Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]([N:22](O)O)=[CH:4][N:3]=1>CO>[NH2:22][C:5]1[C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7][CH:2]=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(Cl)ncc1N(O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncncc1N
Yield: 94.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-({[2-chloro-5-(dihydroxyamino)-4-pyrimidinyl]amino}methyl)-1-pyrrolidinecarboxylate (2.064 g, 5.74 mmol) was dissolved in MeOH (40 mL), degassed and placed under argon. 10% Pd/C (619 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure 1,1-dimethylethyl (2S)-2-{[(5-amino-4-pyrimidinyl)amino]methyl}-1-pyrrolidinecarboxylate (1.589 g, 94%). LCMS: (M+H)+: 294.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Add 4-bromophenyl boronic acid (5.0 g, 24.82 mmol), tetrakis(triphenylphosphine)palladium (0) (0.717 g, 0.620 mmol) and 2 M Na2CO3 (10 mL) to a solution of 2-iodoaniline (4.5 g, 20.69 mmol) in toluene (2 mL):ethanol (20 mL), degas and heat at 80° C. under nitrogen. After 4 h, add water and extract with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography (silica gel) eluting with ethyl acetate:hexane 1:12 to provide the title compound (3.53 g, 69%): Mass spectrum (m/e): 248 (M+1); 249 (M+2). 1HNMR (CDCl3), δ3.62 (s, 2H); 6.75-6.89 (m, 2 H); 7.08-7.18 (m, 2H); 7.21-7.40 (m, 2H); 7.55-7.63 (m, 2H):
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:8]=1)([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=1.C([O-])(=O)C.[K+].C(OCC)(=O)C>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:5][C:6]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2sc(C(C)C)nc2-c2ccc(F)cc2)ccn1
Reaction time: 3 h

Procedure:
Under argon, 200 mg (0.90 mmol) of 2-isopropyl-4-(4-fluorophenyl)-1,3-thiazole, 77 mg (0.45 mmol) of 4-bromo-2-methylpyridine, 133 mg (1.35 mmol) of potassium acetate and 0.4 mg (2 μmol) of palladium(II) acetate in 5 ml of DMA are heated to 150° C. After 3 h, 50 ml of ethyl acetate are added and the reaction mixture is filtered through a silica gel cartridge. 10 ml of water are added to the filtrate. The organic phase is separated off, washed once more with 10 ml of water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 115 mg (41%) of the desired product; 1H-NMR(DMSO-(D6) δ: 8.39 (d, 1H), 7.48 (m, 2H), 7.22 (m, 2H), 7.17 (s, 1H), 7.03 (d, 1H), 3.35 (m, 1H), 2.43 (s, 3H), 1.39 (d, 6H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C:36](O)=[O:37])[CH:18]=1)#[N:16].C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:36]([C@H:26]2[CH2:25][CH2:24][C@H:23]3[C@H:22]4[C@H:31]([CH2:30][CH2:29][C@:27]23[CH3:28])[C@:32]2([CH3:35])[C:19]([CH:18]=[C:17]([C:15]#[N:16])[CH2:34][CH2:33]2)=[CH:20][CH2:21]4)=[O:37])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
0.106 ml of benzhydrylamine were added to a solution of 100 mg of 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)], a catalytic amount of 4-dimethylaminopyridine and 0.131 ml of triethylamine in 4 ml of methylene chloride. 88.0 mg of tosyl chloride were then divided into three portions and added to this reaction mixture at 30 minute intervals at room temperature, whilst stirring. One hour after finishing the addition of the tosyl chloride, the reaction mixture was diluted with methylene chloride, and washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone, to give 138 mg (yield 92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[CH2:18][CH:17]([NH2:19])[C:15](=[O:16])[NH:14][CH2:13][CH2:12]1.Cl.CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:19][CH:17]2[CH2:18][CH2:11][CH2:12][CH2:13][NH:14][C:15]2=[O:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: NC1CCCCNC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(NC2CCCCNC2=O)cc1Br
Yield: 50.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), DL-α-amino-ε-caprolactam hydrochloride (173 mg, 1.05 mmol) and DIEA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The solid found between the bi-layer was collected by filtration to give 2-bromo-4-(2-oxoazepan-3-ylamino)benzonitrile (155 mg)
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:18]>ClCCl>[CH2:10]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:9][O:18]1)[CH2:11][CH3:12]
Reactant: C=CCCCC(CCC)CCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(CCC)CCCC1CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a 250 ml flask containing 6-propylnon-1-ene (4 g, 23,76 mmol, purified by distillation) and anhydrous dichloromethane (260 mL) under nitrogen atmosphere, was added at 0 ° C. meta-chloroperoxybenzoic acid (77%, 10,65 g, 47,53 mmol, 2 eq) and the reaction was stirred for 20 minutes at 0 ° C. before warming to room temperature. The disappearance of starting material is monitored by TLC. The reaction was evaporated almost to dryness and cyclohexane (260 ml) was added and the remaining solid in the flask was extracted several times with cyclohexane. The combined organic phases were then washed with saturated aqueous sodium bicarbonate (5×25 mL). After evaporation of the solvent, the crude was purified by column chromatography (eluent dichloromethane) to give the desired product (3,86 g, 88%) as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:11][CH:12]([CH:15]=O)[CH:13]=O>C(O)(=O)C>[Br:11][C:12]1[CH:13]=[N:10][C:8]2[N:7]([N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=2)[CH:15]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)c1n[nH]c(N)n1
Solvent: CC(=O)O
Product: CC(C)(C)c1nc2ncc(Br)cn2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
3-tert-Butyl-1H-1,2,4-triazol-5-amine (CAS 202403-45-0) (35%, 13 g, 32.5 mmol) was dissolved in acetic acid (50 ml) and 2-bromomalonaldehyde (7.35 g, 48.7 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 3 hours at 60° C. The reaction mixture was evaporated and neutralized with saturated NaHCO3 solution 2N and extracted two times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on 70 g silica gel (heptane:EtOAc 100:0->50:50). The desired 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (6.83 g, 83% yield) was obtained as a white solid, MS: m/e=255.0/257.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][NH:8][C:3]=12
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1CCOC1
Product: Clc1ccnc2cc[nH]c12
Temperature: -20 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (2 g, 13 mmol) in dry THF (100 mL) under N2 at −78° C. was added excess vinyl magnesium bromide (1.0M, 40 mL, 40 mmol). The mixture was stirred at −20° C. for 8 hours before the reaction was quenched with 20% NH4Cl (75 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was subject to chromatography on silica gel to afford 7-Chloro-1H-pyrrolo[3,2-b]pyridine (0.3 g, 16%). 1H NMR (CD3OD, 400 Hz) δ 8.22 (d, J=5.2 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 6.67 (d, J=3.2 Hz, 1H). MS (ESI+) [M+H]+ 153.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(Br)cc21
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Br)ccc2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.66 mmol) and 1-(bromomethyl)-4-fluorobenzene (151 mg, 0.80 mmol) in 1,4-dioxane (5 ml) was added potassium t-butoxide (112 mg, 1.00 mmol). The resulting mixture was stirred at RT overnight. Solids were removed by filtration. Then the mixture was concentrated in vacuo to give 7-bromo-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (222 mg, yield: 100%). MS (M+H)+: 335.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:63])[N:49]([CH3:62])[C:50](=[O:61])[C@H:51]([NH:59][CH3:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:59]([CH3:60])[C@@H:51]([C:50]([N:49]([CH3:62])[N:48]([CH3:63])[CH3:47])=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Then (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.35 g, 1.07 mmol) was dissolved in methylene chloride (20 ml) and a mixture of 1-hydroxy-7-azabenzotriazole (0.15 g, 1.07 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.07 mmol) was added and stirred for 30 min. Then a mixture of (2R)-2-methylamino-3-phenylpropionic acid trimethylhydrazide (0.21 g, 0.89 mmol) and diisopropylethylamine (0.20 ml) was added and the mixture was stirred overnight. Methylene chloride (30 ml) was added and the mixture was washed with water (10 ml). The organic layer was washed with aqueous sodium bicarbonate (10 ml) and brine (50 ml), dried (MgSO4), filtered, concentrated to an oil, and chromatographed on silica (40 g) with heptane:ethyl acetate (3:7) to give 0.43 g of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-2-phenyl-1-(N,N',N'-trimethylhydrazinocarbonyl)ethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester as an oil.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:9]([C:14]([O:16]CC)=O)=[CH:10][CH2:11][CH2:12][C:13]=3[C:5]=2[CH:4]=[CH:3][NH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[CH2:27]1COC[CH2:28]1>>[CH2:27]([CH:12]1[CH2:11][CH:10]=[C:9]([CH2:14][OH:16])[C:8]2[NH:7][C:6]3[CH2:1][NH:2][CH:3]=[CH:4][C:5]=3[C:13]1=2)[CH3:28]
Reactant: CCOC(=O)C1=CCCc2c1[nH]c1c2C=CNC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1CC=C(CO)c2[nH]c3c(c21)C=CNC3

Procedure:
Ethyl 1,2,5,6-tetrahydropyrido[3,4-b]indole-8-carboxylate (0.56 g, 2.16 mmol) was dissolved in dry THF (30 mL) and lithium aluminum hydride (1M in THF, 10.82 mL, 10.82 mmol) was added via syringe. The mixture was heated to reflux for one hour then cooled and NaOH (5% aqueous solution, 2.67 mL) was added. The mixture was filtered through diatomaceous earth and the solvent was removed to afford 0.5 g of title compound.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].Cl[C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:18]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:12][C:10]1([CH3:13])[CH2:11][CH:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:17]2[N:22]=[C:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]3[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]3)[N:20]=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:18]=2)[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9]1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCN(CC)c1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(N(CC)CC)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Temperature: 70 °C
Yield: 66.4 %

Procedure:
4-n-Butylamino-2,2,6,6-tetramethylpiperidine (31.7 g, 149 mmol) is added over 15 minutes to a suspension of 15.0 g (67.8 mmol) of the 2,4-dichloro-6-diethylamino-1,3,5-triazine, 150 ml of xylene, and 7.0 g of powdered sodium hydroxide that had been heated to 70° C. The reaction mixture is heated at reflux for 23 hours. Sodium chloride is removed by filtration, and the filtrate is concentrated to a viscous oil. Further concentration of the oil by Kugelrohr distillation (140°-50° C., 0.05 mm) yields a residue which is crystallized from methanol-water to afford 25.8 g (66% yield) of 2,4-bis[N-(2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-6-diethylamino-1,3,5-triazine, m.p. 74°-76° C.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Br-].[Na+]>C(Cl)Cl>[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:2][C:3]2=[O:4])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: OCCNCc1ccnc(Nc2ccccc2)n1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COCCN1Cc1ccnc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
A solution of chloroacetyl chloride (268 mg, 2.38 mmol) in dry DCM (5 ml) was added dropwise over 10 minutes to a stirred solution of 2-anilino-4-(2-hydroxyethylaminomethyl)pyrimidine (Method 19; 582 mg, 2.38 mmol) and triethylamine (332 μl, 2.38 mmol) in dry DCM (20 ml) under nitrogen. The reaction mixture was then stirred for 20 hours at ambient temperature. The mixture was diluted with DCM and washed with water (×2), saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was dissolved in dry THF (20 ml), sodium bromide (227 mg, 2.2 mmol) added and the mixture stirred at 0° C. under nitrogen sodium hydride (88 mg of a 60% dispersion in oil) was added in one portion and the reaction stirred at 0° C. for 10 minutes and then at ambient temperature for 72 hours. The volatiles were removed by evaporation and the residue partition between EtOAc and water. The layers were separated and the organic layer washed with water, saturated brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with EtOAc. The purified product was triturated with diethyl ether, collected by filtration, washed with diethyl ether and dried to give the title compound (438 mg, 70%) as a white solid. NMR: 3.43 (t, 2H), 3.87 (t, 2H), 4.13 (s, 2H),4.52 (s, 2H), 6.72 (d, 1H), 6.93 (t, 1H), 7.25 (t 2H), 7.75 (d, 2H), 8.42 (d, 1H), 9.55 (s, 1H); m/z 285.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([Br:23])C(=O)C1>O1CCCC1>[Br:23][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Yield: 79.7 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol) and n-bromosuccinimide (2.002 g, 11.25 mmol) in tetrahydrofuran (56.2 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (10-50% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.7 g, 8.97 mmol, 80% yield) as a yellow solid: LCMS (ES) m/e 301, 303 (M, M+2)+.
Reaction SMILES: Cl.[C:2]1([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)/[C:20](/[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:21](\O)/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[C:25]([O:24][C:22]([C:21]1[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([OH:18])[N:16]=[C:14]([CH2:13][C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: N=C(N)CC1(c2ccccc2)CCCC1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 51.8 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (27-01) (4.5 g, 51.8%) was synthesized from 2-(1-phenyl-cyclopentyl)-acetamidine HCl salt (26-01) (4.5 g, 18.86 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (10.2 g, 33.41 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH3:23])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:20]([O:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:23])[C:13]1=[O:22])[CH3:21]
Reactant: CCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOCn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
17.5 g (0.056 mol) of 7-benzyl-1-ethoxymethyl-3-methylxanthine were hydrogenated over 1.8 g of palladium (10%) on activated carbon at room temperature for 8 hours in 500 ml of ethanol. The catalyst was filtered off and the filtrate was concentrated to dryness and crystallized from dimethylformamide/diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([C:20](=[O:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].O>O1CCCC1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([CH:20]([OH:22])[CH3:21])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(C(C)=O)C(=O)OC(C)(C)C)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)O)o1
Yield: 72.5 %

Procedure:
To 2.26 g of tert-butyl 2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-oxobutanoate in 50 ml of tetrahydrofuran, 7.7 ml of 1M lithium tri-sec-butylborohydride in tetrahydrofuran solution was added at -78° C. under stirring, and the resulting reaction solution was stirred at the same temperature for 2 hours. After addition of water, the reaction solution was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=12/1→4/1] to give 1.65 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:7](C(=O)C)[C:6](=[O:11])[N:5](C(=O)C)[C:4]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH3:25][OH:26].Br>O1CCCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:4]2[NH:5][C:6](=[O:11])[NH:7][C:3]=2[CH2:2][O:26][CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CO
Reactant: COc1ccc(C(=O)c2c(CBr)n(C(C)=O)c(=O)n2C(C)=O)cc1
Agent: Br
Solvent: C1CCOC1
Product: COCc1[nH]c(=O)[nH]c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g of 5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one in 50 ml of dry tetrahydrofuran is cooled to -78° C. under argon, 1.0 ml of dry methanol is added by syringe, and the solution is allowed to warm to 25° C. over 1.5 hours. Concentrated hydrobromic acid (1 ml) is then added and the mixture is stirred at 25° C. overnight. The solvent is then evaporated and the residual solid is recrystallized twice from a mixture of methanol and water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-(methoxymethyl)-2H-imidazol-2-one melting at about 211°-212° C. with decomposition. This compound has the following structural formula: ##STR6##
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[O:29][N:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C:30]5[O:29][N:28]=[C:27]([CH3:26])[CH:31]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)on1

Procedure:
The title compound, light yellow solid (23 mg, 72.4%), MS (ISP) m/z=454.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(3-methylisoxazol-5-yl)acetic acid.