Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:24])[C@@H:15]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:25]O.O.[OH-].[Li+]>C1COCC1.O>[CH3:23][CH:21]([CH3:22])[CH2:20][CH2:19][C@@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:24])=[O:25]
Reactant: C=CC[C@H](CCC(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](CCC(C)C)C(=O)O
Reaction time: 12 h

Procedure:
To a 0° C. solution of Example 8C (17.3 g, 52.6 mmol) in THF (200 mL) was added water (25 mL) and 30% hydrogen peroxide (25 mL, 220 mmol). A solution of lithium hydroxide monohydrate (4.38 g, 104 mmol) in water (100 mL) was added and the resulting solution was stirred for 12 hours. The mixture was quenched with aqueous NaHSO3 then concentrated and made basic with 5M NaOH. The aqueous phase was washed with ethyl acetate, then acidified with concentrated HCl to pH 3 and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 171 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.Cl.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>C1COCC1>[C:38]([O:37][C:36]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCN
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 60.4 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (600 mg) in THF (20 mL) was added tert-butyl 8-aminooctylcarbamate hydrochloride (465 mg) and iPr2NEt (0.578 mL). The mixture was heated at 70° C. for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(8-(tert-butoxycarbonylamino)octylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)=[CH:4][C:3]=1[O:28][CH3:29].[Li+].[OH-].O.Cl>CO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccc(O)c(OC)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(C(=O)O)cc2NC3=O)ccc1O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of Example 12 (80 mg, 0.2 mmol) and LiOH (24 mL, 1 mmol) in methanol (10 mL), THF (10 mL), and water (10 mL) was heated to reflux overnight, cooled to room temperature, and adjusted to pH <5 with concentrated HCl. The solid was collected by filtration to provide 55 mg of the desired product. MS (DCI) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.89 (s, 1H), 9.28 (s, 1H), 8.33 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.52 (dd, J=8.1, 1.6 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.17-7.20 (m, 2H), 7.04-7.10 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH:1]1[C:15](=[NH:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.Cl.C[OH:19]>>[C@@H:4]1([N:3]2[CH:2]=[CH:1][C:15]([NH2:16])=[N:14][C:13]2=[O:12])[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]1[OH:19]
Reactant: CO
Reactant: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: Cl
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the diacetyl derivative (30 mg.) of the carbocyclic analog of cyclocytidine, described immediately above, in methanol (15 ml.) saturated with hydrogen chloride was stirred at room temperature overnight. Evaporation of volatile components with a stream of nitrogen, then under reduced pressure, and in a high vacuum left the hydrochloride of the carbocyclic analog of cyclocytidine (30 mg.); the mass spectrum included the expected peaks (m/e 223, 206, 192). A solution of this material in 1 N aqueous ammonia (2 ml.) was heated at 80°-85° for 5 min. Volatile components were evaporated under reduced pressure and, then, in a high vacuum. Crystallization of the residue from ethanol gave the carbocyclic analog of 1-β-arabinofuranosylcytosine. This compound may also be isolated by ion-exchange chromatography, by preparative thin-layer chromatograhy, or by the sequential use of these techniques after impure preparations containing the carbocyclic analog of cyclocytidine are treated with aqueous ammonia. The properties of the pure compound prepared by the procedure of either Part A or Part B are summarized in Part A.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC(Cl)C.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Cl-].[Cl-].[Al+3].Cl>O>[C:24]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=1[CH2:13]2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2

Procedure:
A mixture of 130 g. of methyl 7-methylxanthene-2-carboxylate in 200 ml. of dichloroethane is cooled to -5° C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. The resultant solution is stirred at room temperature for 1.75 hours. After this time, the solution is poured into a mixture of 300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloric acid. The mixture is then extracted with three 500 ml. portions of methylene chloride. The combined extracts are washed with 10% aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 5-acetyl-7-methylxanthene-2-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c(C)c1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2,4-dimethylphenylboronic acid (0.333 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 4 days to give 4-chloro-2-(2,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline as a yellow oil. Mass Spectrum (ESI) m/e=325.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[OH:12])[CH:5]=[CH:6][CH:7]=1.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[O:12][C:21]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCNc1cccc(Br)c1)c1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(c2ccccc2Cl)CCN1c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 164 %

Procedure:
Half of the crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol (0.074 mmol) was mixed with triphosgene (7.5 mg, 0.34 equiv), i-Pr2NEt (26 μL, 2 equiv), pyridine (30 μL, 5 equiv) and acetonitrile (5 mL). The mixture was put in the microwave oven for 30 min at 110° C. LC-MS found the reaction completed. The mixture was concentrated, redissolved in EtOAc (5 mL), washed with 1% aq HCl (2×2 mL), concentrated and purified by preparative HPLC to afford 3-(3-bromo-phenyl)-6-(2-chloro-phenyl)-[1,3]oxazinan-2-one (15.2 mg). LC-MS (3 min) tR=1.86 min., m/z 368,369(M+1). 1H NMR (CDCl3) δ 7.63(d, 1H), 7.56 (s, 1H), 7.43-7.26 (m, 6H), 5.83 (d, 1H), 3.88 (q, 1H), 3.67 (m, 1H), 2.55 (d, 1H), 2.17 (m, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:11][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([OH:12])[N:1]=3)[CH:6]=[CH:7][C:8]=2[CH:17]([C:16]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=2)[C:27]=1[C:28]#[N:29]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1ccc2cccc(O)c2n1
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(O)nc32)cc(Br)c1OC
Temperature: 90 °C
Reaction time: 72 h

Procedure:
2,8-Quinolinediol (193 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (33 μl, 0.3 mmol) and then stirred at 90° C. under LC-MS control for 3 days. The reaction mixture was then cooled down to room temperature, diluted with water to about 100 ml and extracted with ethyl acetate (2×50 ml). The organic solution was washed with 5% aqueous sodium bicarbonate solution (2×50 ml) and then dried over magnesium sulfate, solvent was evaporated under vacuum at 40 C and dried (18 mg, 0.04 mmol, 4%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[CH:14]=1
Reactant: CCOP(=O)(OCC)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diethyl 5-tert-butyldimethylsilyloxy-2-methylphenylphosphonate 1-3 (165 mg, 0.46 mmol) and 0.69 mL of a 1 M solution of tetrabutylammonium fluoride (0.69 mmol) in 4 mL of THF was stirred at rt for 1 h. The mixture was then diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated. The resulting residue was subjected to MPLC on a 12 g column of SiO2 eluting with 35% EtOAc in hexanes (10 min) and then 50% EtOAc (10 min) to provide diethyl 5-hydroxy-2-methyl-phenylphosphonate 1-4 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 1.23 (t, 6H, J=6 Hz), 2.36 (d, 3H, J=1 Hz), 3.9-4.0 (m, 4H), 6.87 (dd, 1H, J=8, 3 Hz), 7.12 (t, 1H, J=8 Hz), 7.20 (dd, 1H, J=14, 3 Hz), 9.55 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O>O>[C:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCc2ccccc2)cc1

Procedure:
A mixture of 50 g. of 1-chloro-4-nitrobenzene, 76 g. of 2-phenylethylamine, and 30 ml. of dimethylsulfoxide is heated for 18 hours at 150°C. The resultant reaction mixture is poured into 3 liters of water. The precipitate formed is recovered by filtration and recrystallized from ether to yield the product, N-(2-phenylethyl)-p-nitroaniline; m.p. 57°-59°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH2:7])[CH3:2].C([O-])(O)=O.[Na+].[N+]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](Cl)(=[O:36])=[O:35])([O-])=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH:7][S:34]([C:26]1[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][CH:27]=1)(=[O:35])=[O:36])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C[C@H](N)c1ccc(OC)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Reaction time: 12 h

Procedure:
A solution of aminoester 16-5 (3.0 g, 13.0 mmol) in CH2Cl2 (20 mL) was treated with aq NaHCO3 (4.4 g in 20 mL H2O). 2,4-Dinitrobenzenesulfonyl chloride (4.3 g, 16 mmol) was added and the reaction mixture stirred for 12 h. The solution was extracted with CH2Cl2 (3×40 mL) and the combined organic solutions washed with satd aq NaHCO3 (40 mL) and brine (40 mL). The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (97:3 CH2Cl2 /MeOH) to give the desired product 16-6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][N:6]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[O:24])=[CH:7][N:6]=1)=[O:4]
Reactant: CCCCSc1ccc(C(=O)OC)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCS(=O)c1ccc(C(=O)OC)nc1
Reaction time: 0.25 h

Procedure:
To the stirred solution of 6.5 g of 5-n-butylmercapto-pyridine-2-carboxylic acid methyl ester in 200 ml of methylene chloride, the solution of 5.7 g of m-chloroperbenzoic acid in 100 ml of methylene chloride is added during 15 minutes while cooling with ice. It is stirred another 15 minutes and allowed to stand at room temperature overnight. It is washed with 10% aqueous sodium bicarbonate and water, dried and evaporated. The residue is recrystallized from benzene-hexane (1:1), to yield the 5-n-butylsulfinylpyridine-2-carboxylic acid methyl ester melting at 150°-154°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])C(O)=O.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:11]([C:10]1[CH:9]=[CH:8][CH:4]=[CH:3][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 3-hydroxy-4nitrobenzoic acid (1b) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol), and an amino tantagel resin (1 g, 0.45 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:18])(=O)=O>>[Cl:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1ccc2nc(S)sc2c1
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sulfuryl chloride (40 mL) was added with stirring to 2-mercapto-6-(trifluoromethyl)-benzothiazole (18.0 g, 76.7 mmol) at <20° C. under a nitrogen atmosphere, and the suspension was then stirred at rt for 2 h. The reaction mixture was poured into ice water with stirring. Precipitation was formed, and stirring was continued for 2 h. The solid precipitate was filtered, and rinsed with water. The wet filter cake was dissolved in 100 mL EtOAc, and the solution was washed with 100 mL water and 50 mL saturated aqueous NaHCO3 solution, then dried over Na2SO4. EtOAc was removed by rotary evaporation, and the residue was dried in vacuo to afford the desired product as a light yellow solid (16.5 g, 91%). GC-EIMS m/z 237 (M+); 1H NMR (CDCl3) δ 8.10 (s, 1 H), 8.00 (d, 1 H), 7.70 (d, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: Cc1ccc(C(O)CN)cc1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: Cc1ccc(C(O)CNC2=NCCN2)cc1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.06 parts of α-(aminomethyl)-p-methylbenzyl alcohol, 7.8 parts of 2-(nitramino)-2-imidazoline and 8 parts of xylene is stirred for 30 minutes at 160°C (oil-bath). The reaction mixture is cooled and acetone is added. The precipitated product is filered off, washed with acetone and dried, yielding α-(2-imidazolin-2-ylaminomethyl)-p-methylbenzyl alcohol; 163.7°C.
Reaction SMILES: C(O)(C)C.C([NH:13][C:14]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[S:15])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:24]1[CH:25]=[C:21]([CH2:20][S:19][CH2:18][CH2:17][NH:16][C:14]([NH2:13])=[S:15])[N:22]=[CH:23]1
Reactant: O=C(NC(=S)NCCSCc1c[nH]cn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: NC(=S)NCCSCc1c[nH]cn1
Yield: 61.7 %

Procedure:
A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole (6.0 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-[2-(4-imidazolylmehylthio)-ethyl]thiourea (7.5 g.). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126°-128°. (ii) The benzoyl thiourea (6.0 g.) was added to a solution of potassium carbonate (1.4 g.) in water (80 ml.), at 60°. The solution was maintained at this temperature for one hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid was removed by filtration and the filtrate was basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohl and concentration, the product was crystallised from isopropyl acetate. Recrystallisation from water gave N-[2-(4-imidazolylmethylthio)ethyl]thiourea (2.5 g.) m.p. 135°-137°. (Found: C, 38.9; H, 5.5; N, 26.1; S, 29.6. C7H12N4S2 requires: C, 38.9; H, 5.6; N; 25.9; S, 29.6).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].O=[C:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](=O)[CH2:41][NH:42]/[C:43](/[NH:52]C(OC(C)(C)C)=O)=[N:44]\C(OC(C)(C)C)=O)[CH2:17][NH:18]/[C:19](/[NH:28]C(OC(C)(C)C)=O)=[N:20]\C(OC(C)(C)C)=O>O>[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH2:39]([C:40]1[NH+:44]=[C:43]([NH2:52])[NH:42][CH:41]=1)[CH2:38][CH2:37][CH2:36][C:16]1[NH+:20]=[C:19]([NH2:28])[NH:18][CH:17]=1.[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)/N=C(\NCC(=O)CCCCC(=O)CN/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1[nH]cc(CCCCc2c[nH]c(N)[nH+]2)[nH+]1
Product: O=C([O-])C(F)(F)F
Temperature: 75 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Toluene (40 mL) and trifluoroacetic acid (650 μL, 8.36 mmol, 10.0 equiv) were added via syringe to a flask charged with ketoguanidine 75 (549 mg, 0.836 mmol, 1 equiv) and the resulting mixture was heated to 75° C. After 16 h, the reaction mixture was allowed to cool to 23° C. and was concentrated under reduced pressure. Water (20 mL) and trifluoroacetic acid (650 μL, 8.36 mmol, 10.0 equiv) were added via syringe to the residue and the resulting mixture was heated to 100° C. After 45 h, the reaction mixture was allowed to cool to 23° C. and was concentrated under reduced pressure to give 2-aminoimidazole 76 (375 mg, 100%) as a brown solid. 1H NMR (500 MHz, CD3OD, 21° C.): δ 6.49 (s, 2H), 2.53 (app-t, J=6.5 Hz, 4H), 1.65 (app-t, J=7.1 Hz, 4H). 13C NMR (125.8 MHz, CD3OD, 21° C.): δ 162.6, 148.8, 128.8, 109.8, 101.4, 28.7, 25.2. FTIR (neat) cm−1: 3179 (br-s), 2361 (w), 1702 (s), 1442 (m), 1205 (s), 1134 (s), 845 (m), 723 (m). HRMS (ESI) (m/z): calc'd for C10H17N6, [M+H]+: 221.1509, found: 221.1512.
Reaction SMILES: [CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(Cl)Cl.O>[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([CH2:30][OH:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(C(=O)O)ccc21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a cooled (0° C.) solution of 2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid (77 mg, 0.17 mmol) and N-methyl morpholine (23 μL, 0.21 mmol) in DCM (3 mL) was added isobutyl chloroformate (27 μL, 0.21 mmol. The mixture was allowed to warm to room temperature and stirred for 2 hrs. After concentration and trituration with ethyl acetate the solid was removed by filtration and the filtrate concentrated in vacuo. The residue containing the mixed anhydride was dissolved in THF (3 mL) and added to a stirred and cooled (0° C.) solution of sodium borohydride (65 mg, 1.7 mmol) in water. The mixture was allowed to warm to room temperature and stirred for 3 hrs., followed by quenching with satd. Na/K tartrate and stirring overnight. The mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases washed with brine and dried (MgSO4). Purification by flash chromatography (eluent 2%, 5% methanol in DCM) afforded 3-cyclopropyl-1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-quinazoline-2,4-dione (39 mg, 52%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C@@H:15]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:16]([OH:20])[C:17]([NH2:19])=[O:18].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]Cl>CS(C)=O>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C@@H:15]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C@@H:16]([OH:20])[C:17]([NH2:19])=[O:18]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([C@H](Sc2ccccc2NCCN(C)C)[C@@H](O)C(N)=O)cc1
Temperature: 70 °C

Procedure:
Potassium carbonate is added to dimethyl sulfoxide, and the mixture is stirred at 70° C. The mixture is cooled to room temperature, and thereto is added (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide, and stirred. To the reaction mixture is added dropwise 2-dimethylaminoethyl chloride, and the mixture is stirred at room temperature. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is dried, and concentrated under reduced pressure to remove the solvent to give (2S,3S)-3-[2-(2-dimethylaminoethylamino)phenylthio]-2-hydroxy-3-(4-methoxyphenyl)-propionamide.