Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH:22]1(N)C2C(=CC=CC=2)CCC1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:22]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCCc2ccccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2 S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound-as a oil: 1H NMR (400 MHz, CDCl3) δ 7.81, 7.38, 7.19, 5.49, 4.56, 2.87, 2.69, 2.57, 2.12, 1.98, 1.91, 1.32; 13C NMR (100 MHz, CDCl3) δ 153.69, 151.42, 140.81, 138.70, 138.29, 129.85, 129.56, 129.18, 127.49, 126.58, 48.71, 30.07, 29.94, 28.56, 26.07, 20.42, 13.96, 11.16; HRMS (FAB) calcd for C18H23N3+H 282.1970, found 282.1975.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:27]CCl>C(O)C>[ClH:27].[C:18]1([CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCCN(CCOCCCc2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(CCOCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (3.2 g, 10 mmol) was dissolved in ethanol (10 ml) and 12N sodium hydroxide (2.5 ml) was added. The mixture was stirred at ambient temperature for 3 h. Excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The mixture was dried (Na2SO4) and the solvent was evaporated in vacuo to give a residue which was re-evaporated twice with acetone. Crystallisation of the residue from a mixture of acetone and ethyl acetate followed by recrystallisation from acetone gave 1.1 g of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[S:18][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=S)Nc2ccccc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3c(Br)cccc3s2)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
To a solution of EXAMPLE 1B (7.1 g) in ethanol (26 mL) was added 30% sodium hydroxide (17.63 mL) and the mixture was stirred for 5 minutes. Water (35 mL) was added and 4 mL aliquots of the mixture were added at 1-minute intervals to a heated (85° C.) solution of potassium ferricyanide(III) (29 g) in water (260 mL). The mixture was maintained at 85° C. for 30 minutes and cooled. The precipitate was collected, washed with water and dried to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][O:34][C:35](=[O:39])[CH:36](Br)[CH3:37]>>[CH3:33][O:34][C:35](=[O:39])[CH:36]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:32])[CH3:1])[N:26]([CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:37]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 38.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo propionic acid methyl ester (31 mL, 0.28 mmol) gave 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (46 mg, 39%). MS (ESI) m/z 521.4 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A reaction mixture of 67.0 mg (0.5 mmoles) of oxindole, 73.0 mg (0.6 mmoles) of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 87.7 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]#[N:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCc2cccc([N+](=O)[O-])c2)c1

Procedure:
1.70 g (10.0 mmol) of 3-nitrobenzyl chloride, 1.48 g (12.4 mmol) of 3-cyanophenol and 3.58 g (25.9 mmol) of potassium carbonate were suspended in 80 ml of dimethylformamide, and the resultant suspension was stirred at 95° C. overnight. After leaving the suspension to cool, 150 ml of water was added to the suspension, and the solid formed was taken by the filtration. The solid was washed with 100 ml of water and then 20 ml of ethyl acetate, and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O.Cl>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(Cl)c(Cl)c1)CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
Lithium hydroxide (55 mg) was added to a solution of the product of step (a) (722 mg) in tetrahydrofuran/water (30 ml). The mixture was stirred at room temperature for 4 hours, diluted with hydrochloric acid (1M, 50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (301 mg). NMR δH (250 MHz, CDCl3) 1.43 (9H, s), 2.59 (3H, s), 2.90 (1H, m), 3.22 (1H, m), 3.77 (1H, m) 4.10 (1H, m), 4.26 (1H, m),5.67 (1H, br s) 7.24 (1H, dd, J=11.0 and 1.0 Hz), 7.68 (2H,m). m/e (CI+) 377 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a solution of 2-chloro-3-nitro-5-tert-butyl pyridine (30 mg, 0.14 mmol) in anhydrous MeOH (1.5 mL) under nitrogen was added a solution of sodium methoxide (1.57 g sodium in 40 mL anhydrous MeOH) (85 uL, 0.14 mmol). The reaction was heated in a sealed tube in an oil bath set at 80-90° C. overnight. The volatiles were removed in vacuo, the residue taken up in EtOAc (15 mL), washed with water (10 mL), brine (10 mL), dried (magnesium sulfate), filtered and evaporated to dryness. Flash chromatography of the residue on silica gel (10% EtOAc in hexanes) gave the desired 2-methoxy-3-nitro-5-tert-butyl pyridine as a glassy yellow solid (12 mg, 0.057 mmol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[CH:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=3)[C:4]#[N:5])[CH:14]=2)[CH2:20][CH:21]1[CH3:24]
Reactant: N#Cc1cc(CO)ccc1F
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(F)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2-dimethyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C:13](=[O:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7].[Si:22](C1NC=CN=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:1][C:2]([CH3:20])([CH3:21])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C:13](=[O:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7]
Reactant: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2C(=O)CCC[C@]12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: ClCCl
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 24 h

Procedure:
446 mg (1.55 mmol) of (4aS,8aR)-5-((R)-5-hydroxy-1,5-dimethyl-hex-3-ynyl)-4a-methyl-3,4,4a,7,8,8a-hexahydro-2H-naphthalen-1-one in 12 ml of abs. CH2Cl2 was treated with 2.03 ml (9 eq.) of TMS-imidazole and kept at RT for 24 h. Pouring onto crushed ice, twofold extraction with ether, washing with water and brine, and drying over sodium sulfate left a crude product, which was purified by flash chromatography (SiO2, hexane/AcOEt=9/1). Thereby, 561 mg of the title compound was obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].O>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH:15]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 6-methoxy-pyridine-3-carbaldehyde (1 g, 7.29 mmol, 1 eq) in 50 ml of dry DCM was added portionwise (methoxycarbonylmethylene)triphenylphosphorane (1.05 eq, 2.56 g). The mixture was stirred at room temperature for 16 hours (overnight). The mixture was then poured into 200 ml of water and the organic substances were extracted with DCM (twice, 150 ml of DCM was used in total) The gathered DCM layers were dried and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 100 g normal phase silica SNAP coloumn and cyclohexane/EtOAc solvent system (gradient 3-22% of EtOAc in 20 coloumn volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (1.04 g, yield=73.8%, purity=95%). MS: [M+H]+=194.17 1H NMR (300 MHz; CDCl3) δ/ppm 3.81 (s, 3H), 3.97 (s, 3H), 6.34 (d, J=16.02 Hz, 1H), 6.77 (d, J=8.79 Hz, 1H), 7.65 (d, J=16.02 Hz, 1H), 7.77 (dd, J=8.70 Hz, J=2.40 Hz, 1H), 8.27 (d, J=2.40 Hz, 1H)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([Cl:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 84.2 %

Procedure:
Following general procedure II, (R)-tert-butyl 1-(5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (200 mg, 0.40 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (170 mg, 0.60 mmol) to afford the desired product (210 mg, 85%) as a orange solid. ESI MS m/z 623 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>C(O)C.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCCCC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
70 ml of water are added to a solution of 90 g (0.64 mol) of 4-chlorobenzaldehyde and 68.5 g (0.6 mol) of 2-heptanone in 300 ml of ethanol and directly thereafter a solution of 1.7 g of sodium hydroxide in 17 ml of water is added. The mixture is initially stirred for 1 hour at room temperature, then 0.6 g of solid sodium hydroxide is added and the mixture is stirred for a further 64 hours. The precipitated product is filtered off with suction, washed with 1 liter of water, pressed out on a clay plate and then dried in vacuo for 16 hours over phosphorus pentoxide. 135 g (95.1% of theory) of 1-(4-chlorophenyl)-1-octen-3-one are obtained in the form of a pale yellow solid of melting point 44°-47° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:11]1[C:16](=[O:17])[S:15][CH2:14][C:12]1=[O:13].[OH-].[K+].Cl>O1CCOCC1>[OH:13][C:12]1[CH2:14][S:15][C:16](=[O:17])[C:11]=1[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: O=C1CSC(=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1ccc(CC2=C(O)CSC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a suspension of 4-methylthiobenzyl bromide (5.6 g. 25.8 mmol), thiotetronic acid (3.0 g, 25.8 mmol) in dioxane (50 ml), was added aqueous potassium hydroxide (25.8 mL). The mixture was stirred at temperatures in the range of 65°-70° C. for 3 hours. Then, the mixture was cooled to room temperature, poured into H20, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3) gave a white solid (1.72 g, 26.5%): m.p. 206°-208° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:6]=2[N:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OC(C)(C)c2nc(Cl)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)C(C)(C)OC3(C)C)CC1

Procedure:
A mixture of 2-chloro-5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidine (1.60 g, 7.52 mmol, 1.0 equiv; intermediate B1) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.81 g, 9.03 mmol, 1.2 equiv; commercially available) in anhydrous DMF (6 mL) was heated by microwave irradiation to 150° C. for 30 min. The organic phase was concentrated under reduced pressure and the residue purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (10:1)→ethyl acetate providing 1.26 g (45%) of the title compound. MS (ISP): 377.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][C:23]=1[O:35][CH3:36]>>[CH3:36][O:35][C:23]1[CH:24]=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][C:22]=1[O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2OC)cc1)c1ccccc1
Yield: 47.62 %

Procedure:
Compound 94 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.12 g, 0.446 mmol) and ethyl 3-(4-hydroxy-3-methoxyphenyl)propanoate (0.1 g, 0.446 mmol) by following the procedure described in scheme 16 (0.06 g, yield: 47.62%); Purity: 98.66%.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH:8][CH2:9][CH:10](CO)O>>[CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:10][CH2:9][OH:8]
Reactant: OCC(O)CO
Reactant: OCCOCCO
Product: OCCOCCOCCO

Procedure:
The preparation is repeated using a 1:1:1 mole ratio of diethylene glycol, triethylene glycol, and glycerin to obtain the desired approximately 1:1:1 mole ratio mixture of sodium 2-[2-(2-hydroxyethoxy)ethoxy]ethanesulfonate, sodium 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethanesulfonate, and sodium 2-(2,3-dihydroxypropoxy)ethanesulfonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>C1COCC1.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1
Reactant: O=C=O
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1ccc(C(=O)O)cc1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
1-Bromo-4-trimethylsilyl-benzene (0.426 ml, 2.18 mmol) was dissolved in THF (20 ml), and n-butyllithium (1.59 M solution in n-hexane, 1.51 ml, 1.40 mmol) was added dropwise at −78° C. After stirring for 20 minutes, crushed dry ice (excess) was added. The reaction solution was stirred at room temperature for one hour, and 1 M hydrochloric acid and water were then added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 4-trimethylsilanyl-benzoic acid (363 mg, 86%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1c2ccccc2oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.54 mL, 3.21 mmol) was added slowly to a solution of, 1,3-dihydroxyxanthen-9-one (689 mg, 3.02 mmol) and pyridine (7.3 mL) in CH2Cl2 (30 mL) at 0° C. The reaction then was allowed to slowly warm to RT and stirred for 16 h. The orange mixture then was dissolved in CH2Cl2 (100 mL), and washed with 10% citric acid (2×25 mL) and brine (1×25 mL). The organics were dried (Na2SO4), concentrated, and purified by Biotage chromatography using 10% EtOAc/hexanes as eluent to yield 702 mg (65%) of trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9H-xanthen-3-yl ester as a light yellow solid. Rf=0.65 (50% EtOAc/hexanes). See R. Pillai et al., J. Org. Chem., 51, pages 717-723 (1986). 1H NMR (DMSO-d6, 400 MHz) δ: 12.90 (s, 1H), 8.20 (d, 1H), 7.96 (dd, 1H), 7.70 (d, 1H), 7.56 (dd, 1H), 7.37 (m, 1H), 7.05 (m, 1H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>N1CCCCC1.CN(C=O)C>[NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](N)C(N)=O

Procedure:
Polymer-bound D-Leu-NH2: FMOC-protected Rink amide resin (30 g, 0.61 mmol/g, 18 mmol) was treated with piperidine/DMF solution (250 mL). The mixture was shaken at rt for 24 h, drained, washed with DMF (5×200 mL), CH2Cl2 (5×200 mL) and dried under vacuum. The resin was then treated with FMOC-D-Leu-OH (22 g, 62 mmol), 1-hydroxybenzotriazole hydrate (2.5 g, 18 mmol), 1,3-diisopropylcarbodiimide (9.8 mL, 62 mmol), and DMF (250 mL). The mixture was shaken for 20 h, drained, washed with DMF (4×200 mL), DMF-water (1:1, 3×200 mL), DMF (3×200 mL), MeOH (3×200 mL), CH2Cl2 (3×200 mL) and dried. The completion of reaction and the loading of the resin-bound FMOC-D-Leu-NH2 (0.56 mmol/g) were determined by the treatment of 52 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 11 mg of FMOC-D-Leu-NH2. The resin-bound FMOC-D-Leu-NH2 was deprotected with 20% (v/v) piperidine/DMF solution (250 mL) to give polymer-bound D-Leu-NH2 (20 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C)c(C(=O)OCC)s2)cc1

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 4-n-propylbenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was not recrystallized. Yield 315 mg, 85%: 1H NMR (DMSO) δ 7.70 (d, 2H), 7.37 (d, 2H), 4.21 (q, 2H), 2.60 (t, 2H) 2.38 (s, 3H), 1.58 (t, 2H), 1.25 (t, 3H), 0.87 (t, 3H); MS-ES (neg) m/z 367.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1.[Na].[CH3:17]I>CO>[NH2:1][C:2]1[N:6]=[C:5]([N:7]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[CH3:17])[O:4][N:3]=1
Reactant: CI
Reactant: Nc1noc(Nc2c(Cl)cccc2Cl)n1
Agent: [Na]
Solvent: CO
Product: CN(c1nc(N)no1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.0 g (0.012 mole) 3-amino-5-(2,6-dichlorophenylamino)-1,2,4-oxadiazole were added to a solution of 0.6 g (0.025 mole) sodium in 100 ml methanol, and 1.6 ml (0.024 mole) methyl iodide are added in drops and stirred for 24 hours at room temperature. The solvent is distilled off under vacuum, the residue taken up in methylene chloride, extracted with water and, after evaporation of the solvent, 2.8 g of the N-methyl compound, which has an mp. of 177°-178° C. after recrystallization from acetic ester/diisopropyl ether is obtained.