Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.COCN[C:13](=[O:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:13](=[O:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccc(Br)nc1

Procedure:
The sub-title compound was prepared from 2,5-dibromopyridine and [3-(methoxymethylamino)-3-oxopropyl carbamic acid, 1,1-dimethylethyl ester by the method of Example 58(a).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[ClH:8].[C:9](=[NH:15])(OCC)[CH2:10][CH3:11]>C(#N)C>[ClH:8].[CH3:7][C:5]1[NH:4][N:3]=[C:2]([NH:1][C:9](=[NH:15])[CH2:10][CH3:11])[CH:6]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CC#N
Product: CCC(=N)Nc1cc(C)[nH]n1
Reaction time: 1 h

Procedure:
A 13.8 g portion of 3-amino-5-methyl-1H-pyrazole was dissolved in 52 ml of acetonitrile, and 22.0 g of ethyl propionimidate hydrochloride was added to the above solution with cooling on an ice bath. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature.
Reaction SMILES: ClC(Cl)C.[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([C@@H:23]3[CH:28]4[O:29][C@@H:25]([CH2:26][CH2:27]4)[C@@H:24]3[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][CH2:39][C:40]([OH:42])=O)[O:21][CH:22]=2)=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:23]3[CH:24]([CH2:30][C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[CH2:38][CH2:39][C:40](=[O:42])[NH:59][CH2:58][CH2:56][OH:57])[CH:25]4[O:29][CH:28]3[CH2:27][CH2:26]4)[O:21][CH:22]=2)=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1)NCCO
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A dichloroethane (0.3 mL) solution of 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoy)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4fluoro-phenyl)-propionic acid (1) (30 mg, 0.057 mmol) was treated with triethylamine (12 μL, 0.086 mmol) and ethyl chloroformate (7 μL, 0.073 mmol). After 30 min., ethanolamine (10 μL, 0.17 mmol) was added and the solution stirred for 18 h. The resulting mixture was partitioned between 10 mL 1 M NaOH and 15 mL dichloromethane. The dichloromethane solution was washed with 1 M NaOH (6×10 mL). A small amount of brine was added to avoid an emulsion. The dichloromethane solution was then washed with brine (15 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave 12 mg (0.021 mmol, 37%) of the title compound. 1H NMR (300 MHz, ppm) δ 8.11 (s, 1 H) 7.3–7.2 (m, 1 H) 7.11–7.06 (m, 1 H) 6.84–6.78 (m, 2 H) 6.2–6.1 (m, 1 H) 5.00 (d, J=4.0 Hz, 1 H) 4.81 (d, J=4.4 Hz, 1 H) 3.7–3.6 (br m, 2 H) 3.5–3.3 (m, 6 H) 2.84–2.79 (m, 2 H) 2.66–2.57 (m, 1 H) 2.4–2.0 (m, 4 H) 1.9–0.8 (overlapping m, 21 H).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1)(=[O:6])[CH3:5]>CO.C(O)(=O)C>[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]1[C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(=O)OCCCCCC1=CCCC1=O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OCCCCCC1C(=O)CCC1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
98 g [1.5 mols] of potassium cyanide were suspended in 600 ml of methanol, and 105 g [0.5 mol] of 2-(5-acetoxypentyl)- cyclopent-2-ene-1-one, dissolved in 45 ml of acetic acid, were added dropwise within 2.5 hours. After 20 hours, agitation at room temperature, the suspension was dropped into ice-water with agitation, extracted thrice with diethyl ether, the ether phases were united, washed with water, dried over sodium sulfate and concentrated. The oily residue was stirred for 5 hours at room temperature in 200 ml of pyridine and 30 ml of acetic anhydride, the solvent was then distilled off under reduced pressure and the residue was distilled in a bulb tube. 102 g having a boiling point of 180° C. at 0.4 mm Hg were obtained; IR spectrum: 2220 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20]([OH:38])=[CH:19][CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:38][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:22]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(Cl)ccc2O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
A flask was charged with tert-butylbromoacetate (0.42 ml), dry DMF (20 ml), potassium carbonate (0.36 g) and the product from example 1 step (ii) (0.9 g) and then stirred at room temperature overnight. The mixture was quenched in water and extracted with diethylether, dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give the sub-title compound as a colourless oil, yield 0.6 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
6-(3,5-difluoro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 5 from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-3,5-difluorobenzene, as a white solid: mp 218–219° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.67–7.65 (m, 2H), 7.49 (d, 2H, J=7.73 Hz), 7.19 (t, 1H, J=9.29 Hz), 6.96 (d, 1H, J=8.88 Hz), 1.7 (s, 6H); MS(APCI) m/z 290 ([M+H]+, 100%); Anal. Calc. For C16H13F2NO2: C, 66.43, H, 4.53, N, 4.84. Found: C, 66.01, H, 4.46, N, 4.67.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([CH2:33][NH2:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([CH2:33][NH:34][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCc1cccc2c1Cc1ccccc1-2
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 62.8 %

Procedure:
A mixture of 2.97 g of 6-chloropurine riboside, 2.25 g of fluorenylmethyl amine and 1.31 g of triethylamine is refluxed in 70 ml of ethanol under nitroen for 20 hrs. Upon cooling, solid material crystallizes out which is filtered and retreated with boiling ethanol. Solid material obtained is filtered and dried affording 2.9 g (63%) of N6 -fluorenylmethyl adenosine having a melting point of 139°-142° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1C=CC=CC=1)=[O:16].NC1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1)=[O:16]
Reactant: CN1C(C(=O)Nc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Reactant: Cc1cnc(N)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)s1
Yield: 23.7 %

Procedure:
1.0 gm (3 millimols) of 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were refluxed with 1.15 gm (10 millimols) of 2-amino-5-methyl-thiazole and 0.1 gm of p-toluenesulfonic acid in 250 ml of xylene for 72 hours. After cooling, the reaction mixture was washed with 2N hydrochloric acid and with water, dried and evaporated in vacuo. The residue was purified column-chromatographically (Merck-silica gel 60; particle size: 0.2-0.5 mm; eluant: chloroform/ethanol, 95:5), yielding 0.25 gm (24% of theory) of 4-hydroxy-2-methyl-N-(5-methy-2-thiazolyl)-2H-1,2-benzothiazine-3-caboxamide-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[N:13]=[N:12]1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([NH:20][C:21]2[C:22](=[O:34])[N:23]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[N:24]([CH3:27])[C:25]=2[CH3:26])=[O:19])[N:13]=[N:12]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
1-(2-Chloro-4-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (15 g, 54.0 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A)(11.30 g, 54.0 mmol) were slurried in EtOAc (150 mL). The reaction mixture was cooled to 10° C. and triethylamine (18.82 mL, 135 mmol) was added dropwise, followed by dropwise addition of T3P (50% w/w in EtOAc) (47.7 mL, 81 mmol) over 15 mins, maintaining a temperature <10° C. The reaction mixture was allowed to warm to RT and stirred for 2.5 hrs. The resulting mixture was quenched with sat. sodium bicarbonate (aq) (150 ml). The layers were separated and the organic layer was washed with sat. sodium bicarbonate (aq) (50 ml), water (150 ml) and brine (150 ml). The organic extracts were dried over MgSO4 and charcoal. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crude material was slurried in ethyl acetate (335 ml) and heated to reflux with stirring. The hot mixture was filtered and the filtrate was seeded and at left to stand at room temperature overnight. The resulting crystalline solid was collected by filtration and dried under reduced pressure at 40° C. over 2 days to yield the title compound.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]([Mg]Br)([CH3:20])=[CH2:19]>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]([CH3:20])=[CH2:19])[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: C=C(C)[Mg]Br
Solvent: CSC
Solvent: C1CCOC1
Product: C=C(C)C1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one, (X), prepared in Example 1, Step (c), (33.12 mmol, 6.50 g), CuBr.Me2S (3.312 mmol, 681 mg) and Me2S (6.63 ml) were stirred in 97.5 ml of dry THF at -40° C. under nitrogen and treated with 49.68 mmol (66.24 ml of 0.75M in THF, prepared from treating isopropenyl bromide with 1.1 equivalents of Mg) of isopropenylmagnesium bromide added dropwise. The reaction was quenched with 120 ml of 1M HCl (aq.) and extracted with 4×60 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 5.6 g (23.53 mmol, 71%) of colorless oil as a mixture of diastereomers. The diastereomers were separted by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associaes, Milford, Ma., to provide a "less polar isomer" and a "more polar isomer."
Reaction SMILES: [CH2:1]([O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:44][SH:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH:27]1[C:28]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:44][S:45][CH2:17][C@H:15]([OH:16])[CH2:14][O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[O:34])[C:30]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCCCOC[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCOC[C@@H](O)CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C

Procedure:
A solution of (S)-2-((dodecyloxy)methyl)oxirane (1.1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1 eq) and 1M K2CO3 (1.1 eq) in tBuOH (0.1 M) was stirred at 25° C. for 15 hours. The reaction mixture was concentrated en vaccuo to remove tBuOH and dissolved in EtOAc. The EtOAc solution was washed three times with water, and once with brine. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hex to give the title product as a colorless viscous oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH2:2]([O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][NH:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)[C@H]1C=CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C=CCN1
Reaction time: 3 h

Procedure:
(1:1) 1.5 g (0.006 mol) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester were dissolved at 5° C. in 10 ml trifluoroacetic acid and stirring was continued at room temperature for 3 hours. Evaporation of the solvent in vacuo gave 2.05 g (quant.) of (R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl ester trifluoroacetate (1:1) as a yellow oil. MS m/e (%): 142 (1), 68 (100), 45 (10), 41 (15). [α]D=+95.4° (c=1% methanol).
Reaction SMILES: Cl.C([N:4]([CH2:7][CH3:8])CC)C.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(Cl)(=O)=O>C(Cl)Cl>[C:9]([N:4]1[CH2:7][CH2:8]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
Amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 mL) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 mL) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high vacuum. To a suspension of the HCl salt in CH2Cl2 (50 mL) at 0° C. was added triethylamine (3.55 mL, 25.5 mmol) followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0° C. for 1 h and then was warmed to room temperature stirring for 2 h. The reaction was cooled to 0° C., triethylamine (3.6 mL, 25.5 mmol) was added and methane sulfonyl chloride (0.97 mL, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0° C. and for 22 h at room temperature. The reaction was evaporated and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The organic phase was washed with water (200 mL) and the combined aqueous phases were extracted with diethyl ether (200 mL). The combined organic extracts were washed with water (100 mL), saturated NaCl (200 mL) and were dried (Na2SO4), filtered, and evaporated. The crude product was purified on silica gel (1/1-hexane/CH2Cl2) to afford N-trityl aziridine 183 (3.84 g, 86%) as a white foam: 1H NMR (CDCl3) δ 7.4-7.23 (m, 16H), 4.32 (m, 1H), 3.81 (s, 3H), 3.06 (dt, 1H, J=1.8, 17.1), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J=5.0).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(C)CC(=O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CC(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methoxy-pyridine-2-carbonyl)indole (Example 72) and isovaleryl chloride. m.p.: 162-163° C. (ethyl acetate/hexane)
Reaction SMILES: [C:1]([CH:5]1[C:9](=[O:10])[CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:18]1([O:24][P:25](Cl)([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:4][O:3][C:1]([C:5]1[CH2:6][S:7][CH2:8][C:9]=1[O:10][P:25]([O:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:26])=[O:2]
Reactant: COC(=O)C1CSCC1=O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)CSC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.1 %

Procedure:
To a solution of 3-carbomethoxytetrahydrothiophene-4-one (Gianturco M. A., Friedel P., Giammarino A. S., Tetrahedron, 20:1772 (1964)) (4.0 g, 25 mmol) and triethylamine (6.6 g, 65 mmol) in 50 mL dry THF at 0° was added, over a 15 minute period, diphenylchlorophosphate (17.5 g, 65 mmol). The reaction mixture was stirred at room temperature for 2 days, then treated with ice-cold water and extracted with diethyl ether. The extracts were washed with saturated NaHCO3, brine, dried with Na2SO4, and evaporated to yield an oil (10.6 g).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: OC1CCC(Cc2ccccc2)CC1

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfudc acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[S:22][C:13]=12.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[CH:24])[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#C[Si](C)(C)C)sc23)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To the suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile (97 mg, 0.22 mmol) in 10 mL of methanol is added potassium carbonate (46 mg, 0.33 mmol) The mixture is stirred at room temperature for 30 minutes, concentrated in vacuo and then partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 38 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 198-200° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 5.01 (s, 1H), 7.38 (s, 1H), 7.72 (s, 1H), 7.79 (s, 1H), 8.63 (s, 1H), 9.85 (s, 1H); MS 372.0 (M−H)−.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N(C(NC)=O)CCCC3CCCCC3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[O-2:48].[Al+3].[O-2:50].[O-2].[Al+3]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([O:48][C:5]([NH:6][CH:7]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:8]3)=[O:50])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-2]
Reactant: CCCCc1nc2ccc(N(CCCC3CCCCC3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Product: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-N-(3-cyclohexyl-n-propyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.15 (aluminium oxide: petroleum ether/ethyl acetate=2:3)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([NH:40][C:32]3[N:31]([CH2:30][CH2:29][O:28][CH2:26][CH3:27])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:42][CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (25 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.