Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:24])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:24])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:7][CH2:6]1)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: COC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
A solution of 0.50 g (1.30 mmol) of {4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid methyl ester in 25 ml of THF was treated slowly at −78° C. with 1.48 ml (1.48 mmol) of lithium hexamethyldisilylazide 1M in THF. After 30 min at −78° C., a solution of 0.67 ml (4.54 mmol) of tert-butyl bromoacetate in 2.5 ml of THF was added dropwise. The solution was stirred at −78° C. for 5 h, poured on cooled aqueous 10% KHSO4 solution and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. The residue was purified on a SiO2-column (n-heptane/EtOAc 1:1 to 2:3) to afford the titled compound in 18% yield as light yellow foam. MS: 499.1 (MH+, 2Cl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:34])[C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:34])[C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N,N-dimethylpiperidin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.53 (d, J=13.18 Hz, 1H) 1.77 (m, J=16.10 Hz, 2H) 2.10 (br. s., 1H) 2.33 (s, 3H) 2.57-2.89 (m, 6H) 2.90-4.77 (m, 5H) 7.63 (br. s., 1H) 7.74 (t, J=7.54 Hz, 1H) 8.09 (d, J=7.81 Hz, 1H) 8.24 (br. s., 1H) 8.35-8.66 (m, 2H) 9.86 (br. s., 1H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=O.CO[C:29]1C=C[C:32]([NH2:35])=[CH:31][N:30]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:22][O:24][C:25]1[CH:26]=[CH:29][N:30]=[CH:31][C:32]=1[NH:35][C:11]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:13]
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccncc1NC(=O)c1c[nH]c2c1C(=O)CCC2
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a stirring solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol) and triethylamine (293 μl, 2.1 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added ethyl chloroformate (191 μl, 2 mmol). After stirring an additional 30 minutes, a solution of 2-methoxy-5-amino-pyridine (216 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was added. The reaction mixture was allowed to stir for an additional 75 minutes, then poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacua. To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), then heated at reflux for 1 hour. After cooling in an ice water bath, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacua, and the residue recrystallized from ethyl acetate to give N-(4-methoxy-3-pyridyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole 3-carboxamide (56 mg); m. p. 209-210° C. (Compound 1).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].C([C@H]1OC1)Cl>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:19][CH:20]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC1COc1ccc(C#N)cc1
Agent: ClC[C@@H]1CO1
Product: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared according to the procedures described in steps (i) to (v) above for the synthesis of tert-butyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate, but using (S)-(+)-epichlorohydrin in place of epichlorohydrin in step (i).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:17])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[Cl:17]
Reactant: COc1cc2nc[nH]c(=O)c2cc1Br
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1Br
Temperature: 80 °C
Yield: 62 %

Procedure:
6-bromo-7-methoxyquinazolin-4(3H)-one (53 mg, 0.21 mmol) was taken into thionyl chloride (1.5 mL) followed by addition of catalytic DMF. The mixture was heated to 80° C. for 2 h then concentrated. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give 6-bromo-4-chloro-7-methoxyquinazoline (36 mg, 62% yield) as a brown solid. MS (EI) for C9H6BrClN2O: 275 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]([F:25])([F:24])[F:23])[C:5]#[N:6].Cl.[OH:27]N.C1N=CN([C:34]([N:36]2C=NC=C2)=[O:35])C=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:36][C:34](=[O:27])[O:35][N:6]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]([F:25])([F:23])[F:24]
Reactant: N#Cc1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)c(Cl)c1
Reactant: NO
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(-c3c(C(F)(F)F)oc4cc(O)ccc4c3=O)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzonitrile (0.3 g, 0.8 mmol) was dissolved in EtOH (5 ml) and cooled with an ice bath. Hydroxyamine HCl salt (46 mg, 0.85 eq.) and TEA (0.11 ml, 1 eq.) were added. The reaction mixture was stirred overnight at room temperature. The solvent was removed and the residue (0.4 g) was suspended in anhydrous THF (5 ml). After addition of CDI (0.24 g, 1.5 eq.) and TEA (0.13 ml), the suspended solution was stirred and heated at 50° C. overnight. After removal of THF, the mixture was suspended in water (15 ml) and the pH was adjusted to 8. The aqueous layer was extracted with EtOAc (10 ml×2). Then, the aqueous layer was acidified to pH˜2 and was extracted with EtOAc (15 ml×4). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the crude product was purified by prep-HPLC to afford desired product in Example 18 (44 mg, 10%) as tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)C.O.Cl>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CC(O)Cn1c(N)cc(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)Cn1c(N)c(N=O)c(=O)n(C)c1=O

Procedure:
To 79 g (0.4 mol) of 6-amino-1-(2-hydroxypropyl)-3-methyl- 2,4-(1H, 3H)-pyrimidinedione (IV), dissolved in 500 ml of ethanol, was added 30 g NaNO2 (0.43 mol) which was dissolved in water, whereafter 36 ml conc. hydrochloric acid was added. The red crystals were dissolved through boiling and the sodium chloride was filtered off. The red filtrate was used for synthetizing 5,6-diamino-1-(2-hydroxypropyl)-3-methyl-2,4-(1H, 3H)-pyrimidinedione (VI) NMR.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].C([O:40][C:41]([N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=O)(C)(C)C.[C:50](OC(=O)C)(=O)C>>[C:41]([N:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:45][CH2:44]1)(=[O:40])[CH3:50]
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(=O)N1CCCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 51 %

Procedure:
In a similar manner to Example 6, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 15; 52.0 mg) was reacted with 1-(t-butoxycarbonyl)homopiperazine (50.6 mg) and acetic anhydride (50 μL) to obtain 9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (31.7 mg, 51%).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>CN(C=O)C.O>[N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([F:47])=[CH:49][CH:50]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a stirred solution of compound (xi) (15 g, 61.98 mmol) in DMF (150 mL) was added HATU (28.28 g, 74.34 mmol) at 0° C. The reaction mixture was stirred for 15 min and DIPEA (16.01 mL, 92.26 mmol) was added followed by 4-fluoroaniline (7.57 g, 68.68 mmol) at the same temperature. The reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The reaction was then poured into cold water (500 mL) and stirred for 15 min. The solid was filtered and washed with water (3×100 mL) and dried (Na2SO4) to give 2-azido-4-bromo-N-(4-fluorophenyl)-benzamide (xii) (19 g, 91%) as an off-white solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[Cl:26])=[C:11]([Cl:27])[CH:10]=1>>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[Cl:27])=[C:17]([Cl:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Product: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl

Procedure:
Trimethylsilyldiazomethane (2.0 M solution in hexanes, 37 mL, 74 mmol) was added slowly to a suspension of 4-(4-bromo-2-chloro-phenylamino)-5,6-dichloronicotinic acid (25) (14.67 g, 37 mmol). After the addition was complete the resulting slurry was diluted with hexanes (600 mL) and the solids isolated by filtration washing with hexanes. The desired product was isolated as an off-white solid (10.06 g). The hexanes washes were concentrated and the solids passed through a plug of silica gel eluting with dichloromethane. Concentration of the product-containing fractions provided an additional 3.83 g desired product (26) for a total of 13.89 g (91%). MS (APCI+) m/z 409, 411, 413 (M+; Cl, Br pattern) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11](C)[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.12 gms. (0.02 mole) of 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) in 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature of the reaction mixture at circa 0° C. Stirring is continued for 30 minutes and then the reaction mixture is allowed to stand at room temperature overnight. Solvent is stripped and the residue suspended in water. Upon removal of the water there is obtained 1-(p-acetamidophenyl)-3-(4-pyridylmethyl)urea.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].[OH-].C([N+](C[CH2:22][CH2:23][CH3:24])(CCCC)CCCC)CCC.[OH-].[Na+].Cl[CH:28]=CC>O>[CH3:28][C:23](=[CH2:22])[CH2:24][O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH3:6]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCC(C)CO
Reactant: CC=CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COCC(C)CC
Temperature: 70 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
In a 3000 mL reaction flask was charged 2-methyl-1-butanol (440 g, 5.0 mol), a 40% by weight in water solution of tetrabutyl ammonium hydroxide (100 g, 0.15 mol), and a 50% by weight solution of NaOH (488 g, 6.1 mol). The mixture was heated to 70° C. and 3-chloro-2-propene (550 g, 6.1 mol) was fed into the reaction over 3 hours. The reaction was aged for 7 hours at 70° C., then cooled to room temperature. The reaction was quenched with 600 mL of water, and the layers separated. The organic layer washed with 600 mL water and 600 mL of brine. The crude product was purified by distillation to give 482 g of ether, a 68% yield.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12]OCCOCCO)=[O:9])(=[O:3])[CH3:2].[Cl-].C(OC1C(=CC=CC=1)C(O)=O)(=O)C.C(O)C[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50].C(OC(C)C)(C)C>>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50])=[O:9])(=[O:3])[CH3:2]
Reactant: OCCCCCCCCCCO
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Agent: CC(=O)Oc1ccccc1C(=O)O
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Product: CC(=O)c1ccc(C(=O)OCCCCCCCCCCO)c(O)c1C(C)=O

Procedure:
The compound (IV) was prepared according to the procedure described in Example 1 for the synthesis of (XIX), starting from 5 g of the chloride of acetylsalicylic acid, 3.5 ml of TEA and 2.17 g of 1.10-decandiol. The product was purified by chromatography utilizing an eluent mix constituted by ethylether/hexane 7:3 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and a solid residue was obtained which, trirurated with isopropyl ether, produced 1.37 g of 1.10-decandiol bis-acetylsalicylate (IV) with m.p.=75° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH3:8])[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:8][N:7]([CH2:9][C@H:13]1[CH2:31][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12]1)[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN(C1CCOCC1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](CN(Cc2ccc(Cl)cc2Cl)C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(tetrahydro-2H-pyran-4-yl)-1-tert-butyloxycarbonyl-(3R)-pyrrolidine-3-yl-methylamine (0.36 g, 1.26 mmol), 2,4-dichlorobenzaldehyde (0.44 g, 2.52 mmol) and sodium triacetoxyborohydride (0.67 g, 3.15 mmol) in 1,2-dichloroethane (15 ml) is stirred at room temperature for 18 h. Water (2 ml) is added to the reaction mixture and stirring continued for 5 min. The organic phase is separated using a hydrophobic frit and evaporated. The resulting oil is dissolved in methanol and purified using a SCX-2 column (10 g), then washed with methanol. The basic product elutes with methanolic ammonia (2M). Evaporation gives the required compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15](Br)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:19](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:20].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Yield: 70 %

Procedure:
Dissolve 5-bromo-N-methyl-N-propyl-isophthalamic acid methyl ester (2.7 g, 8.6 mmol) in toluene (16 mL) and place the solution under nitrogen. Add in sequence 2,6-di-tert-butyl-4-methylphenol (a few crystals), tetrakis(triphenylphosphine)palladium (0) (185 mg, 0.16 mmol), and tributylvinyl tin (3 g, 9.5 mmol) and reflux for 4 h. Filter though a filtering agent and concentrate. Add diethyl ether (70 mL) and 20% aqueous potassium fluoride (70 mL) and stir vigorously. Collect the diethyl ether layer and extract with diethyl ether two additional times. Concentrate and purify (silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes) to give the title compound (1.58 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6](O[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][CH:24]1[CH2:27][CH:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:16]([O:23][C@@H:24]1[CH2:25][C@H:26]([C:28]2[N:29]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)[CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[CH2:16]([O:23][C@H:24]1[CH2:25][C@H:26]([C:28]2[N:29]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)[CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(COC2CC(c3nc4ccccc4[nH]3)C2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@@H](OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](OCc2ccccc2)C1
Reaction time: 16 h

Procedure:
DMAP (0.020 g, 0.16 mmol) and di-tert-butyldicarbonate (0.83 g, 3.77 mmol) were added to a suspension of 2-(3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole (0.96 g, 3.43 mmol) and triethylamine (1.20 mL, 8.58 mmol) in dichloromethane (15 mL) and the mixture was stirred for 16 h. Water was added, the resulting layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give tert-butyl 2-(cis-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.43 g, 1.14 mmol, 33% yield) and tert-butyl 2-(trans-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.47 g, 1.23 mmol, 36% yield).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:3]=12.[CH2:16]=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:3]3=[N:2][CH:7]=[CH:6][CH:5]=[C:4]3[CH2:8][C:9]=2[CH:15]=1
Reactant: c1ccc2c(c1)Cc1cccnc1O2
Reactant: C=O
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: ClCc1ccc2c(c1)Cc1cccnc1O2

Procedure:
Hydrogen chloride gas is passed through a mixture of 10 g of 5H-[1]benzopyrano[2,3-b]pyridine, 1.4 g of paraformaldehyde, 110 ml of concentrated sulfuric acid and 22 ml of concentrated hydrochloric acid at 80°C for 12 hours, while 2 g of paraformaldehyde is added in several portions to the reaction mixture. The reaction mixture is poured into water, and the whole mixture is neutralized with sodium carbonate, and extracted with a large amount of chloroform. The chloroform layer is dried, concentrated to 30 ml, and cooled. The crystalline precipitate is filtered off, and recrystallized from chloroform to give 7-chloromethyl-5H-[1]benzopyrano[2,3-b]pyridine melting at 172°-174°C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1N2CCN(CC2)C1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-ol (1.0 mg, 6.3 mmol) and triethylenediamine (0.780 mg, 7.0 mmol) cooled to 0° C. in DCM (20 mL) was added p-toluenesulfonylchloride (1.31 g, 7.0 mmol) in DCM (5 mL). The reaction mixture was stirred overnight and then washed with 0.5 N HCl (20 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.0 g) which was used without further purification.
Reaction SMILES: C1COC2C=CC([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=CC=2O1.[C:27]([C:31]1[CH:36]=[CH:35][C:34](NC2C(F)=CN=C(Cl)N=2)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].NC1C=CC2[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]C=2C=1>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([N:19]([C:20]2[CH:25]=[CH:24][C:23]3[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:22]=3[CH:21]=2)[C:14]2[N:13]=[C:12]([NH2:11])[C:17]([F:18])=[CH:16][N:15]=2)=[CH:35][CH:36]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(N(c3ccc(C(C)(C)C)cc3)c3ncc(F)c(N)n3)ccc2O1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-(4-tert-butylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield N2-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.16 (bs, 1H), 9.84 (bs, 1H), 8.16 (d, 1H, J=5.4 Hz), 7.56 (d, 2H, J=8.1 Hz), 7.49 (s, 1H), 7.35 (d, 2H, J=8.7 Hz), 7.13 (dd, 1H, J=1.8 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6 and 10.5 Hz), 3.52 (dd, 1H, J=10.5 and 16.5 Hz), 3.20 (dd, 1H, J=6.6 and 16.5 Hz), 1.27 (s, 9H); LCMS: ret. time: 26.52 min.; purity: 96%; MS (m/e): 437 (MH+).