Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O1CC[CH2:13][CH2:12]1.C([Mg]Cl)C.S(=O)(=O)(O)O>[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: C1CCOC1
Agent: [Cu]Br
Agent: CC[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCP(C(C)(C)C)C(C)(C)C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride, 0.28 g (0.002- mol (corresponding to 2% by mol)) of copper(I) bromide and 60 ml of tetrahydrofuran were placed. To the contents of the flask, 55 ml (0.11 mol) of a tetrahydrofuran solution of ethylmagnesium chloride having a concentration of 2 mol/liter was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 2 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 50 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 92° C. to 95° C. under reduced pressure of 20 Torr were collected. As a result, 15.7 g (purity: 98.0%) of the aimed di-tert-butylethylphosphine was obtained as an oily substance. The yield was 88.2%.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7](=O)[CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])C.C[O-].[Na+]>CO>[CH3:1][N:2]1[C:7]([OH:6])=[CH:8][C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:3]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1O
Yield: 87.5 %

Procedure:
9.2 g (0.2 mol) of methylhydrazine were added dropwise to a mixture of 34.4 g (0.2 mol) of pivaloylacetic acid ethyl ester, 10.8 g (0.2 mol) of sodium methylate and 100 ml of methanol at 20° C. When the exothermic reaction had subsided, the reaction mixture was heated for 2 hours under reflux and then concentrated, the residue was taken up in 200 ml of water and this solution was acidified with concentrated hydrochloric acid to a pH of ca. 6. The resulting precipitate was filtered off, dried and recrystallized from isopropanol. 27 g (87% of theory) of 1-methyl-3-tert.-butyl-5-hydroxy-pyrazole were obtained in the form of colorless crystals of melting point 150° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:28]=2[F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cc(F)cc(F)c1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)cc(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3,5-trifluorobenzyl alcohol (119 mg; 0.736 mmol), example 84 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[Br:16]N1C(=O)CCC1=O>Br.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([Br:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:14])[F:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
A mixture of (3-trifluoromethyl-phenyl)-acetic acid methyl ester (6.0 g, 25.9 mmol) and N-bromosuccinimide (9.2 g, 51.7 mmol) and a few drops of hydrobromic acid (48% solution) in chloroform (250 mL) was heated under reflux for two days. The reaction mixture was concentrated to dryness, taken up in methylene chloride and loaded onto a column of silica gel. Elution with 5% ethyl acetate/hexanes gave Bromo-(3-trifluoromethyl-phenyl)-acetic acid methyl ester (3.0 g, 39% yield) as colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CCN(C(C)C)C(C)C.CN(C(O[N:50]1N=[N:57][C:52]2C=CC=N[C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CN>CN(C=O)C>[NH2:50][CH2:51][CH2:52][NH:57][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(Cl)c4)ccc3=O)ccnc2c1
Reactant: 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
Solvent: NCCN
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)NCCN)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid (494 mg, 1093 μmol), DIEA (191 μL, 1093 μmol), and HATU (416 mg, 1093 μmol) in DMF (5 mL) was stirred at 23° C. for 15 minutes. This dark solution was then added to a second solution of ethylenediamine (730 μL, 10933 μmol) in DMF (2 mL). The reaction was then stirred overnight at 23° C. followed by a partition between 9:1 CHCl3/IPA (75 mL) and NaOH (1 M, 25 mL). The organic was separated, dried over MgSO4, then concentrated onto dry silica (15 g). The product was purified on silica (40 g) eluting with 10% 2 M NH3 in MeOH/DCM, and isolated as a fluffy lyophilized solid from 1:1 ACN/water. MS (ESI pos. ion) m/z: 494 (MH+); calc'd for C25H24ClN5O4: 493. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (t, J=6.27 Hz, 2H) 3.26 (q, J=6.02 Hz, 2 H) 3.87 (s, 3 H) 4.68 (d, J=4.52 Hz, 4 H) 6.95 (d, J=5.52 Hz, 1 H) 7.05 (dd, J=9.29, 2.26 Hz, 1 H) 7.13 (d, J=10.04 Hz, 1 H) 7.28 (d, J=2.01 Hz, 1 H) 7.51-7.58 (m, 1 H) 7.82-7.97 (m, 3 H) 8.13 (d, J=10.04 Hz, 1 H) 8.50 (t, J=5.27 Hz, 1 H) 8.62 (d, J=5.52 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(F)cc2)C1
Yield: 76 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 4-fluoro-benzoyl chloride to afford the title compound as a colourless oil (4.3 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1Br.C([Li])CCC.[O:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>>[F:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[CH:20]1[O:16][CH:17]2[CH:18]=[CH:19]1
Reactant: c1ccoc1
Reactant: Fc1cc(Br)c(Br)cc1F
Agent: [Li]CCCC
Product: Fc1cc2c(cc1F)C1C=CC2O1

Procedure:
1,2-Dibromo-4,5-difluorobenzene was treated with n-butyllithium followed by furan to give 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene, which was treated with acid to produce 6,7-difluoronaphthalen-1-ol.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:25])([F:24])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[CH2:22]O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>CCOCC>[Br:2][CH2:22]/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:25])([F:24])[F:5])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: OC/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-c2ccc(/C=C/CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123 %

Procedure:
PBr3 (26 μL, 0.28 mmol) was added to a solution of alcohol 101 (0.159 g, 0.540 mmol) in Et2O (10 mL) at 0° C. The mixture was warmed to room temperature and stirred for 1 h, then quenched with ice and extracted with Et2O. The organic fraction was dried and evaporated, and then column chromatography of the residue on silica gel (eluting with CH2Cl2) gave 4-[(1E)-3-bromo-1-propenyl]-4′-(trifluoromethoxy)-1,1′-biphenyl (102) (0.123 g, 71%) as a white solid: mp 121-123° C.; 1H NMR (CDCl3) δ 7.60 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 6.69 (d, J=15.6 Hz, 1H), 6.45 (dt, J=15.6, 7.8 Hz, 1H), 4.18 (dd, J=7.8, 0.9 Hz, 2H). APCI MS m/z 277 [M+H−HBr]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42]Br>C1COCC1.ClCCl>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[CH2:19][O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCCC1COc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Dissolve 160 mg (0.4 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)-furo[2,3-d]pyrimidine (Example 38A) in 0.8 ml of THF and add 110 μl (0.8 mmol) of triethylamine and 87 μl (0.8 mmol) of 3-bromopropionic acid methyl ester. Stir the mixture at 20-40° C. overnight, then dilute with dichloromethane and wash with saturated sodium hydrogencarbonate solution. Concentrate the solution under reduced pressure and purify the resulting oil by preparative RP-HPLC (eluent: acetonitrile/water gradient). 90 mg (44% of theory) of the target product are obtained.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 539.0 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.49 (DCM/MeOH/NH3aq, 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15]C(O)=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].CC1C=C(O)C(=CC=1)C(O)=O.C(Br)C.S1(CCCC1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: Cc1ccc(C(=O)O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCBr
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C)cc1OCC

Procedure:
More particularly, the present invention relates to a process for the preparation of 3-ethoxy-4-(ethoxycarbonyl)phenyl acetic acid of Formula I, comprising reacting 4-methylsalicylic acid of Formula III, with ethylbromide in a dipolar aprotic solvent at a selected temperature within a range of ambient to 100° C., preferably 30-40° C. during a period of one to several hours. The suitable dipolar aprotic solvent is selected from the group consisting of dimethylsulphoxide, N, N-dimethyl formamide, sulfolane and N-methyl-1-pyrrolidone. The reaction is carried out in the presence of an inorganic base, preferably selected from the group consisting of potassium carbonate and sodium carbonate. The reaction is worked up following the conventional method to afford ethyl 2-ethoxy-4-methylbenzoate of Formula IV in practically quantitative yield. The compound of Formula IV is then reacted with lithium diisopropyl amide (LDA) of Formula VIII,
Reaction SMILES: C[CH:2]([C:4]1[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[N:6][C:7]2[C:12]([CH:13]=1)=[N:11][CH:10]=[C:9]([F:14])[CH:8]=2)[OH:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([CH:2]=[O:3])[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])=[N:6]2)=[N:11][CH:10]=1
Reactant: CC(O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1nc2cc(F)cnc2cc1C=O
Reaction time: 8 h

Procedure:
To a solution of methyl (7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol (50 mg, 0.15 mmol) in DCM (0.5 mL) was added pyridinium dichromate (113 mg, 0.3 mmol) at 25° C. The reaction mixture was stirred for overnight at same temperature. The reaction mixture was filtered through Celite™. The filtrate was concentrated in vacuo to give 7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carbaldehyde: LC-MS (ESI) m/z 331.1 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][C:15]2=[CH2:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH2:23].[OH-].[Na+].OO>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCC(CO)c2cccc(CO[Si](C)(C)C(C)(C)C)c21

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-methylene-1-ethyl-1,2,3,4-tetrahydroquinoline (2.04 g) in tetrahydrofuran (50 ml), 10M solution (3.2 m) of borane-dimethylsulfide complex in tetrahydrofuran was added dropwise with stirring under ice-cooling. After stirring the mixture for 2 hours at room temperature, water was added to the reaction mixture, and furthermore 3N aqueous solution of sodium hydroxide (10 ml) and 30% hydrogen peroxide (10 ml) were added thereto. After stirring for 2 hours at room temperature, the reaction mixture was subjected to salting-out and extracted with dichloromethane. After the extract was dried, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)]to give 8-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.98 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([OH:21])=[O:20])=[CH:5]2.[H][H]>CO.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]([CH2:18][C:19]([OH:21])=[O:20])[CH2:5]2
Reactant: Cc1ccc2nc(-c3ccccc3)c(CC(=O)O)cc2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc2c(c1)CC(CC(=O)O)C(c1ccccc1)N2

Procedure:
1.00 g (3.61 mmol) of 13 was taken up in 80 ml of methanol, 1 g of Raney Ni (water-wet) was added, and the mixture was hydrogenated overnight at 50° C. at a hydrogen pressure of 5 bar. The catalyst was filtered off, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (ethyl acetate/cyclohexane), giving a yellowish solid, which was identified as the racemic cis-compound 14.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1cccc(C(=O)OC(C)C)c1
Product: COc1ccc(C(C#N)(CCCN(C)CCc2cccc(C(=O)OC(C)C)c2)C(C)C)cc1OC

Procedure:
Reaction of 1f with 2f produced 3ae. MS found M+H=481. The oxalate salt of 3ae was recrystallized from ethyl acetate; mp 130-132° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH:14]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:15][NH:16][C:17]2[N:25]=[C:24](NCCC3N=CN(C(C)C)C=3)[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[C@@H:37]2[CH2:41][C@H:40]([NH:42][C:43]([CH:45]3C[CH2:46]3)=[O:44])[C@@H:39]([OH:48])[C@H:38]2[OH:49])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.[C:93]([O:97][C:98](=[O:106])[NH:99][CH:100]1[CH2:105][CH2:104][NH:103][CH2:102][CH2:101]1)([CH3:96])([CH3:95])[CH3:94]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:93]([O:97][C:98](=[O:106])[NH:99][CH:100]1[CH2:105][CH2:104][N:103]([C:24]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[C@@H:37]3[CH2:41][C@H:40]([NH:42][C:43](=[O:44])[CH2:45][CH3:46])[C@@H:39]([OH:48])[C@H:38]3[OH:49])=[C:17]([NH:16][CH2:15][CH:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:25]=2)[CH2:102][CH2:101]1)([CH3:96])([CH3:94])[CH3:95]
Reactant: CC(C)n1cnc(CCNc2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)C5CC5)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to cyclopropanecarboxylic acid ((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate by replacing cyclopropanes-carboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide and by replacing 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine with piperidin-4-yl-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[CH2:26]([NH:29][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1)[CH2:27][CH3:28]
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of 710 mg (2.0 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 10 ml of N,N-dimethylformamide was treated with 0.5 ml (6.0 mmol) of propylamine and stirred at room temperature under argon for 2 hrs. The solution was evaporated, the residue was triturated in 5 ml of water and the crystals were filtered off. Additional crude product was obtained by extracting the aqueous phase with methylene chloride. The combined crude products (0.65 g) were chromatographed on 25 g of silica gel (methylene chloride/methanol 2%, 5%, 10%). There were obtained 540 mg of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was dissolved in 5 ml of acetonitrile and thereupon converted with ethereal hydrochloric acid into the hydrochloride. By recrystallization from acetonitrile there were obtained 560 mg (62%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one hydrochloride (1:2) of m.p. 169°-173° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=O)[C:31](O)=[O:32])[CH:24]=1>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]2[C:31](=[O:32])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[CH:10]=3)[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:24]=1
Reactant: Nc1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2ccncc2)c1
Yield: 47.4 %

Procedure:
A mixture of 3-amino-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (575 mg) and 3-(3-pyridyl)pyruvic acid (0.37 g) in ethanol (10 ml) was stirred under reflux for 1.5 hours. After evaporation of the solvent, the residue was chromatographed on silica gel column (chloroform-methanol, 9:1) and crystallized from ethanol to give 2-(3-pyridylmethyl)-4-[3-[(E)-2-(4-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (395 mg)