Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:12]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1nc2cnc3ccccc3c2n1CCCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfoxide (3.6 mL, 1.5 eq.) and oxalyl chloride (3.5 mL, 1.1 eq.) were sequentially added dropwise to chilled (dry ice/acetone bath) dichloromethane (100 mL). A solution of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (10 g, 37 mmol, 1 eq.) in dichloromethane was added dropwise. Triethylamine (15.5 mL, 3 eq.) was added. The ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After about 2 hours analysis by TLC indicated that the reaction was complete. The reaction mixture was diluted with dichloromethane (175 mL) and water (200 mL) and made basic (pH 10) with aqueous 5% sodium carbonate. The organic layer was washed sequentially with water (2×200 mL) and brine (150 mL) and then concentrated under reduced pressure to provide 9.9 g of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal.
Reaction SMILES: C([NH:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])C.[NH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[OH2:3].[NH2:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([NH:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1.[NH2:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([NH:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(NC(C)=O)c(Br)cc1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Br)cc1C(=O)NN1CCN(C)CC1
Product: O
Yield: 73.8 %

Procedure:
Reaction between 4-acetylamino-5-bromo-2-methoxybenzoyl chloride (prepared from 2.1 g. of corresponding acid and thionyl chloride), N-amino-N'-methyl piperazine (0.85 g.) and triethylamine (2 ml.) in toluene followed by alkaline hydrolysis as described in Example 20 gave 4-amino-5-bromo-2-methoxy-N-[4-methyl-1-piperazinyl]-benzamide hemihydrate (1.78 g., 68%) m.p. 174°-6° (ex-chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].Cl>O1CCCC1.O>[CH2:29]([O:28][C:26](=[O:27])[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH2:8])[C:4]=1[F:9])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 4-chloro-2-fluoro-phenylamine (15, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at −78° C. for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to −78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (2, 10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (16, 12.5 g, 78.3%). MS(ESI) [M+H+]+=280.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(N2CCOCC2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), morpholine (1.05 mL, 12.0 mmol) was added thereto, followed by stirring at 150° C. for 8 hours. The reaction mixture was purified through silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:3) to afford the entitled Compound 40 (118 mg, 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:19]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24])[CH3:20]>CCOC(C)=O>[CH2:19]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:20]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.
Reaction SMILES: C([C@@:5]1([OH:26])[C@H:9]([O:10]CCCC)[C@@H:8]([C:15](=[SnH2])[OH:16])[O:7][C@H:6]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[I-].[Na+]>CN(C=O)C>[CH2:28]([O:26][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:15][OH:16])[O:7][C@H:6]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Reactant: CCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
Utilizing the procedures of Examples 50 and 51, 2',3'-O-dibutylstannylene uridine (19.1 g) was treated with bromopentane (7 ml, 1.3 eq.) and sodium iodide (4.5 g) in DMF (90 ml). Purification on a silica gel column utilizing MeOH/CH2Cl2 5%→10% yielded the a mixture of 2' and 3' isomers of the product as a dark oil (9.8 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37].O1CCOCC1.CCOCC>C(OCC)(=O)C>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1.[ClH:37]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.85 g, 1.7 mmol) was dissolved in ethyl acetate (2 mL). To the solution was added 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL, 8.0 mmol). The mixture was stirred at room temperature for 3 hours. Ether was added, the mixture was centrifuged, and then the solvents were decanted. The residue was dried under vacuum to afford the desired product as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=409.2
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O.N>C(O)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: Cc1cccc(C)c1-n1ncc(C#N)c1N
Reactant: OO
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (9.4 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 1A) are dissolved in 25 ml of ethanol, and a mixture of 20 ml of 30% strength hydrogen peroxide and 40 ml of 25% strength ammonia is added. The solution is stirred at room temperature overnight and then concentrated to about 15 ml in a rotary evaporator. The oily emulsion resulting thereby is taken up in dichloromethane. It is washed several times with water and saturated sodium thiosulphate solution. Drying over magnesium sulphate is followed by removal of the solvent in vacuo. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.88 g (40% of theory) of the product is obtained as colourless solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][C:22]([CH3:28])([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al](Cl)(CC)CC.CCOCC>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][C:22]([C:25]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[NH:8][CH:9]=2)=[O:26])([CH3:28])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC1(C(=O)Cl)CCC(OCc2ccccc2)CC1
Agent: CC[Al](Cl)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCC(OCc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (531 mg, 2.68 mmol) and 4-benzyloxy-1-methyl-cyclohexanecarbonyl chloride (2.15 g, 8.05 mmol) in anhydrous Toluene (16 ml) was treated with Et2AlCl (1M in Hexanes, 5.36 ml, 5.36 mmol), dropwise. The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with sat. NaHCO3, and extracted with ethyl acetate (3×). The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown oil. Silica gel chromatography using 0-50% Et2O in DCM as eluant provided 205 mg (18%) of (4-benzyloxy-1-methyl-cyclohexyl)-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone as a pale yellow solid. M−H=426.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH:39][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:35]
Reactant: O=C(O)CCCCCNC(=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of dicyclohexylcarbodiimide (112 mmoles) in anhydrous tetrahydrofuran (44 ml) was gradually added to a suspension of N-benzoyl-6-aminohexanoic acid (93.5 mmoles), prepared as described in example 1, glycine ethyl ester hydrochloride (112 mmoles), triethylamine (112 mmoles) and anhydrous 1-hydroxybenzotriazole (112 mmoles) in tetrahydrofuran (330 ml), kept under stirring at 0° C. The reaction mixture was brought at room temperature and kept under stirring for 16 hours.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28].[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:38]([C:37]3[CH:39]=[CH:40][C:34]([O:33][C:32]([F:31])([F:41])[F:42])=[CH:35][CH:36]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:29])=[O:28]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1Cl)CC2

Procedure:
White solid. MS (ESI): 557.07 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride and 4-(trifluoromethoxy)-aniline.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Se](=O)=[O:17]>>[O:3]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:5]=1)[CH:2]=[O:17]
Reactant: CC(=O)c1cccc(N2CCCC2=O)c1
Reactant: O=[Se]=O
Product: O=CC(=O)c1cccc(N2CCCC2=O)c1

Procedure:
1-(3-Acetylphenyl)pyrrolidin-2-one (1.2 g, 5.9 mmol) was reacted with selenium dioxide (0.98 g, 8.9 mmol) using the method described in Example 1 to give crude oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde as a yellow oil: m/z (ES+) 218.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-].[Na+].Cl[CH2:13][CH:14]=[O:15]>CO.O>[CH3:9][O:15][C:14]1[CH:13]=[CH:4][N:3]2[CH:5]=[CH:6][N:7]=[C:2]2[N:1]=1
Reactant: Nc1nccc(Cl)n1
Reactant: C[O-]
Reactant: O=CCCl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccn2ccnc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
2-Amino-4-chloropyrimidine (1.00 g, 7.72 mmol) and sodium methoxide (1.25 g, 23.2 mmol) were suspended in methanol (20 ml) and heated under reflux for 2 h then cooled to ambient temperature. Chloroacetaldehyde (2.4 ml of a 45% w/w solution in water, 15.44 mmol) was added and the mixture heated under reflux for 22 h, allowed to cool to ambient temperature then pre-adsorbed directly onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-4%) gave 7-methoxyimidazo[1,2-a]pyrimidine (0.77 g, 67%) as a white crystalline solid: δH (400 MHz, CDCl3) 4.04 (3H, s), 6.41 (1H, d, J 7), 7.31 (1H, d, J 1), 7.50 (1H, d, J 1), 8.17 (1H, d, J 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.ClC1C=C(C(C(F)(F)F)=C)C=C(Cl)C=1.ClC1C=C(C2(C(F)(F)F)[O:44][N:43]=[C:42]([C:45]3[CH:56]=[CH:55][C:48]4[B:49]([OH:54])[O:50][C:51]([CH3:53])([CH3:52])[C:47]=4[CH:46]=3)C2)C=C(Cl)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([C:10]([F:11])([F:12])[F:13])[O:44][N:43]=[C:42]([C:45]3[CH:56]=[CH:55][C:48]4[B:49]([OH:54])[O:50][C:51]([CH3:53])([CH3:52])[C:47]=4[CH:46]=3)[CH2:9]2)[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Agent: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared by using the same method as described in 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol with 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene to replace 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene. It was obtained as a white solid. MS: m/z=478.1 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH2:28][OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH:28]=[O:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C=O)OC[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.42 mmole) in dry CH2Cl2 (0.5 ml) there was added dropwise a solution of dry DMSO (0.049 ml, 0.69 mmole) in dry CH2Cl2 (0.1 ml) at -78° C. over 5 min. After stirring for 10 min at -78° C., a solution of (2S,3R,4S,5S)-[3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.1 g, 0.345 mmole) in dry CH2Cl2 (0.1 ml) was added dropwise to the resulting milky suspension over 5 min at -78° C. After stirring for 15 min at -78° C., triethylamine (0.24 ml, 1.73 mmole) was added dropwise to the reaction mixture over 3 min, and stirring was continued for 30 min at -78° C. The reaction mixture was then warmed up to room temperature gradually and partitioned between CH2Cl2 (10 ml) and water (10 ml). The methylene chloride layer was washed with brine (5 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (1:9) as an eluent to give (2R,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde (0.085 g, 86% yield) as a colorless oil; EI-MS: m/z 288 (M+); 1H-NMR (CDCl3)d: 0.85 (3H, d,J=7 Hz), 0.87 (9H,s), 2.28 (1H,m), 3.12 (1H,dd,J=4 & 5 Hz), 3.28 (3H,s), 3.59 (1H,dd,J=5 & 11.5 Hz), 3.81 (1H,d,J=4 Hz), 3.81 (1H,dd,J=9 & 11.5 Hz), 4.08 (1H,dd,J= 4 & 5 Hz), 9.80 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(Cl)cc1

Procedure:
A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 189 g (1.2 mole) of 1-bromo-3-chloropropane, 249 g (1.8 mole) of anhydrous potassium carbonate, and 600 ml of acetone was stirred vigorously and heated to reflux for 16 hr under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration, and the acetone and excess bromochloropropane were removed by heating under reduced pressure. The residue was dissolved in petroleum ether, and the resulting solution was cooled in an ice-isopropyl alcohol bath to produce a white solid. The solid was collected by filtration and washed with cold petroleum ether. The filtrate was concentrated and cooled to yield two more crops of white crystals. The combined solids were dried under vacuum at ambient temperature to yield 107 g (87%) of white, flaky solid, m.p. 35°-36° C.
Reaction SMILES: F[C:2]1[C:7](=[O:8])[NH:6][C:5](CC([O-])=O)=[N:4][C:3]=1N1CCOCC1.[Na+].[F:20][C:21]1[C:22](=[O:46])[NH:23][C:24]([CH2:33][C:34]([N:36]2[C:44]3[C:39](=[C:40]([F:45])[CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)=[O:35])=[N:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:4]1[CH:3]=[CH:2][C:7](=[O:8])[NH:6][CH:5]=1.[F:20][C:21]1[C:22](=[O:46])[NH:23][C:24]([CH2:33][C:34]([N:36]2[C:37]3[C:42](=[CH:41][C:40]([F:45])=[CH:39][CH:38]=3)[CH2:43][CH:44]2[CH3:2])=[O:35])=[N:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: O=C(Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1)N1CCc2c(F)cccc21
Agent: [Na+]
Product: CC1Cc2cc(F)ccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Product: O=c1ccnc[nH]1
Yield: 66.8 %

Procedure:
5-Fluoro-2-[2-(5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl)-3H-pyrimidin-4-one is prepared by following the procedure described in example 1a (step 5a) using 182 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (obtained in step 2a) and 197 mg of 5-fluoro-2-methyl-2,3-dihydro-1H-indole (reference example 1a). After silica column purification, eluent: 98/02 dichloromethane/methanol, 85 mg of 5-fluoro-2-[2-(5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([S:46][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCS
Product: CCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octanthiol, mp 51°-52° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:39][CH3:40])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:39]([N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:16]1[CH2:17][C:18]2[CH:19]=[C:20]([NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=3)[CH:21]=[CH:22][C:23]=2[CH2:24][CH2:25]1)[CH3:40]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.33 g, 2.3 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in-vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL), the organic layer was separated, dried over MgSO4, filtered, and concentrated to afford N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-methanesulfonyl-benzamide (1.02 g). [M+H]+=470.