Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH:4]([CH3:6])[CH3:5].CCCCCBr.[CH3:14][C:15](=[CH:18][CH2:19][CH3:20])[CH:16]=[O:17].Cl>CCOCC>[CH3:5][CH:4]([CH2:3][CH2:2][CH:16]([OH:17])[C:15]([CH3:14])=[CH:18][CH2:19][CH3:20])[CH3:6]
Reactant: CCC=C(C)C=O
Reactant: CC(C)CCBr
Agent: Cl
Agent: [Mg]
Solvent: CCCCCBr
Solvent: CCOCC
Product: CCC=C(C)C(O)CCC(C)C
Temperature: 10 °C
Yield: 76 %

Procedure:
69.5 g (2.9 g atoms) of magnesium are placed in 500 ml of absolute ether. Subsequently, a solution of 438 g of isoamyl bromide, which contains ca 1.5% n-amyl bromide in accordance with gas chromatography, in 1.2 l of absolute ether is added dropwise so that the exothermic reaction maintains the ether constantly at the boiling point. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes. The Grignard solution is thereupon cooled to 10° C. Then, 236.5 g (2.41 mol) of 2-methyl-2-pentenal in 600 ml of absolute ether are added dropwise within 40 minutes, the temperature being held between 10° and 20° C. during the addition. In order to complete the reaction, the mixture is held at reflux temperature for a further 1 hour. The mixture is subsequently added to ice, decomposed with aqueous hydrochloric acid, the ethereal solution is washed neutral with sodium carbonate solution and saturated sodium chloride solution and then dried. The crude product (480 g) remaining after distillation of the solvent is fractionally distilled over a Widmer column and gives 312 g of 2,6-dimethyl-6-nonen-5-ol (III) of boiling point 62° C./0.05 mm Hg; nD25 =1.4479, which contains 1.5% of 4-methyl-3-decen-5-ol in accordance with gas chromatography (Carbowax, 130° C.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:26](Cl)=[O:27].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:24]=[C:23]([F:22])[CH:31]=[C:30]([F:32])[CH:29]=1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Yield: 59 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 3,5-difluorobenzoyl chloride (0.219 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.251 g, 2.48 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-3,5-difluorobenzamide (0.280 g, 59% yield). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H), 7.29 (s, 1H), 6.91 (t, J=2.4 Hz, 1H), 3.58 (q, J=5.7, 5.1 Hz, 2H), 3.51 (t, J=4.8 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.7, 161.5, 161.4, 137.6, 110.7, 106.9, 50.7, 39.9 ppm; HRMS (ESI) calcd for C9H8F2N4O2S (M+) 226.0666. found 226.0662.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7].[O:10]1CCOCC1.[Se](=O)=O.O>C(O)(=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](=[O:10])[CH:6]=[O:7]
Reactant: C1COCCO1
Reactant: O=CCCCC(F)(F)F
Agent: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Product: O=CC(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine 5,5,5-trifluoropentanal (2.01 g, 14.35 mmol), 1,4-dioxane (10 mL), selenium dioxide (1.62 g, 1.0 eq), water (0.51 mL), and acetic acid (0.69 mL). Heat the mixture at 90° C. and stir overnight. Allow the reaction mixture to cool to room temperature. Filter, wash the solids with dioxane. Combine the filtrate and washings to give the title compound (2.21 g, 100%). GCMS m/z=154.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[CH:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:22]3[N:21]=[CH:20][O:19][CH:23]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1cocn1
Product: C[C@]1(c2cc(NC(=O)c3cocn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=353.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (8.1 g, 38 mmol) and 2-(chloromethyl)quinoline (6.0 g, 38 mmol) in DMF (100 mL) were added K2CO3 (21 g, 153 mmol) followed by KI (317 mg, 1.9 mmol). The mixture was stirred at 50° C. for 5 h. The mixture was cooled to RT, water (100 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The organics were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=9, 1H), 8.15 (d, J=9, 1H), 7.87 (d, J=9, 1H), 7.80-7.72 (m, 2H), 7.65-7.56 (m, 2H), 7.32-7.26 (m, 1H), 7.23-7.16 (m, 1H), 5.44 (s, 2H).
Reaction SMILES: C(O[C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14]O[CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)C=C.[S:33]1CCC(=O)CC1.O1CCC(=O)CC1>>[O:32]=[C:17]([NH:16][CH:6]1[CH2:5][CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][S:33][CH2:12][CH2:11]2)[CH2:7]1)[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1
Reactant: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCSCC1
Agent: O=C1CCOCC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CCN(C2CCSCC2)C1

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, tetrahydro-4H-thiopyran-4-one was substituted for tetrahydro-4H-pyran-4-one and was isolated as a white solid. 1H-NMR (DMSO) δ: 1.48-1.60 (m, 2H), 1.90-2.50 (m, 8H), 2.60-2.70 (m, 2H), 2.79-2.96 (m, 2×), 3.70-4.05 (m, 6H), 5.05-5.25 (m, 2H), 5.75-5.95 (m, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 8.18 (m, 2H), 9.00 (m, 1H). MS m/z: 472 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+].[NH2:24][C:25](=[S:37])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[N:28]1>C(OCC)C>[CH3:11][C:10]1[S:37][C:25]([CH2:26][N:27]2[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[N:28]2)=[N:24][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)c(C)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
Under a nitrogen atmosphere, to a solution (10 mL) of 1-[3-(trifluoromethyl)phenyl]propan-1-one (1.0 g, 4.95 mmol) in diethyl ether was added bromine (0.15 mL, 5.94 mmol) at 0° C., and the mixture was stirred at room temperature overnight. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (4 mL), the compound (175 mg, 0.82 mmol) obtained in Example 1b was added and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (112 mg, 35%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[CH:21]=[N:22]O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(O)cc2)sc(C=NO)c1-c1cccc(O)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(O)cc2)sc(C#N)c1-c1cccc(O)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
A mixture of 3-(3-hydroxyphenyl)-5-(4-hydroxyphenyl)-4-methylthiophene-2-carbaldehyde oxime (0.76 g, 2.3 mmol) and pyridinium hydrochloride (2.7 g, 23 mmol) was heated at 195-205° C. in a 200 mL round bottom flask fitted with a 250 mL bump trap. After 2 h, the reaction mixture was cooled to 23° C. and taken up in a minimum of ethyl acetate (100 mL). The organic phase was washed with water (2×50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product as a brown solid (0.61 g) which was pre-adsorbed on silica gel (2 g). Flash chromatography (10 g silica gradient 20%-30%-40% ethyl acetate-hexane) gave the title compound (0.37 g, 52%, m.p. 220-22° C.) as a pale orange solid after recrystallization from hot ethyl acetate-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:42][CH:41]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:38]([CH3:37])[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]4[CH:51]=[N:50][CH:49]=[N:48][CH:47]=4)=[CH:44][CH:45]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(-c2cncnc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4cncnc4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and N-methyl-1-[4-(pyrimidin-5-yl)phenyl]methanamine (42 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). The crude product was purified using prep method A.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][CH:12]([Cl:14])[CH3:13])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[C:9](=[O:10])([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: Sc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)OC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
A solution of benzenethiol (50 g, 450 mmol) and 1-chloroethyl chloroformate (65 g, 450 mmol) in CH2Cl2 (300 mL) was cooled to 0-4° C. in an ice-water bath. To the mixture was added a solution of triethylamine (450 mmol) in dichloromethane (200 mL) dropwise over 30 min. The reaction was removed from the ice bath and stirred at ambient temperature for 12 h. The reaction was washed with water (3×500 mL), the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the product as a pale yellow liquid (96 g, 98.5%). 1H NMR (CDCl3, 400 MHz): δ 1.82 (d, 3H), 6.6 (q, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-amino-4-fluorobenzoate (5.47 g, 30 mmol) and pyridine (2.55 mL, 33 mmol) in DCM (150 mL) was added 2,6-difluorobenzenesulfonyl chloride (4.45 mL, 33 mmol). The reaction was stirred overnight at rt. After 16 h, the reaction mixture was concentrated, triturated with ether, and dried in vacuo to generate 7.87 g (66% yield) of the product of Step A as a white powder. MS (ESI): 360 (M+H).
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2(C(O)=O)[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2([C:5](=[O:2])[CH3:6])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Reactant: CCOCC
Agent: [Li]
Solvent: CI
Solvent: O
Product: CC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
To a stirred solution of 17.4 parts of lithium in 140 parts of dry 1,1'-oxybisethane is added dropwise a small amount of a solution of 193.7 parts of iodomethane in 210 parts of dry 1,1'-oxybisethane. After the reaction is started by heating, there are added 420 parts of dry 1,1'-oxybisethane. The remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 45 minutes. Then there are added portionwise (quickly) 41.8 parts of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained). Upon completion, stirring at reflux is continued for one hour. The reaction mixture is cooled in an ice-bath and decomposed by the dropwise addition of 1000 parts of water. The organic layer is separated and discarded. The aqueous phase is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from 2,2'oxybispropane, yielding 26 parts (62.4%) of 1-{4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinyl}ethanone; mp. 133.7° C.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]([C:9]([O:11]CC)=[O:10])[CH2:6][N:5]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][O:2]1.O.[OH-].[Li+]>O.CO>[C:17]([O:16][C:14]([N:5]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[CH2:8][C:4]21[CH2:3][O:2][CH2:1]2)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)C2(COC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 5-tert-butyl 7-ethyl 2-oxa-5-azaspiro[3.4]octane-5,7-dicarboxylate (514 mg, 1.80 mmol) and lithium hydroxide monohydrate (378 mg, 9.0 mmol) in 1 mL of H2O and 10 mL of MeOH was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was stirred with saturated aqueous solution of 2-hydroxypropane-1,2,3-tricarboxylic acid (15 mL) and then extracted with DCM (15 mL×2). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo to afford 5-(tert-butoxycarbonyl)-2-oxa-5-azaspiro[3.4]octane-7-carboxylic acid (444 mg, yield: 95.9%) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:59])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[Br:59]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3.24 g, 4.44 mmol) in DMF (20 mL) was added NBS (750 mg, 4.21 mmol). After stirring at rt for one hour, NBS (75 mg 0.42 mmol) was added and the resulting mixture was stirred for another 40 minutes to complete the reaction. The reaction mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), brine (20 mL) and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-40%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3 g, 83%).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.C(=O)CCC=C.[CH3:16][C@@H:17]1[O:22][C@@H:21]([O:23][C@@H:24]2[C:29]3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@](O)(C(CO)=O)C2)[CH2:20][C@H:19](N)[C@@H:18]1O>C(O)C>[CH2:24]([O:23][CH:21]([O:22][CH2:17][CH3:16])[CH2:20][CH2:19][CH:18]=[CH2:5])[CH3:29]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: CCOCC
Agent: C=CCCC=O
Agent: FB(F)F
Solvent: CCO
Product: C=CCCC(OCC)OCC

Procedure:
Boron trifluoride diethyl etherate (0.2 mL) was added, with stirring, to a solution of 4-pentenal (Cherif, A.; Farquhar, D. N-(5,5-diacetoxypent-1-yl)doxorubicin: A new intensely potent doxorubicin analogue. J. Med. Chem. 35, 3208-3214 (1992)) (2.5 g, 29.8 mmol) in ethanol (150 mL). The mixture was refluxed for 10 min under nitrogen, then the ethanol was removed under reduced pressure. The residue was taken up in dichloromethane (25 mL), and the solution was washed with 10% sodium acetate solution (15 mL) and water (2×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated. The residue was chromatographed on a column of silica gel using chloroform/methanol (97:3) as eluent. 4-Pentenal diethyl acetal was obtained as an oil (4.5 g, 96%). 1H NMR (CDCl3) δ 5.88-5.61 (m, 1 H, H4), 5.03-4.87 (m, 2 H, H5), 4.38 (t, 1 H, J=7, H1), 3.30-3.61(m, 4 H, 2×CH2), 2.07-1.96 (m, 2 H, H2), 1.64-1.53 (m, 2 H, H3), 1.09 (t, 6 H, J=7, 2×CH3).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11].Cl.[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
1.68 ml (12.0 mmol) of triethylamine are added to a suspension containing 2.58 g (12.0 mmol) of H-Val-OtBu.HCl and 4.62 g (11.0 mmol) of Z-Asp(OtBu)-OSu in 25 ml of dimethylformamide (DMF). The reaction mixture is left to stand overnight, then evaporated under reduced pressure. The residue is mixed with 50 ml of ethyl acetate and the suspension obtained is successively washed with 25 ml of water, 3 times with 25 ml of 1 mol/liter hydrochloric acid each, 3 times with 25 ml of 5% aqueous sodium hydrogenocarbonate each and finally with 25 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 4.3 g (81.7%) of oily Z-Asp(OtBu)-Val-OtBu protected dipeptide, Rf1 =0.85.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:76]=CC(CN(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)=[CH:39][CH:38]=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:36])=[CH:76][CH:35]=3)[C:31](=[O:32])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccc(F)cc1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1Cc1ccc(F)cc1
Yield: 52.2 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (4-fluoro-benzyl)-(2-hydroxyethyl)-amide (313) (91 mg, 0.16 mmol). The product was obtained as a colorless sticky solid (46 mg, 52.2%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.I[CH3:25]>CN(C=O)C.CCOCC>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][N:21]3[CH3:25])=[CH:17][CH:16]=2)=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CI
Reactant: COc1cc(OC)cc(C(=O)c2ccc3cc[nH]c3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(OC)cc(C(=O)c2ccc3ccn(C)c3c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Potassium hydroxide (0.21 g, 3.7 mmol) was added to a mixture of (3,5-dimethoxy-phenyl)-(1H-indol-6-yl)-methanone (0.69 g, 2.5 mmol) in DMF (7 mL) at 0° C. followed by addtion of iodomethane (0.2 mL, 2.7 mmol) and stirred at 0° C. for 2 hours. The mixture was diluted with ether (15 mL) and washed with brine (2×10 mL). The organic phase was dried over MgSO4, concentrated and purified via flash column chromatography (EtOAc/Hexane) to give (3,5-dimethoxy-phenyl)-(1-methyl-1H-indol-6-yl)-methanone as an off-white solid (0.54 g, 75% yield): 1H NMR (DMSO-d6) δ 3.80 (s, 6H, 20CH3), 3.85 (s, 3H, NCH3), 6.55 (d, J=3 Hz, 1H, Ar), 6.78 (t, J=2 Hz, 1H, Ar), 6.83 (d, J=2 Hz, 2H, Ar), 7.47 (d, J=2 Hz, 1H, Ar), 7.61 (d, J=3 Hz, 1H, Ar), 7.68 (d, J=8 Hz, 1H, Ar), 7.90 (brs, 1H, Ar). The product was used in the next step without further purification.