Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)=[O:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[O:18]=[C:16]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccccc1COc1cccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (60 mg, 0.2 mmol) was dissolved in DCM (2 ml). 4-(Trifluoromethyl)benzylamine (42 mg, 0.24 mmol) was added, then EDC (46 mg, (0.24 mmol) was added and then DMAP (29.3 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. 1% Hydrochloric acid (1 ml) and water (1 ml) were added to the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic portion was evaporated in vacuum and 82 mg solid product was left. It was then used directly in next step.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.[Li+].[BH4-].CCCCCC.C(OCC)(=O)C>C1COCC1>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:8]2[CH:9]=[CH:10][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[CH:7]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)C=Cc1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc(C=CCO)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 13 (3 g, 10 mmol) in 150 mL anhydrous THF was added LiBH4 (0.27 g, 12 mmol) under nitrogen and the mixture was stirred at room temperature for 24 h. The reaction was quenched by the addition of 1 M H2SO4 solution. The resulting solution was extracted with dichloromethane. The extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulphate, filtered and evaporated under vacuum to give light yellow solid which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 14.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.20 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: C(C1C=CC(COC2C=C([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])C=C(C)C=2)=CC=1)#N.Cl.C(=O)([O-])[O-].[NH4+].[NH4+]>C(Cl)Cl.C(O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([OH:21])(=[O:20])=[O:18]
Reactant: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 179.1 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (20 mL) at 0° C. The mixture was stinred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% K2CO3 (50 mL). The organic phase was washed with 50 mL of 10% K2CO3 and dried over K2CO3. The solvent was removed in vacuo. The residue was diluted with CH2Cl2, treated with HCl in methanol (30 mL), and concentrated. The residue was then purified by crystallization (methanol and ethyl acetate) to give the title compound as a white solid (345 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.16 (s, 2H), 6.53 (t, 2 H, J=9.3 Hz)), 6.86 (s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1H, J=4.0 Hz), 9.24 (br s,2 H) and 9.44 (br s, 2 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2ClO4S: 431.1 (M+H). Found: 431.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]2[O:15]CC(C)(C)N=2)=[CH:9][CH:8]=1)=[O:6].Cl.[O:24]1CCOCC1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([OH:15])=[O:24])=[CH:11][CH:12]=1)=[O:6]
Reactant: C1COCCO1
Reactant: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1

Procedure:
A mixture of 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl) toluene, prepared according to Example 3, (47.8 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1,4-dioxane is brought to reflux for 18 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSO4, and concentrated. Crude product is purified by column chromatography using silica gel, and eluting with hexane/ethyl acetate/acetic acid. Cleaner fractions are combined and recrystallized from methylene chloride/hexanes to afford 4-(4-chloro-1-oxobutyl)-α, α-dimethylphenylacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]1([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-(phenyl)phenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 455 ([M+H]+); Anal. Calcd for C28H17F3N2O: C, 74.00; H, 3.77; N, 6.16. Found: C, 73.99; H, 3.81; N, 5.92.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.C[Si]([N:19]=C=O)(C)C.[ClH:22]>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (35.6 g, 179 mmol) in CH2Cl2 (600 mL) was added trimethylsilylisocyanate (82.5 g, 716 mmol, 4 equiv.). The reaction was stirred at rt for 2 h. After concentration, the resulting white solid was dissolved in CH2Cl2 (500 mL) and treated with a solution of HCl (4 M in dioxane, 135 mL, 3 equiv.). The solution quickly became heterogeneous. The suspension was then stirred at rt overnight. Upon concentration, the desired product was isolated as a white solid (33 g, 104%). [Note: the mass balance was found to be 104%, which arises from additional HCl that could not be removed by standard evaporation under vacuum]. 1H NMR (500 MHz, CD3OD): 4.77 (s, 1H), 4.55 (s, 1H), 3.69 and 3.64 (AB, JAB=12.1, 2H), 3.47 and 3.40 (AB, JAB=11.3, 2H), 2.22 and 2.15 (AB, JAB=11.5, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC(C)([O-])C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCOCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)thiazolo[5,4-b]pyridine (0.201 g, 0.471 mmol) in 2.5 mL THF was added a solution of trimethylsulfoxonium iodide (0.207 g, 0.943 mmol) and potassium tert-butoxide (0.106 g, 0.943 mmol) in 2.5 mL DMSO. The yellow slurry was sealed and heated to 60° C. After 6 h, the reaction mixture was cooled, quenched with ice and sat'd aq. NH4Cl. The reaction mixture was partitioned between satd aq NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was purified by silica gel chromatography, 0-50% EA/hexanes, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)thiazolo[5,4-b]pyridine as a solid. MS (ESI) m/z: Calculated: 440.2; Observed: 441.1 (M++1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: O=C1CCC(O)C(C(c2ccccc2)c2ccccc2)N1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-oxo-5-hydroxy-6-benzhydryl piperidine (18.15 gm, 64.5 mmole) in acetone (150 ml) at -5° C. was added Jones reagent (2.67M, 94 mmole), and the reaction mixture was further stirred for 4 hrs. At the end of this period, the excess reactant was decomposed with 2-propanol and the solution concentrated under vacuum to half of its volume. The contents of the flask were then diluted with water (1000 ml) and extracted with methylene chloride (3×1000 ml). The combined organic phases were dried (anhyd. magnesium sulfate) and the methylene chloride was removed under vacuum to afford 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 85%).
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][N:24]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:52][CH2:53][NH:54][CH3:55])[CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[CH:38]=[CH:39][C:25]1=2.[C:56](O)(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[ClH:1].[CH3:55][N:54]([CH2:53][CH2:52][N:44]([CH2:45][C:46]1[CH:47]=[CH:48][N:49]=[CH:50][CH:51]=1)[CH2:43][CH2:42][CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:25]2[N:24]([CH3:23])[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28](=[O:34])[N:27]([CH3:35])[C:26]=2[CH:36]=1)[C:56](=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(O)c1ccccc1
Reactant: CNCCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (WSC) (144 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (115 mg, 0.75 mmol) were added to a DMF solution (5 ml) of 1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (227 mg, 0.5 mmol) and benzoic acid (92 mg, 0.75 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure, and a 4N-hydrogen chloride ethyl acetate solution (0.14 ml) was added to the residue (an ethyl acetate solution). The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to thereby obtain 120.5 mg (yield: 40%) of N-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamide dihydrochloride as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C
Reaction time: 28 h
Yield: 15 %

Procedure:
To a solution of 1.03 mmol 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 15 ml tetrahydrofuran were added successively 1.23 mmol 4-hydroxybenzotrifluoride, 1.43 mmol triphenylphosphine and 1.43 mmol di-tert-butyl azodicarboxylate. The reaction mixture was stirred at 70° C. for 28 h and was then cooled to room temperature and concentrated in vacuo. The crude material was purified by chromatography (ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 15%). MS (m/e): 276.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([C:15]([O:17]CC)=[O:16])=[CH:12][CH:11]=2)=[CH:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2c[nH]c3ncccc23)s1
Temperature: 80 °C
Yield: 88 %

Procedure:
Ethyl 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-2-carboxylate (0.89 g, 3.3 mmol) was partly dissolved in 1,4 dioxane and 10 mL 1N NaOH added. The reaction mixture was heated to 80° C. where it became homogenous. After 2 hours the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and a 10% citric acid solution. A precipitate formed which was filtered off, washed with water and dried to 0.71 g, 2.9 mmol, 88% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[N:19][C:15]=3[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)C=CC=CC=1>C(O)(=O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCCCOCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: c1ccc(CCCCOCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(CCCCOCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-(4-phenylbutoxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(4-phenylbutoxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (0.50 g, 0.95 mmol) was dissolved in a mixture of acetic acid (5 ml) and water (0.6 ml). The reaction mixture was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.27 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11](Cl)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>>[NH:19]([C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)[NH2:20]
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1NN
Yield: 99 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])N=C=O.[NH2:14][C:15]([O:17]CC)=O>>[CH2:2]1[CH:3]([CH2:1][CH:2]2[CH2:13][CH2:12][CH:8]([N:9]=[C:10]=[O:11])[CH2:7][CH2:3]2)[CH2:7][CH2:8][CH:12]([N:14]=[C:15]=[O:17])[CH2:13]1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: CCOC(N)=O
Product: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1

Procedure:
1.57 moles toluene diisocyanate of 80% 2,4- and 20% 2,6- isomers; urethane content 14.7%; NCO 0.05%; Inh. V. 1.69
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=[N:17][OH:18])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:14][CH2:15][C:16]2=[N:17][O:18][CH2:13][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1

Procedure:
A solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C4) (7.12 g, 28.6 mmol) in dichloromethane (168 mL) was placed in a room temperature water bath. Triethylamine (0.299 mL, 2.14 mmol) was added, followed by addition of bleach (aqueous sodium hypochlorite solution, 6.15%, 71 mL, 59 mmol) at a rate slow enough to maintain the internal reaction temperature between 22° C. and 25.5° C. Upon completion of the addition, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 35% ethyl acetate in heptane) provided the product as a yellow oil. The indicated relative stereochemistry of compound P1 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 5.65 g, 22.8 mmol, 80%. LCMS m/z 248.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.51-1.63 (m, 1H), 2.17-2.24 (m, 1H), 3.40-3.52 (m, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.2 Hz, 1H), 3.57 (dd, half of ABX pattern, J=10.2, 5.8 Hz, 1H), 3.68-3.77 (m, 1H), 3.79 (dd, J=11.8, 8.1 Hz, 1H), 4.23 (dd, J=13.5, 1.2 Hz, 1H), 4.54-4.65 (m, 3H), 4.77 (d, J=13.5 Hz, 1H), 7.27-7.39 (m, 5H).
Reaction SMILES: [C:1]1([O:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(O)C=C(Cl)C=1.[N+](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.ClC1C=C(ON)C=C(Cl)C=1.[CH3:42][C:43]([C:46]([NH:48][C:49]1[N:58]=[C:57]([NH:59][C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])[C:56]2[CH2:55][C:54](=O)[CH2:53][CH2:52][C:51]=2[N:50]=1)=[O:47])([CH3:45])[CH3:44]>C(O)C>[CH3:45][C:43]([C:46]([NH:48][C:49]1[N:58]=[C:57]([NH:59][C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])[C:56]2[CH2:55][C:54](=[N:8][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:53][CH2:52][C:51]=2[N:50]=1)=[O:47])([CH3:42])[CH3:44]
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Reactant: NOc1ccccc1
Agent: NOc1cc(Cl)cc(Cl)c1
Agent: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Oc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOc1ccccc1)CC2

Procedure:
When the bridging group n is =NO--, 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal is prepared from 1,4-cyclohexanedione mono-ethylene ketal and cyanoguanidine, as previously described. The 2,4-diamino moieties are then protected by the reaction of 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal with pivalic anhydride in the presence of 4-dimethylaminopyridine, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal. The 6-ethylene ketal functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone. A second intermediate, an O-(phenyl)hydroxylamine, is prepared by the reaction of an appropriately substituted or unsubstituted phenol, for example, 3,5-dichlorophenol, with O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al (Tetrahedron, 28, 3833 (1972)). The so-prepared O-(phenyl)hydroxylamine, for example, O-(3,5-dichlorophenyl)hydroxylamine, is then reacted with the 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone in ethanol, yielding the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Treatment of the 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline with methanolic hydrochloric acid yields the targeted 2,4-diamino-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Example 12 provides a detailed description of how this reaction is conducted.