Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=N[C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=NC=1.[F:22][C:23](F)([F:27])C(O)=O.C1(C)C=CC=CC=1>ClCCl>[F:22][CH:23]([F:27])[CH2:20][N:10]1[CH:11]([C:13]([OH:15])=[O:14])[CH2:12][N:8]([CH3:5])[C:9]1=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1CC(C(=O)O)N(CC(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)[CH3:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>CS(C)=O>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[N:16]=2)=[C:7]([O:12][CH3:13])[CH:6]=1)[CH3:4]
Reactant: Fc1cccc(F)n1
Reactant: CCc1ccc(O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccc(Oc2cccc(F)n2)c(OC)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (1.2 mmol; 50 mg) in anhydrous DMSO (1 mL) under argon, was added 4-ethyl-2-methoxyphenol (1 mmol; 152.2 mg) followed by 2,6-difluoropyridine (1 mmol; 0.1 ml). The reaction mixture was stirred at 120° C. overnight. After quenching with NaOH (0.1N; 3 mL), the mixture was extracted with dichloromethane (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title compound as a light yellow oil (250 mg; 1 mmol; 100%), used without further purification.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]#[CH:14])=[CH:10][C:4]=2[O:3]1.[N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]=[S:18]>C1COCC1>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:12][C:13](=[CH2:14])[S:18]/[C:17]/3=[N:16]\[C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)N=C=S
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)O2
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)OCC)S1

Procedure:
A solution of Example 1 (0.22 g, 1.05 mmol) and ethyl isothiocyanatoformate (0.11 mL, 1.05 mmol) in dry THF was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.32 (3H), 4.27 (2H), 4.70 (2H), 5.30 (2H), 7.00-7.25 (3H); MS (ESI) 343 (M+H).
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.C(O[C:12]([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[N:22]=1)=[O:13])C.CC[O-].[Na+].C(O)C>C(Cl)Cl>[CH2:28]([O:27][C:23]1[N:22]=[C:21]([CH2:20][N:19]2[C:18]3[CH:17]=[CH:16][NH:15][C:14]=3[C:12](=[O:13])[NH:6][C:7]2=[S:8])[CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cccc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 15.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.12 g, 0.90 mmol) was added to 3-[(6-ethoxy-pyridin-2-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid ethyl ester (0.24 g, 0.82 mmol) in CH2Cl2 (5 mL) and the solution was stirred at ambient temperature for 35 minutes. The solvent was evaporated and 0.4M NaOEt in ethanol (3 mL, 1.2 mmol) was added to the residue and the mixture was refluxed for 1 h. More NaOEt (0.4M in ethanol, 1.5 mL, 0.6 mmol) was added and the solution was refluxed for another 1.5 h. The solvent was evaporated, the residue was dissolved in water and the pH adjusted to neutral pH with 1M HCl. The resulting solid was collected, washed, and dried to give crude product. This material was purified by preparative HPLC to yield the title compound (38 mg, 15%) as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].Br[CH2:10][C:11]#[N:12]>C1COCC1>[OH:7][CH2:6][C:5]#[C:4][CH2:3][O:8][CH2:10][C:11]#[N:12]
Reactant: N#CCBr
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.5 g, 188 mmol) was added to a solution of 2-butyne-1,4-diol (16.1 g, 187 mmol) in THF (150 mL) at 0° C. under nitrogen. After 1 h at 0° C., bromoacetonitrile (8.33 mL, 120 mmol) was added slowly and the reaction was allowed to warm to rt. After 22 h at rt, the reaction was quenched with 1 N HCl (150 mL) and extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 4.35 μg (29%) of (4-hydroxy-but-2-ynyloxy)-acetonitrile.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=1.[CH3:20][CH:21]([NH:23][C:24](=[O:32])OC1C=CC=CC=1)[CH3:22]>CN(C)C=O>[CH3:20][CH:21]([NH:23][C:24]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([NH:3][C:24]([NH:23][CH:21]([CH3:20])[CH3:22])=[O:32])[N:9]=[CH:8][N:7]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:32])[CH3:22]
Reactant: CC(C)NC(=O)Oc1ccccc1
Reactant: Nc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)NC(C)C)c2)ncn1
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
Sodium hydride (48 mg, 1.2 mmol) was suspended in N,N-dimethylformamide (2.5 ml); 6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) was added thereto at room temperature under nitrogen stream; the reaction mixture was stirred for 30 minutes; phenyl N-(2-propyl)carbamate (215 mg, 1.2 mmol) was added thereto; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between a solvent mixture of ethyl acetate-tetrahydrofuran (1:1) and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; ethyl acetate); eluted fractions were concentrated; ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (31.3 mg, 0.079 mmol, 7.9%) as white crystals.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:8][CH2:9][CH2:10][CH3:11])[CH2:6][NH2:7])[CH2:2][CH3:3].Br[CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][NH:7][CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1)[CH2:10][CH3:11]
Reactant: CC1CCOC(CBr)O1
Reactant: CCCOC(CN)OCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCOC(CNCC1OCCC(C)O1)OCCC
Temperature: 25 °C

Procedure:
2,2-Dipropoxyethylamine (0.11 mole), 2-bromomethyl-4-methyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17](O)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[F:31])=[O:18])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1F
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)Nc3ccc(C(F)(F)F)cc3F)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (100 mg) and 4-amino-3-fluorobenzotrifluoride (106 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(2-fluoro-4-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (58.6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCOc1cc(CN2CCCC2)ccn1
Reactant: COc1c(N)c(=O)c1=O
Product: Nc1c(NCCCOc2cc(CN3CCCC3)ccn2)c(=O)c1=O

Procedure:
By the methods of Example 1, 1-amino-2-methoxycyclobut-1-ene-3,4-dione and 3-[4-(pyrrolidinomethyl)pyrid-2-yloxy]prop-1-ylamine are reacted to form the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([CH2:12][N:13]([CH2:32][CH:33]3OCCO3)[C:14]([C:16]3[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]4[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=4[F:30])[CH:20]=3)=[O:15])[N:11]=[C:5]2[CH:4]=1)#[N:2].CS(O)(=O)=[O:40]>CC#N.O>[O:15]=[C:14]1[C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]3[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=3[F:28])[C:20]=2[CH:33]=[CH:32][N:13]1[CH2:12][C:10]1[N:11]=[C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:40])[CH:8]=[CH:7][N:6]2[CH:9]=1
Reactant: CS(=O)(=O)O
Reactant: N#Cc1ccn2cc(CN(CC3OCCO3)C(=O)c3cc(C(=O)c4c(F)cc(F)cc4F)c[nH]3)nc2c1
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Temperature: 95 °C

Procedure:
The product from step B (430 mg, 0.884 mmol) was dissolved in methanesulfonic acid (2.0 mL) and heated to 95° C. in an oil bath for 25 min. After cooling in an ice-water bath, the reaction mixture was diluted with 2:3 MeCN—H2O (3 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (174 mg). LC/MS: m/z 467(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.46 (s, 2H), 7.01 (d, 1H), 7.33 (t, 2H), 7.58-7.59 (m, 2H), 7.61 (s, 1H), 7.79 (s, 1H), 7.91 (d, 1H) 8.12 (d, 1H), 8.33 (s, 1H), 8.72 (d, 1H), 13.12 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7](O)[C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1
Reactant: OC1Cc2ccc(Br)cc2CNc2ccc(Cl)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)C=Cc1ccc(Br)cc1CN2
Yield: 87.3 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocine-12-ol (0.85 g, 2.5 mmole) in dioxane (10 mL) was added concentrated HCl (1 mL). The reaction was heated to reflux for 24 hours. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to give 8-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (0.7 g, 87%). HPLC Rt=4.33 min. m/z=320 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:28]=1[CH2:29][N:30]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:31]([C:34]1[CH:39]=[C:38]([F:40])[C:37](F)=[CH:36][C:35]=1[F:42])(=[O:33])=[O:32]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:37]2[C:38]([F:40])=[CH:39][C:34]([S:31]([N:30]([CH2:29][C:28]3[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:27]=3[O:26][CH3:25])[C:43]3[S:47][N:46]=[CH:45][N:44]=3)(=[O:32])=[O:33])=[C:35]([F:42])[CH:36]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:7]=1
Reactant: O=C1Cc2cc(-c3cc(Cl)ccc3O)ccc2N1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4c(c3)CC(=O)N4)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-(5-chloro-2-hydroxyphenyl)indolin-2-one (0.132 g, 0.51 mmol) and potassium carbonate (0.105 g, 0.76 mmol) in dimethylsulfoxide (3 mL) was added N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.239 g, 0.54 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and stirred for 16 h at ambient temperature. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (5 mL). The organic phase was washed with water (2 5 mL) and brine (2 5 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 10-50% gradient of ethyl acetate in hexanes to afford 4-(4-chloro-2-(2-oxoindolin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless foam that was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-Amino-4-hydroxymethylpyrimidine (750 mg, 6.0 mmol, Reference Compound No. 4-1) and tert-butyldimethylsilyl chloride (990 mg, 6.6 mmol) were suspended in anhydrous N,N-dimethylformamide (8.0 mL), then imidazole (0.90 g, 13 mmol) was added thereto and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (50 mL), and then washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure, the precipitated solid was filtered off with 50% ethyl acetate-n-hexane solution, and dried under reduced pressure to give 1.2 g of the title Reference Compound as a white solid (Yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To stirred solution of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (20 ml) was added benzoyl chloride (0.92 ml, 7.93 mmol). The mixture was refluxed for 4 hr under nitrogen atmosphere. The reactant mixture was cooled to the room temperature and poured into 200 ml water. The resulting mixture was stirred overnight and then filtered in vacuo. The filter cake was washed with water (20 ml*3) and dried in vacuo to give 2-(N-benzoyl)amino-5-nitropyrimidine as a white solid (790 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
2-hydroxy-5-methyl-3-nitroacetophenone (200 mg, 1.02 mmol), 4-benzyloxy-3-nitrobenzaldehyde (300 mg, 1.16 mmol) and 3 equivalents of sodium hydroxide (120 mg) were introduced into 80% aqueous ethanol solution and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution was acidified by 2N hydrochloric acid solution and diluted with water. The resulting solid was filtered, washed with large amount of water and methanol, and then dried to give 430 mg (Yield 97%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.[CH2:17]([C:20]1([CH3:44])[C:29]2[C:24](=[C:25]3[CH2:33][CH2:32][CH2:31][C:26]3=[C:27](Br)[CH:28]=2)[N:23](C(OC(C)(C)C)=O)[C:22]([CH3:42])([CH3:41])[C:21]1=[O:43])[CH:18]=[CH2:19].ClC1C=C(O)C=CC=1C1C=C2C(=C3CCCC=13)NC(C)(C)C(=O)C2(C)C>>[CH2:17]([C:20]1([CH3:44])[C:29]2[C:24](=[C:25]3[CH2:33][CH2:32][CH2:31][C:26]3=[C:27]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])[CH:28]=2)[NH:23][C:22]([CH3:42])([CH3:41])[C:21]1=[O:43])[CH:18]=[CH2:19]
Reactant: C=CCC1(C)C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2CCC1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CC1(C)Nc2c(cc(-c3ccc(O)cc3Cl)c3c2CCC3)C(C)(C)C1=O
Product: C=CCC1(C)C(=O)C(C)(C)Nc2c1cc(-c1c(C)noc1C)c1c2CCC1
Yield: 31 %

Procedure:
Using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole instead of tert-butyl 2,2,4,4-tetramethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate of Example 1, 10), using tert-butyl 4-allyl-6-bromo-2,2,4-trimethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate obtained in Example 50, 1) instead of 4-bromo-3-chlorophenol of Example 1, 10) and according to a similar method, the title compound (25 mg, 31%) was obtained.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[CH:21][NH:20][CH:19]=1)[CH3:12]>ClCCCl>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[C:21]([CH:4]=[O:5])[NH:20][CH:19]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCC(=O)c1cc[nH]c1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCC(=O)c1c[nH]c(C=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of DMF (1.2 mL) in 1,2-dichloroethane (25 mL) at 0° C. was treated with POCl3 (1.5 mL). The resulting solution was warmed to ambient temperature and then treated with a solution of γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (2.06 g) in 1,2-dichloroethane (10 mL). The reaction mixture was heated to 55° C. After 3.5 hours, the reaction was quenched with the addition of 1N NaOH (16 mL), and then stirred overnight at ambient temperature. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was dried (MgSO4) and concentrated. The resulting oil was chromatographed on SiO2 (100 g) using 4:1 hexane/ethyl actetate to afford 5-formyl-γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (0.54 g).
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][CH2:19][CH2:20][C@@H:21]([NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.C(OC(=O)N(CCC[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1)CCN1CCCC1)C1C=CC=CC=1.Cl>C(Cl)Cl.O1CCOCC1>[CH2:22]([C@H:21]([NH:29][C:30]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1)=[O:31])[CH2:20][CH2:19][CH2:18][NH:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@H](CCCN(CCN1CCCC1)C(=O)OCc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H](CCCN(CCN1CCCC1)C(=O)OCc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@H](CCCNCCN1CCCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[(R)-4-(3-Biphenyl-4-yl-ureido)-5-phenyl-pentyl]-(2-pyrrolidin-1-yl-ethyl)-carbamic acid benzyl ester. To a solution of ((R)-4-tert-butoxycarbonylamino-5-phenyl-pentyl)-(2-pyrrolidin-1-yl-ethyl)-carbamic acid benzyl ester (0.06 g, 0.16 mmol) in CH2Cl2 (1.7 mL) was added HCl in dioxane (3 M, 0.6 mL), and the solution was stirred (25° C., 1 h). The solution was concentrated in vacuo, and the residue was dissolved in MeOH (2 mL) and treated with basic resin, and the resulting suspension was stirred (25° C., 1 h). The suspension was filtered and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (2.0 mL). The solution was treated with 4-biphenylisocyanate (0.033 g, 0.17 mmol), and the reaction mixture was stirred for 4 h (25° C.), during which time a precipitate, the desired product, formed. The product was collected as a clear semi-solid (0.064 g, 64%). MS (electrospray): mass calculated for C38H44N4O3, 604.79; m/z found, 605.3 [M+H]+, 627.3 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.09–7.49 (m, 21H), 5.01–5.04 (m, 2H), 3.41 (br s, 1H), 3.14–3.30 (m, 2H), 2.85–2.92 (m, 2H), 2.49–2.58 (m, 8H), 1.17–1.56 (m, 8H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:42][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCCC2)no1
Yield: 58.2 %

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclohexylamine (198 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (250 mg).