Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1nc(C=O)n(C)n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(Cl)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1): where 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from step 5 below, was substituted in place of 6-[2-(3-chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.47-1.74 (m, 8H), 1.79 (s, 6H), 2.01-2.11 (m, 8H), 2.36-2.42 (m, 1H), 2.56 (d, J=16 Hz, 1H), 2.60-2.66 (m, 2H), 2.77 (d, J=16 Hz, 1H), 3.53 (d, J=16 Hz, 1H), 3.62 (d, J=16 Hz, 1H), 7.25 (dd, J=8.2, 1.8 Hz, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H). Anal. Calcd. For C27H33ClN4O3.0.25H2O: C, 64.66; H, 6.73; N, 11.17. Found: C, 64.88; H, 6.74; N, 10.86. ESIMS (MH+): 498.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Anhydrous chromium trioxide (CrO3) (1.94 g, 19.4 mmol) is added to a solution of anhydrous pyridine (3.07 g, 38.8 mmole) in anhydrous methylene chloride (CH2Cl2) (50 ml). The resulting mixture is stirred at room temperature for 15 mins. A solution of N-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2-one (0.74 g, 3.23 mmol) in anhydrous CH2Cl2 (5 ml) is added all at once. After stirring at room temperature for 5 mins, the mixture is decanted and the dark, gummy residue is washed with more CH2Cl2. The combined CH2Cl2 supernatant is evaporated i.v. The residue is tabken up in diethyl ether and filtered to remove chromium salts. The ethereal filtrate is washed with 5% NaHCO3, 5% HCl, 5% NaHCO3 and brine, dried with MgSO4, filtered, and evaporated i.v. to yield N-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.54 g) as an off-white solid: ir(CHCl3) 5.77, 5.80, 7.36, 7.60, 7.99, 8.50 and 11.95 cm-1 ; nmr (CDCl3) δ0.23(s, 3), 0.27 (s, 3), 0.98 (s, 9), 2.63 (ddd, 1), 2.65 (dd, 1), 3.07 (ddd, 1), 3.37 (dd), 3.97 (m, 1), and 9.78 (t, 1); mass spectrum m/e 170 and 128.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31]>C(O)CCC>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCCCO
Product: CC(=O)[O-]
Temperature: 20 °C

Procedure:
Sunitinib base (1.5 g) was suspended in n-butanol (7.5 ml) and acetic acid (2.3 ml) was added in one portion with stirring at 20° C. Adding of acetic acid facilitated complete dissolution of sunitinib base within 2 minutes. The solution was stirred for 60 minutes during which orange precipitate was formed. The precipitate was recovered by filtration, washed with t-butyl methyl ether (50 ml) and dried on air for 12 h at 20° C. (Yield 1.074 g).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1([CH:19]=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CSC
Product: Clc1ccc(C2OC2c2ccccc2)cc1
Yield: 46 %

Procedure:
To a stirred solution of dimethyl sulphide (0.1 mmol), rhodium (II) acetate (0.01 mmol) and p-chlorobenzaldehyde (1 mmol) in dichloromethane (4 ml) was added a solution of phenyldiazomethane (1 mmol in 6 ml of tert-butylmethyl ether) at room temperature over a period of 24 hours. After addition was completed the solvent was removed in vacuo and the residue was chromatographed over silica to provide the title oxirane in 46% yield.
Reaction SMILES: [Cl-].C([N+]1C=CC=CC=1)CCCCCCCCCCC.O.[C:21](Cl)(Cl)=[O:22].[Cl:25][C:26]1[CH:27]=[C:28]([NH2:35])[C:29](=[CH:33][CH:34]=1)[C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1>[CH:34]1[C:26]([Cl:25])=[CH:27][C:28]2[NH:35][C:21]([O:31][C:30](=[O:32])[C:29]=2[CH:33]=1)=[O:22]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Yield: 67 %

Procedure:
According to the same manner as in Example 4, except that the flask was changed to 300 ml flask, laurylpyridinium chloride was not used, 103 g of water was added, and that amounts of toluene, phosgene and 4-chloroanthranilic acid were changed to 34 g, 40 g and 35 g, respectively, 35.6 g of 7-chloroisatoic anhydride (purity: 73.8%) was obtained. The yield was 67% and the volume efficiency was 9 g/100 ml.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper (I) iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0->10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.Br[C:39]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:40]=1[F:47].OC1C=C2C(=CC=1)C(C(C1C=CC(OCCN3CCCCC3)=CC=1)=O)=C(C1C=C(F)C=C(F)C=1F)C=C2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:39]1[C:40]([F:47])=[CH:41][CH:42]=[C:43]([F:46])[C:44]=1[F:45])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1ccc(F)c(Br)c1F
Agent: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)ccc(F)c3F)ccc2c1
Yield: 45.1 %

Procedure:
Couple trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.81 g, 3.37 mmol) with 2-bromo-1,3,4-trifluoro-benzene (1.42 g, 6.75 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 0.79 g (45%) of the title compound: mass spectrum (ion spray): m/z=520.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
A methylene chloride solution (5.0 ml) of N-acetylglycine ethyl ester (72.5 mg, 0.50 mmol) and N-methylimidazole (50.4 mg, 0.61 mmol) was cooled to −45° C., and a methylene chloride solution (0.5 ml) of palmitoyl chloride (142.6 mg, 0.50 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (0.5 ml) of titanium tetrachloride (340.4 mg, 1.78 mmol) and a methylene chloride solution (0.5 ml) of tributylamine (372.4 mg, 2.01 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. Water was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. Further, the water layer was extracted twice with methylene chloride, and the organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=3:2) to obtain the title compound (148.8 mg, yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11].B.C1COCC1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCCCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCO
Reaction time: 8 h

Procedure:
A solution of suberic acid monomethyl ester (15 g, 7.97 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (32.0 mL, 0.25M) at -20° C. was treated ##STR1## dropwise with BH3.THF (1M solution in THF, 7.97 mL, 7.97 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and was subsequently allowed to reach room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with methanol (10 mL) and 10% HCl (10 mL). Extraction with NaHCO3 (1×20 mL), water (2×10 mL), and brine (1×10 mL), afforded methyl-8-hydroxy-octanoate (7) as a crude white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]2[O:41][CH:40]=[N:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1>CC(O)C.Cl>[ClH:1].[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[O:41][CH:40]=[N:39][CH:38]=5)[CH:32]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: Nc1cccc(-c2cnco2)c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Temperature: 120 °C
Yield: 98 %

Procedure:
To a mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (0.5 g, 1.2 mmol) in i-PrOH (4 mL) was added 5-(3-aminophenyl)oxazole (0.25 g, 1.56 mmol) and 2 drops of conc. HCl. The reaction was heated in a microwave to 120° C. for 40 min. and allowed to cool to rt. The resulting solid was filtered off, washed with i-PrOH and dried to give the title compound as a tan solid (0.68 g) in 98% yield. ES-LC/MS m/z=542 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:28])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of 3-fluoro-5-morpholin-4-ylbenzoic acid (1.01 g, 4.4 mmol) in methylenechloride (30 ml) is added DMC (0.908 g, 5.4 mmol) and the mixture is stirred for 10 minutes. To this mixture is added 4-bromonaphthalen-1-amine (1.0 g, 4.50 mmol) and Hunig's base (3.21 ml). The mixture is stirred vigorously overnight at room temperature. The mixture is poured into water (200 ml) and extracted with EtOAc (2×100 ml). The organic layers are combined, dried over Na2SO4, filtered and concentrated. The residue is recrystallized from EtOH (50 ml) to give N-(4-bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide as white crystals (1.26 g, 65%). Mp: 187-189° C. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.18 (d, J=6.3 Hz, 1H), 8.02 (d, J=6.0 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.72 (t, J=5.1Hz, 1H), 7.67 (t, J=5.4 Hz, 1H), 7.51 (d, J=5.7 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J=6.3 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H), 3.74 (t, J=3.3 Hz, 4H), 3.24 (t, J=3.9 Hz, 4H). MS 429 (M+1).
Reaction SMILES: [Br-].[C:2]1([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:33]1[O:43][C:36]2([CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]2)[O:35][CH2:34]1>>[C:2]1([CH:8]=[C:39]2[CH2:40][CH2:41][C:36]3([O:43][CH2:33][CH2:34][O:35]3)[CH2:37][CH2:38]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Product: C(=C1CCC2(CC1)OCCO2)c1ccccc1

Procedure:
For example, when n is the bridging group --CH2--, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 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 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1

Procedure:
Under an argon atmosphere, to a mixture of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (1.80 g, 6.76 mmol) in CH2Cl2 (15 mL) was added DMF (4 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (1.20 mL, 14.2 mmol) at 0° C. and the mixture was stirred for an hour while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>C(O)C.C(O)(=O)C>[Br:1][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: BrBr
Reactant: O=C(O)c1cccc(O)c1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxybenzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40%). MS (DCI) m/z 234 (M+NH4)+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[CH2:11]([N:13]1[C:17](O)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1)[CH3:12]>>[Cl:8][C:17]1[N:13]([CH2:11][CH3:12])[N:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:16]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: CCn1nc(C(F)(F)F)cc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1nc(C(F)(F)F)c(C=O)c1Cl
Temperature: 25 °C

Procedure:
Dimethylformamide (13.36 g 182.7 mmol) was cooled to about 0° C. and 60.69 g (395.8 mmol) of phosphoryl chloride was added dropwise with stirring to form a pink slurry. This was allowed to warm to ambient temperature and then 32.92 g (182.7 mmol) of 1-ethyl-5-hydroxy-3-(trifluoromethyl)pyrazole was added dropwise with stirring to it. There appeared to be an endotherm and the mixture became dark brown to black. The mixture was then heated at reflux (108° C.) overnight and, after cooling, was poured into an ice-water mixture with stirring. A precipitate formed and then dissolved. The solution was extracted with dichloromethane (3×150 mL) and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a dark brown to black oil.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.C[C@@H](N)[C@@H](O)C1C=CC=CC=1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: B1CCON1
Reactant: O=C1CCCc2ccccc21
Agent: B
Agent: C[C@@H](N)[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1S, 2R)-(+)-Norephedrine (7.78 g, 51 mmol), toluene (150 mL), and trimethylboroxine (4.8 mL) were combined at ambient temperature and stirred for 5 days. Water, toluene and excess boroxine were distilled off until about 70 mL volume remained. The reaction was chased with toluene (3×90 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (8.71 g, 98%). 1H NMR (C6D6) δ; 7.36-6.98 (m, 5H), 5.33(d, J=8 Hz, 1H), 3.43 (dq, J=8 Hz, J=6 Hz, 1H), 2.72 (bs, 1H, 0.37 (s, 3H), 0.36(d, J=6 Hz, 3H). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from norephedrine (218 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give 3.16 g (80% ee) of the (S) tetralol as a colorless oil.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@@H:12]([CH3:30])[C@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[Si:23]([O:22][C@H:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C@H:12]([CH3:30])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the method described in Example 5b) from tert-butyllithium (3.95 ml, 1.7M in hexanes), (3R,4S)-3-[4-(4-bromophenoxy)-3-(tert-butyldimethyl-silanyloxy)pentyl]pyridine (2.52 g, Example 11b)) and tri-isopropylborate (1.68 ml) in tetrahydrofuran (20 ml) to afford the sub-title compound as a foam (1.22 g) after chromatography on silica eluting with ethyl acetate and then ethyl acetate:methanol (4:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g, 14.8 mmol) in CHCl3 (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in three portions. The mixture was stirred at room temperature for 2 days. The mixture was cooled to 0° C. and to this was added dropwise Na2S2O3 (10 g) in water (60 mL), followed by Na2CO3 (6 g) in water (20 mL). The reaction mixture was stirred for 20 minutes. The aqueous phase was extracted with CHCl3 (2×200 mL), and the combined organic phases were concentrated at low temperature (<25° C.). The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).