Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:41][C@@H:42]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:43]1.[OH-].[Na+]>C(Cl)Cl>[C:8]([O:12][C:13]([NH:15][CH2:16][C:17]([NH:41][C@@H:42]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:43]1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Et3N (2.5 mL, 17.6 mmol), N-tert-butoxycarbonylglycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (12.16 g, 16 mmol) were added to the CH2Cl2 (80 mL) solution of the (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 16 mmol). The reaction mixture was stirred at 25° C. for 16 hours, and then mixed with a 2M NaOH solution (80 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The obtained organic layers were combined, washed with water (100 mL×2) and aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and then concentrated. The objective (R)-3-{N-(tert-butoxycarbonyl)glycyl}amino-1-(4-chlorobenzyl)pyrrolidine (5.40 g, 92%) was obtained by column chromatography (SiO2, ethyl acetate).
Reaction SMILES: C=[C:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[OH:16]C(C(O)(C)C)(C)C.I([O-])(=O)(=O)=O.[Na+].C(Cl)(Cl)(Cl)Cl.C(#N)C.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.ClCCl>[C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][CH2:3][C:2](=[O:16])[CH2:8][CH2:7][C:6]=2[CH:9]=1)(=[O:15])[CH3:14]
Reactant: CC(C)(O)C(C)(C)O
Reactant: C=C1CCc2cc(C(C)O)ccc2OC1
Agent: Cl[Ru](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc2c(c1)CCC(=O)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
4.7 mg (0.023 mmol) of ruthenium chloride trihydrate are added at 0° C. to 188 mg of 1-(3-methylene-2,3,4,5-tetrahydro-1-benzoxepin-7-yl)ethanol as a mixture with its pinacol dimer, prepared according to example 15, and 1.28 g (5.99 mmol) of sodium periodate in solution in a carbon tetrachloride/acetonitrile/water (2/2/3) ternary mixture. After stirring at ambient temperature for 24 hours, a saturated sodium thiosulfate solution and dichloromethane are added. After separating the phases, the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are washed with brine, are then dried and are finally concentrated under vacuum. Rapid filtration through silica gel (ethyl acetate/heptane 30/70) provides 87 mg (55%) of 7-acetyl-4,5-dihydro-1-benzoxepin-3(2H)-one in the form of a white solid; M.p.=80–82° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1([N:9]([CH:36]2[CH2:38][CH2:37]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30](O)=[O:31])=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:8][CH2:7]1>>[CH:36]1([N:9]([CH:6]2[CH2:7][CH2:8]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:31])=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:37][CH2:38]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Reactant: C1CCNC1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N4CCCC4)s3)nc21

Procedure:
This compound was prepared according to Example 20 using pyrrolidine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-(pyrrolidine-1-carbonyl)thiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]([CH2:17][C:18]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])([CH3:20])[CH3:19])=[O:16])([CH3:7])([CH3:6])[CH3:5]>CCOCC>[CH3:3][N:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:4]([CH3:5])([CH3:6])[CH3:7])=[O:16])[S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(CC(=O)Oc1ccccc1C(C)(C)C)NS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: CN(C(C)(C)CC(=O)Oc1ccccc1C(C)(C)C)S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 96 %

Procedure:
A freshly prepared solution of diazomethane in anhydrous ether was added in excess to a solution of N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamide (13.1 g) in ether. The resulting yellow solution was allowed to stand at RT overnight, then was washed with 10% HCl followed by 2.5N aq NaOH. The organic solution was dried (MgSO4), and concentrated to afford 13.0 g of pure N-methyl-N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl)trifluoromethanesulfonamide as a white solid, a 96% yield. m.p. 42°-44° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N.O1CCOCC1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:36])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (1100 mg, 2.29 mmol) and HATU (2 eq., 1695 mg, 4.5 mmol) were initially charged in dry DMF (28 ml) at 0° C., and a 0.5 M solution of ammonia in dioxane (6 eq., 23.6 ml, 13.4 mmol) and DIEA (2 eq., 576 mg, 4.5 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 3 h (HPLC control). The reaction mixture was then diluted with ethyl acetate (200 ml). The organic phase was washed successively with saturated sodium bicarbonate solution (50 ml), 10% strength citric acid (3×50 ml) and saturated sodium chloride solution (50 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 50:3). This gave a colorless solid (1050 mg, 96% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:2].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:16]=[O:18])=[C:8]([Cl:13])[CH:7]=1)[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-chloro-phenyl)-acetic acid ethyl ester was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 48 h to give the title compound as brown solid which was used in the next step without further purification. MS: m/e=257.0 [M+NH4+].
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:16][C:11]1[N:10]=[C:9]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([I:15])[CH:12]=1
Reactant: C1COCCN1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: CCN(CC)CC
Product: Clc1cc(I)cc(N2CCOCC2)n1
Temperature: 100 °C

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2,6-dichloro-4-iodopyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then heated in an oil bath at 100° C. for 18 hours. LCMS analysis indicated the formation of the desired product (M+H=324.9/326.8, Rt=0.98 min). Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed via ISCO to yield 4-(6-chloro-4-iodopyridin-2-yl)morpholine as a light brown solid (63%). LCMS (m/z) (M+H)=324.9/326.8, Rt=0.98 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C:60]1[CH:61]=[CH:62][C:63]([F:74])=[C:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=2)[CH:65]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:58][CH2:59][C:60]4[CH:65]=[C:64]([C:66]5[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=5)[C:63]([F:74])=[CH:62][CH:61]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 72 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-amino)carbonyl]benzoic acid (0.045 g, 0.1 mmol) in CH2Cl2 (2 mL) was stirred under argon at room temperature. HBTU (0.038 g, 0.1 mmol) was added followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.0231 g, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol). The resulting mixture was stirred for three days. The solvents were pumped off and the residue was purified on the CombiFlash (12 g silica gel column) eluted with 70-100% EtOAc/hexane) to afford the title compound. LC-MS m/z 664.8 (M+H)+, 1.75 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[C:23][C:24]3([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][C:24]3([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)cc1Cl
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CCC3(O)CCOCC3)cn2)cc1Cl
Reaction time: 4 h
Yield: 83.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-tetrahydropyran-4-yl-ethynyl)-pyrazin-2-yl]-propionamide (prepared as in Example 50, 200 mg, 0.376 mmol) in methanol (30 mL) was treated with 10% palladium on activated carbon (39 mg). The reaction mixture was then placed on a Parr shaker under a hydrogen atomsphere of 50 psi for 4 h. The mixture was filtered, and solvents were concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-tetrahydropyran-4-yl-ethyl)-pyrazin-2-yl]-propionamide (169 mg, 84%) as a fluffy solid: (ES)+-HRMS m/e calcd for C26H34ClN3O5S (M+H)+ 536.1981, found 536.1988.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(C)Oc1ccc(F)cc1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
To a solution of 4-fluorophenol (8.0 g, 71.4 mmol) in dimethylformamide (130.0 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and 2-bromopentan-3-one (836) (10.7 g, 64.9 mmol). The suspension was heated at 70° C. for 18 h, cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-20% EtOAc in hexanes) to provide the desired 2-(4-fluorophenoxy)pentan-3-one (837) (5.2 g, 40.8%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[N:33]12CCN(CC1)C[CH2:34]2.CC(O)=O>O.CS(C)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:34]#[N:33])[N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Oc3ccnc(C#N)n3)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of [3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (161 mg), potassium cyanide (76 mg) and 1,4-diazabicyclo[2,2,2]octane (13 mg) in water (0.4 ml) and DMSO (2 ml) is left at 5° C. for 4 h. This mixture is acidified with AcOH to pH 4-5, quenched with brine and extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the crude product is purified on silica (15 g) with cyclohexane/EtOAc=5/1 to afford pure [3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])=[O:3].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15].N1C2C(=CC=CC=2)C=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)O
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
T-Butyl 2,4,5-trichlorophenyl carbonate is a known compound and one method for its preparation is described in an article by W. Broadbent, J. S. Morley and B. E. Stone in the Journal of the Chemical Society (C), 1967 pages 2632-2637. Briefly, in this method a solution of phosgene in toluene is treated with 2,4,5-trichlorophenol at -10° C, followed by addition of dimethylaniline at such a rate that the reaction temperature is maintained at 5°-10° C. The mixture is heated to 20°-24° C and maintained at this temperature for 12 hours. The mixture is cooled by addition of ice and the suspension filtered. From the organic layer in the filtrate, 2,4,5-trichlorophenyl chloroformate is isolated. A solution of the crude 2,4,5-trichlorophenyl chloroformate in methylene chloride is reacted with a solution of t-butanol and quinoline in methylene chloride. The reaction mixture is maintained at 20°-24° C for 12 hours. The mixture is cooled by addition of ice and the suspension is filtered. From the organic layer in the filtrate t-butyl 2,4,5-trichlorophenyl carbonate is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12]O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 80 °C

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (50 g.) was dissolved in glacial acetic acid (180 ml.) and the solution treated with 30% hydrogen peroxide (70 ml.) and heated at 80° C for 20 hours. The solvent was removed in vacuo and the residual oil diluted with water (25 ml.) and re-evaporated. The resulting oil was dissolved in chloroform (100 ml.), washed with aqueous sodium carbonate (2 × 25 ml.), saturated brine (2 × 25 ml.), dried (MgSO4) and the solvent removed in vacuo to give 3-Methyl-5,6,7,8-tetrahydroquinoline-1-oxide (60 g.) as a pale yellow solid which was used without purification. The N-oxide (60 g.) was dissolved in acetic anhydride (120 ml.) and added to boiling acetic anhydride (120 ml.) and the mixture heated at reflux for 30 minutes. The solvent was removed in vacuo and the residual oil was treated with 10% hydrochloric acid (700 ml.) and the solution heated on a steam bath for 2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodium hydroxide and extracted with ether (3 × 100 ml.). The combined ethereal extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo. The resultant oil was distilled at 0.15 mmHg to give a colourless oil (22 g.) b.p. 70°-78° C which crystallised from n-hexane to give 8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline as colourless needles m.p. 58° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C=O)C>[CH2:9]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: C#CCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15 ml of 4-pentin-1-ol is added in drops at 0° C. to a suspension of 17.4 g of sodium hydride (55%) in 200 ml of DMF, and it is stirred for 1 hour at 0° C. Then, 30 ml of benzyl bromide is added in drops at this temperature, and it is stirred for another 2 hours at 0° C. Then, the reaction is carefully neutralized with 1N hydrochloric acid. The phase separation is carried out between diethyl ether and water, and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. The residue is distilled in an oil pump vacuum, and 22.7 g of 5-benzyloxypent-1-ine is obtained as a colorless oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([O:11][CH2:12][CH2:13][OH:14])(=[O:10])[CH:8]=[CH2:9].N1(C2CCCCCCC2)CCCCCCN1.C=CC1C=CC=CC=1>>[C:7]([O:11][CH2:12][CH2:13][O:14][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(=O)OCCO
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: C=Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)CC(C)=O

Procedure:
Eighty four parts of diketene was added dropwise to solution containing 116 parts of 2-hydroxyethyl acrylate, 0.03 parts of diazabicyclooctane and 200 parts of styrene at 70° to 80° C. and mixed for one hour. The obtained solution was condensed at a reduced pressure to obtain 200 parts of acetoacetoxyethyl acrylate. The compound was reacted with 68 parts of aluminum isopropoxyde as generally described in Production Example 27 to obtain a ligand compound D-V of 209 parts (IR absorption 1606 cm-1 and 1525 cm-1 which are derived from chelating).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11]O.CC1C=CC(S([O-])(=O)=O)=CC=1.Br.Br.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[N:38][CH:39]=[N:40][C:41]=3[OH:43])[N:36]=[C:35]2[CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:48]1[CH2:47][CH2:46][CH:45]([CH2:44][C:35]2[N:34]([CH2:33][C:30]3[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=3)[C:42]3[C:37](=[N:38][CH:39]=[N:40][C:41]=3[OH:43])[N:36]=2)[CH2:50][CH2:49]1
Reactant: Oc1ncnc2nc(CC3CCNCC3)n(Cc3ccc(F)cc3)c12
Reactant: OCC1COc2ccccc2O1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Oc1ncnc2nc(CC3CCN(CC4COc5ccccc5O4)CC3)n(Cc3ccc(F)cc3)c12
Yield: 34 %

Procedure:
A mixture of 3.2 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol 4-methylbenzenesulfonate {ester}. 4.5 parts of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-ol dihydrobromide, 4 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. After cooling, the reaction mixture was filtered over diatomaceous earth and the filtrate was 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 acetontrile. The product was filtered off and dried, yielding 1.5 parts (34%) of 8-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-7-[(4-fluorophenyl) methyl]-7H-purin-6-ol; mp. 175.2° C. (compound 59).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.ICC>CN(C)C=O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCC(O)(c2cccc(Cl)c2F)C1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
In a sealed tube a mixture of (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)pyrrolidin-3-ol (0.31 g, 1.01 mmol), dimethyl formamide (3 mL) and iodoethane (0.16 mL, 2.02 mmol) was heated under microwave irradiation at 80° C. for 2×15 minutes. The resulting mixture was evaporated, morpholine (2 mL) was added and the mixture was heated under microwave irradiation at 130° C. for 30 minutes. Aqueous LiCl (5%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.131 g). [α]D=+27.2° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 71-74° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 13), 228, (10), 157 (12), 72 (26), 71 (bp).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20]Br>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1COc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 5-hydroxyindole (5.0 g, 37.6 mmol) in dimethylformamide (200 mL) at room temperature was added cesium carbonate (18.4 g, 56.3 mmol). The reaction mixture was stirred at 60° C. for 30 min followed by the addition of 2,6-dichlorobenzyl bromide (9.0 g, 37.6 mmol). After stirring at 60° C. for 16 h, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na2SO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded a clear oil (8.05 g, 73%). MS(ES) m/e 292.0 [M+H]+.