 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoic acid was dissolved in 50 ml of methylene chloride; then, 1.5 ml (4.0 mmol) of a methylamine-solution in ethanol was added. The reaction mixture was cooled down to 0° C. and 0.91 g (4.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.50 g (11.9 mmol) of 4-dimethylaminopyridine were added. After stirring for two hours at ambient temperature, it was poured into crashed ice/HCl (1N) and extracted twice with MeCl2. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 0.97 g of the title compound in form of colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O1CCCC1.[CH3:26][NH2:27]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:27][CH3:26])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 0.25 h

Procedure:
A suspension of 14.3g (0.05 mol) of 7-chloro-5-phenyl-1,2,3,5-tetrahydro-4H-1,5-benzodiazepin-2,4-dione in 1l of tetrahydrofuran and 200 ml of benzene was saturated with methylamine. A solution of 11.5 g (0.06 mol) of titanium tetrachloride in 200 ml of benzene was added at 0° through a dropping funnel. After stirring at 0° to 10° for 15 min, the mixture was heated to reflux for 1 1/2 hrs. It was then partitioned between water and benzene. The benzene layer was separated, dried and evaporated. Crystallization of the residue form methylene chloride/hexane yielded the above-named product, mp 215°-217°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C@@H:27]1[CH2:31][O:30][C:29]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:28]1)(=O)=O>C(O)C.O.CN(C)C=O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:26][C@@H:27]1[CH2:31][O:30][C:29]2([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[O:28]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=S(=O)(OC[C@@H]1COC2(CCCCC2)O1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)OC[C@@H]1COC2(CCCCC2)O1
Reaction time: 0.5 h

Procedure:
The solution from 2-acetoxy-benzoic acid (0.6 g, 3.33 mmol) in ethanol (3.5 ml) is treated with a solution of caesium carbonate (0.54 g, 1.67 mmol) in water (35 ml) and stirred. After 30 min, the mixture is freeze-dried. The residue is added with stirring to a solution of [2S]-1,4-dioxa-spiro[4,5]dec-2-yl-methyl trifluoromethanesulphonate (1.15 g, 3.79 mmol) in N,N-dimethylformamide (10 ml). After 16 h at 20° C., the mixture is concentrated, the residue is taken up in dichloromethane (50 ml), and the solution is washed twice with water, dried over magnesium sulphate and concentrated. The residue is purified by column chromatography (toluene/ethyl acetate=50/1). Yield: 601 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17](=O)[CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)Nc1cncnc1NCc1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Yield: 30.4 %

Procedure:
A mixture of 36 parts of N-[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]-1-(phenylmethyl}-4-piperidineacetamide and 935 parts of phosphoryl chloride was stirred and refluxed for 8 hours. After cooling, the reaction mixture was evaporated. The residue was decomposed in ice water. The whole was treated with a sodium hydroxide solution. 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, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and crystallized from acetonitrile. The product was filtered off and dried, yielding 10.6 parts (30.4%) of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine; mp. 136.4° C. (compound 4).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C(OCC)C>[C:11]([C:9]1[CH:10]=[C:6]([CH2:4][OH:3])[N:7]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To an oven dried round bottom flask containing 5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.64 g, 2.2 mmol) was added anhydrous THF (20 mL) followed by the drop wise addition of DIBAL-H (0.96 mL, 4.9 mmol) under nitrogen. After stirring at room temperature for 30 minutes the reaction was diluted with 100 mL diethyl ether and quenched with 5 mL Methanol stirring for an additional 30 minutes at room temperature. The resulting slurry was treated with 5 g MgSO4 and filtered through a pad of diatomaceous earth. The filter cake was washed with 3×75 mL portions of ether and the combined filtrates concentrated under vacuo to afford the desired alcohol as a clear oil (0.515 g, 96%). No further purification was necessary. Expected mass=244. Observed mass=245.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@:22](Br)([C@@H:23]([OH:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH:18]=[CH:19]2)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][C@@H:9]1[CH3:31])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([OH:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH:18]=[CH:19]2)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][C@@H:9]1[CH3:31])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(=O)O[C@]1(C(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 45.6 %

Procedure:
300 mg of 17α-acetoxy-9α-bromo-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione is debrominated as described in Example 1(E) with tributyltin hydride, worked up, and purified, thus isolating 115 mg of 17α-acetoxy-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione, mp 270°-272° C.