Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:10]1=[O:33])C1C=CC=CC=1>C1COCC1.[Pd]>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:33]
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1O
Yield: 116.4 %

Procedure:
Using the method of Example 56, 20% Pd/C (25 mg), 3-benzyloxy-1-(2-fluorophenyl)-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example T-4, 0.14 g, 0.31 mmol) were combined in 25 mL of THF, to give 0.13 g of the title compound as a solid, mp>250° C.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][C:13]([C:16](Cl)=O)=[CH:12]1.N1C=CC=CC=1>O1CCOCC1>[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][NH:10][C:9]2[N:1]=[CH:2][N:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[N:5]3)=[CH:12]1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C(Cl)c1ccsc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: c1nc(NCc2ccsc2)c2[nH]cnc2n1

Procedure:
In the other version of the process, 1 mole equivalent of adenine is heated in a conventional manner (Phytochemistry 16, (1977) 1865) with from 1 to 10, preferably from 2 to 5, mole equivalents of thiophene-3-carbonyl chloride in the presence of a proton acceptor (e.g. pyridine), possibly in a solvent, such as dioxane, at as high as 200° C., and the mixture is worked up in a conventional manner and if necessary recrystallized, for example as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([I:11])[C:3]=12.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:9]=[C:10]([I:11])[C:3]=12
Reactant: COc1ccc(CCl)cc1
Reactant: Clc1ccnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1.31 g, 4.688 mmol) in DMF (40 mL) was added K2CO3 (1.30 g, 9.38 mmol) and 1-(chloromethyl)-4-methoxybenzene (0.766 ml, 5.63 mmol). The reaction mixture was stirred at room temperature overnight to yield two regioisomeric products is a 5.5:1 ratio by LC-MS. The mixture was partitioned between EtOAc and H2O. The phases were separated and the organic layer washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark yellow solid. The crude product was purified by flash column chromatography, eluting with 3:1 hexanes/EtOAc and loaded with 10:1:1 CH2Cl2/MeOH/THF due to poor solubility. The desired N1-regioisomeric product (1.256 g, 67%) was obtained as a white crystalline solid. LRMS (APCI pos) m/e 400, 402 (M+, Cl pattern). The undesired N2-regioisomer, 4-chloro-3-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine, was not isolated.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(#N)C>>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccncc1)N1CCCC2(CCN(C3CCCCC3)C2=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (15 mg, 0.000055 mol), isonicotinoyl chloride hydrochloride (12 mg, 0.000066 mol), and triethylamine (27 μL, 0.00019 mol) in acetonitrile (0.5 mL, 0.01 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 18 mg of the desired product. LC-MS: 342.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH2:11])[CH:3]=1.[C:12]([CH2:14][C:15](Cl)=[O:16])#[N:13]>C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Reactant: N#CCC(=O)Cl
Solvent: c1ccccc1
Product: N#CCC(=O)Nc1cc(N)ccc1[N+](=O)[O-]

Procedure:
9.04 gm (0.059 mol) of 1,3-diamino-4-nitrobenzene, 5.69 gm (0.054 mol) of cyanoacetyl chloride were boiled in 100 ml of benzene for 4 hours at reflux. The precipitation of the reaction product occurred during the reaction and was completed by concentration of the reaction solution. The separated precipitate was purified by recrystallization from acetic acid. On the basis of the analysis data and IR- and NRM-measurements the product has the formula: 1-amino-3-cyanoacetylamino-4-nitrobenzene and a melting point of 218°-220°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(N2CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 75 °C

Procedure:
To a solution of 0.20 g (0.6 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-bromoquinoline (Compound 1) in 2.90 g (4.0 mL, 29 mmol) of triethylamine were added 0.030 g (0.16 mmol) of copper(I) iodide, 0.35 g (0.50 mL, 3.5 mmol) of (trimethylsilyl)acetylene and 0.074 g (0.11 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 75° C. for 20 hours. The reaction mixture was cooled, methylene chloride was added and the mixture was adsorbed onto silica gel. The mixture was separated by flash chromatography (hexanes) to give the title compound as a yellow solid. PNMR (300 MHz, CDCl,) d 0.20 (9 H, s), 1.35 (6 H, s), 1.84 (2 H, t, J=6.0 Hz), 2.39 (3 H, s), 3.59 (2 H, t, J=6.0 Hz), 6.78 (1 H, d, J=1.7 Hz), 6.84 (1 H, rid, J=7.8,1.7 Hz), 7.12-7.17 (5 H, several overlapping d's).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2](=[O:1])[CH2:3][CH2:4]2
Reactant: O=C(O)Cc1ccc2c(c1)CCC2=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Methyl(1-oxoindan-5-yl)acetamide can be obtained in the following way: 16 g of N,N'-carbonyldiimidazole are added portionwise to a solution of 12.5 g of (1-oxoindan-5-yl)acetic acid in 250 ml of tetrahydrofuran maintained at 0° C. After reacting for 1 hour at a temperature in the region of 20° C., the solution is cooled to -10° C. and a stream of monomethylamine is passed into the mixture for 5 minutes. After returning to a temperature in the region of 20° C., the reaction mixture is evaporated under reduced pressure. The residue is taken up in 1 liter of dichloromethane. The organic phase is washed three times with 500 ml of distilled water, dried over magnesium sulphate and then evaporated. The resulting brown solid is purified by flash chromatography on silica (eluent dichloromethane/methanol (96/4 by volume)). 9 g of N-methyl(1-oxoindan-5-yl)acetamide are thus obtained in the form of a white solid melting at 169° C. (1H NMR spectrum in CDCl3, T=300K, δ in ppm: 2.69 (2H, m, COCH2), 2.80 (3H, d, NCH3), 3.14 (2H, t, J=5 Hz, CH2), 3.65 (2H, s, CH2), 5.47 (1H, broad s, NH), 7.26 (1H, d, J=7 Hz, arom. CH), 7.42 (1H, s, arom. CH), 7.74 (1H, d, J=7 Hz, arom. CH)).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Clc1ccccc1Br
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(Oc2ccccc2Cl)cn1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder were suspended in 10 ml of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 115° C. for 23 hours under stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was dried to a solid, and 120 ml of chloroform was added to the residue. The mixture was washed with 70 ml of an aqueous sodium hydroxide solution at pH of 9. The solvent layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[CH2:32][CH2:31][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>CO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:31][CH2:32]2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(CN)cc1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3CCCC(=O)O)cc1
Reaction time: 3 h

Procedure:
Methyl 4-[8-[4-(aminomethyl)benzyl]-4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate (265 mg, 0.56 mmol) was dissolved in a 1:1 solution of methanol and THF, and 1N LiOH (1.7 mL, 1.7 mmol) was added to the resulting solution at room temperature. After 3 h, the reaction reached complete conversion, and the resulting solution was neutralized with 1N HCl (1.7 mL, 1.7 mmol) and concentrated in vacuo to give a white solid. LRMS (M+1)=455.3.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
151 mg of sodium hydroxide (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 532 mg of 4-methoxybenzyl mercaptan dissolved in 10 ml of dry dimethylformamide. The mixture was then stirred at room temperature for 30 minutes, after which 1.05 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-methanesulfonyloxypyrrolidine [prepared as described in step (2) above] was added. The reaction mixture was then stirred at room temperature for 30 minutes and then at 40° C. for 6 hours. At the end of this time, it was treated and purified according to the procedure described in Preparation 1-(4), to afford 385 mg of the title compound as an oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2COCC[Si](C)(C)C.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:17])=[O:18])=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: C[Si](C)(C)CCOCn1cnc2c(I)ncnc21
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]cnc12

Procedure:
Prepared from 256 mg (0.51 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 191 mg (0.51 mmol) of 6-iodo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-purine dissolved in 2 mL THF with 0.25 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 1 mL methanol and 1 mL 6N hydrochloric acid mixture to give after purification 2.05 mg of the final product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:32]([CH3:33])=[C:31](I)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH:23][C:31]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:24])[C:32]=1[CH3:33])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(N[C@@H](C)[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 110 °C
Yield: 99 %

Procedure:
To a solution of 61F (325 mg, 0.94 mmol) in degassed toluene:DMSO (2:1, 7 mL) at rt was added 61G (260 mg, 0.94 mmol), Cs2CO3 (614 mg, 1.89 mmol) and a solution of Pd2(dba)3 and (S)—N,N-dimethyl-1-[(R)-2-(diphenyphosphino)ferrocenyl]ethylamine (1:6 ratio, 0.06 mol %) in nitrogen degassed toluene (3 mL). The reaction was degassed with nitrogen for 30 min, sealed and heated at 110° C. for 48 h. Cool to rt and extract with EtOAc (50 mL) and wash with water followed by sat'd aqueous NaHCO3. Dry over MgSO4, filter and concentrate. Purification by flash chromatography (40 g ISCO silica gel cartridge, 0-10% EtOAc in hexane gradient) gave the title compound (460 mg): MS (ES) m/z 494.29 [M+H]+
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([O:18][CH3:19])[C:12]=3[OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([O:18][CH3:19])[C:12]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Yield: 92.7 %

Procedure:
To a solution of 2-(1-adamantyl)-4-bromo-6-methoxyphenol (3.30 g, 79.78 mmol) in acetone (32 mL) was added benzyl bromide (1.72 g, 10.07 mmol) followed by K2CO3 (1.69 g, 12.2 mmol). This mixture was stirred and heated at reflux temperature for 20.75 h under argon. Acetone was removed at reduced pressure, and 2 N HCl (30 mL) was added. The mixture was extracted with EtOAc (150 mL), and the organic layer was washed with brine and dried. After removal of solvent at reduced pressure, the residue was crystallized (MeOH) to give 3.99 g (95%) of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenyl bromide as a white solid, mp 89-91° C. IR 2901, 2847, 1444, 1201 cm−1; 1H NMR (CDCl3) δ 1.67 (m, 6H, AdCH2), 2.00 (bs, 3H, AdCH), 2.05 (bs, 6H, AdCH2), 3.85 (s, 3H, OCH3), 5.07 (s, 2H, C6H5CH2), 6.96 (d, J=2.3 Hz, 1H, 6-ArH), 7.01 (d, J=2.3 Hz, 1H, 2-ArH), 7.30-7.52 ppm (m, 5H, C6H5).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:20][C:16]2[O:15][C:14]([CH3:21])([CH3:13])[C:18](=[O:19])[CH:17]=2)=[CH:3][CH:2]=1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccnc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccnc3ccccc23)=CC1=O
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 4-quinolinecarboxaldehyde (2.8 g, 17.8 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred for 4 hours, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified by column chromatography (silica gel, pet. ether-ethyl acetate) to yield a yellow crystalline solid (1.2 g, 32% yield), m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([OH:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33]Cl>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([O:26][CH2:31][O:32][CH3:33])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: COCCl
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(O)nn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCOC)nn(C)c1=O
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxy-5-benzyloxy-2-methyl-3(2H)-pyridazinone (120 mg, 0.317 mmol) in dry DMF (2 ml) was added 60% sodium hydride (20 mg, 0.50 mmol) at 5° C. under nitrogen atmosphere. The mixture was stirred for 5 minutes, and then 80% chloromethyl methyl ether (0.04 ml, 0.47 mmol) was added. After ice-bath was removed, the mixture was stirred at room temperature for further 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with water 2 times, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 115 mg of Compound (I-7-1) as oil (yield: 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17](=[O:25])[C@@H:16]1[CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](O)([CH3:52])([CH3:51])[CH3:50].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:49]([O:23][C:22](=[O:24])[CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C@@H:16]([CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C:17]1=[O:25])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)O
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 50 ml of dichloromethane were dissolved 1.7 g of (S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid produced in Reference Example 34, 2 ml of tert-butanol and 1.6 g of 4-dimethylaminopyridine. To the solution was then added 0.6 g of WSC, and the mixture was stirred for 24 hours at room temperature. Dichloromethane was distilled off, and the residue was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous saline solution, which was then dried (Na2SO4), followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (AcOEt), followed by crystallization from ether/hexane to afford 1.02 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]=[N+]=[N-])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H](N=[N+]=[N-])c1cccc(C#N)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: C[C@H](N)c1cccc(C#N)c1

Procedure:
(S)-1-(3-cyanophenyl)-1-azidoethane (1.42 mmol) was dissolved in benzene (4 mL), H2O (500 μL) was added followed by triphenylphosphine (2.90 mmol). The resultant mixture was heated to 80° C. for 3.5 h. 25 mL of 2N HCl was added and the mixture washed 3×20 mL diethyl ether. These washes were discarded and the aqueous phase made strongly basic by the addition of 5N NaOH. This basic aqueous phase was then extracted 3×25 mL diethyl ether, these extracts combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was used without further purification (150 mg). 1H NMR (500 MHz, CDCl3): δ 7.70 (m, 1H); 7.62 (d, J=7.8 Hz, 1H); 7.54 (m, 1H); 7.44 (t, J=7.8 Hz, 1H); 4.20 (q, J=6.6 Hz, 1H); 1.40 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: c1ccc(C2CCCN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of Methyl 2,5-dichloronicotinate (120 mg, 0.58 mmol,) in isopropanol (10 ml), 2-phenylpyrrolidine (86 mg, 0.58 mmol, available from Matrix Scientific #018619) and N,N-Diisopropylethylamine (90 mg, 0.70 mmol) were added. The mixture was heated under reflux overnight. After cooling to room temperature, the mixture was evaporated and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml) and brine (10 ml), dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 20:1 to afford the title compound (D72) (167 mg) as colorless oil.