Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH:27]1([C:2]2[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=3)[CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: C[C@@H](NC(=O)COc1ccc(Br)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](NC(=O)COc1ccc(C2CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 120 °C
Yield: 7 %

Procedure:
To a solution of (R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide (100 mg, 0.23 mmol) and cyclopropylboronic acid (26 mg, 0.30 mmol) in dioxane (2 mL) were added 1.27 M potassium phosphate (0.36 mL) and tetrakistriphenyl phosphine palladium (13 mg, 0.012 mmol) at room temperature. The mixture was stirred at 120° C. using microwave oven for 2 hours. The mixture was dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 6.5 mg, (7% yield) of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].CCN(CC)CC.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:16]([CH3:18])([CH3:17])[O:4][CH2:1][C:2]#[CH:3])([CH3:15])([CH3:14])[CH3:12]
Reactant: C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of prop-2-yn-1-ol (168 g, 3 mol), Et3N (412 g, 4.08 mol) in CH2Cl2 (3500 mL) was added a solution of TBSCl (543 g, 3.45 mol) in CH2Cl2 (500 mL) at 0° C. Then the reaction mixture was warmed up to room temperature and stirred overnight. The mixture was washed by water (3000 mL), dried over Na2SO4, and concentrated to give crude product, which was purified by flash chromatography (petroleum ether) and distillation to give compound S-1 as a yellow liquid. (110 g, 43%)
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([OH:34])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[Br:37][CH2:38][C:39](Br)=[O:40]>>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:35]([C:7]([CH2:5][CH3:6])([CH:9]([O:34][C:39](=[O:40])[CH2:38][Br:37])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:36]
Reactant: O=C(Br)CBr
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Product: CCC(C)(CC)C(OC(=O)CBr)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 32.3 %

Procedure:
Diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) was acylated with bromoacetyl bromide (0.50 g) in a manner similar to the acetylation described in Example 26. Diethyl 3(bromoacetoxy)-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.40 g) was isolated as a colourless gum. NMR (CDCl3): δ 1.3(6H,t), 1.7-1.9(2H,m), 2.3(2H,m), 3.8-3.95(2H,m), 4.1(4H,m), 6.0(1H,t), 7.1-7.3(15H,m), 7.9(1H,2 xs). FAB M/S: MH+ 626,628. IR: 1746 cm -1, carbonyl.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc[nH]1
Yield: 77.6 %

Procedure:
Prepared following the experimental method described in Preparation 4b starting from 10.0 g (90.0 mmol) of 1H-pyrrole-2-carboxylic acid (purchased from Aldrich®, cat. no. P7,360-9) and 9.22 g (99.0 mmol) of aniline. 13.0 g (78% yield) of the title compound were obtained as a brownish solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH:16]=O)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[C:24](=O)([O-])[O-:25].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH2:16][CH:24]=[O:25])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(NC=O)c2c(OC)c(F)c(F)cc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NCC=O)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
The whole (0.0018 mole) of the ethyl 6,7-difluoro-1-(formylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVI) [prepared as described in Step (D2) above] was dissolved in 8 ml of dimethylformamide. 0.51 g (0.0037 mole) of potassium carbonate and 0.78 g (0.0052 mole) of methyl iodide were then added to the solution, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the solvent was distilled from the mixture under reduced pressure. The residue was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 0.5 g of ethyl 6,7-difluoro-1-(N-formylmethylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVII, R10 =methyl) as a colorless powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C:15](=[O:28])[N:14]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=O)=O.[C:38]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)([OH:40])=[O:39].C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.ClCCl.C(O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:14]2[C:15](=[O:28])[C@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C@H:13]2[C:10]2[CH:11]=[CH:12][C:7]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([C:38]([OH:40])=[O:39])[CH:46]=3)=[CH:8][CH:9]=2)=[CH:34][CH:33]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)c1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (51.1 mg, 0.094 mmol) and 3-carboxyphenylboronic acid (21.9 mg, 0.132 mmol) were dissolved in 1:1 toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.14 mL) was added and the solution degassed. Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 0.005 mmol) was added and the reaction stirred vigorously for 2 h at refluxing temperature under a nitrogen atmosphere. The cooled reaction was diluted into dichloromethane (15 mL), water (3 mL) was added and the pH was adjusted to 3 with 5% aqueous sodium bisulfate. The layers were separated and the aqueous layer extracted with dichloromethane (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% methanol in dichloromethane) to afford 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-3-carboxylic acid (41.9 mg, 86% yield) as a colorless foam; Rf 0.15 (5% methanol in dichloromethane); 1H NMR (300 MHz, CDCl3) δ?8.31 (m, 1H), 8.09 (dt, J=7.8, 1.5 Hz, 1H), 7.79-7.39 (m, 6H), 7.23-7.32 (m, 4H), 6.90-7.02 (m, 4H), 4.75 (t, J=5.7 Hz, 1H), 4.69 (d, J=2.1 Hz), 3.12 (m, 1H), 2.10-1.90 (m, 4H) ppm; MS [M−H] 512.5. In the same manner was obtained:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:39])=[C:13]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:39])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]2=[O:37])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one was obtained (67%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.51 (br s, 1H), 7.41-7.16 (m, 16H), 7.10-7.03 (m, 2H), 7.02-6.97 (m, 1H), 6.96 (s, 1H), 6.85-6.79 (m, 1H), 6.58-6.48 (m, 2H), 5.17 (s, 1H), 4.92 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31]I>>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:15])([F:16])[F:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(OCC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Yield: 52 %

Procedure:
Step AW (1): 2-(4-(2,2,2-Trifluoroethoxy)phenyl)acetic acid (6.00 g, 25.6 mmol, reference: D. Page, et al. Bioorganic Med. Chem. Lett. (2008), 18, 3695) was deprotonated with NaHMDS (2.0 M in THF, 38.4 mL, 77 mmol) and reacted with 1-chloro-4-iodobutane (8.40 g, 38.4 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (4.32 g, 13.3 mmo, 52% yield) as a clear viscous oil that eventually formed a waxy solid. LC-MS (M−H)− 323.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24-7.27 (m, 2 H), 6.90 (d, J=8.5 Hz, 2 H), 4.32 (q, J=7.9 Hz, 2 H), 3.45-3.56 (m, 3 H), 2.00-2.12 (m, 1 H), 1.71-1.83 (m, 3 H), 1.29-1.49 (m, 2 H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.FC(F)(F)S(O[C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Br:28])[CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2)(=O)=O.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>[Cl-].[Na+].O.O.C(OCC)(=O)C.C(Cl)Cl>[Br:28][C:26]1[CH:27]=[C:18]([C:37]2[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=2)[C:31]#[N:32])[CH:19]=[C:20]2[C:25]=1[CH:24]=[N:23][CH:22]=[CH:21]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cc(Br)c2cnccc2c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2cc(Br)c3cnccc3c2)c1
Yield: 62.4 %

Procedure:
An aqueous solution (50 mL) of sodium carbonate (3.5 g) was added to a THF (200 mL) solution of Intermediate 8 (3.9 g), 3-cyanophenylboronic acid (which may be referred to as sbo1; 1.6 g; WAKO), PdCl2dppf.CH2Cl2 (1.78 g; TCI) at room temperature and the resulting mixture was stirred as it was for 6 and half hours. Ethyl acetate (300 mL), saturated brine, and water were added to extract the reaction mixture, then the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; chloroform/methanol) to give the title compound (2.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH3:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([CH3:17])=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:3]12
Reactant: CC1=NCCn2c1cc(-c1ccccc1)c2C
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1c(-c2ccccc2)cc2n1CCNC2C
Yield: 66 %

Procedure:
3,4-Dihydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine (0.5 g) was dissolved in a mixture of 20 ml of methanol and 2 ml of water under argon. The solution was treated portionwise with 0.25 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.6 g of yellow oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.5 g (66%) of 1,2,3,4-tetrahydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 196°-197° C. (dec.).
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.[OH-].[Na+]>CO.O1CCCC1.O>[C:28]([C:24]1[CH:23]=[C:22]2[C:27]([CH:18]([NH:17][C:15]([NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[CH:7]=[N:6][NH:5]4)=[O:16])[CH2:19][CH2:20][O:21]2)=[CH:26][CH:25]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)OCCC2NC(=O)Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A solution of the product of Example 1D (1.00 g, 2.37 mmol) in a mixture of 5 mL methanol and 5 mL tetrahydrofuran was treated with 5M sodium hydroxide (2 mL ) in methanol, and stirred at ambient temperature for 90 minutes. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to give 0.75 g of the title compound (86% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.20 (m, 2H), 7.10-6.90 (m, 4H), 4.91 (m, 1H), 4.30-4.12 (m, 2H), 2.20-2.00 (m, 2H), 1.22 (s, 9H). MS (ESI) m/e 365 (M+H)+. Calc'd. For C17H16N4O2.1.0 H2O: C, 65.95; H, 6.85; N, 14.65. Found: C, 65.93; H, 6.69; N, 14.41.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][C:9]1([CH3:13])[O:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][O:8]1
Reactant: CCOC(=O)C1COC(C)(C)OC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.03 g, 37.35 mmol) in tetrahydrofuran (20 ml) was added dropwise to a cooled to 0° C. suspension of lithium aluminum hydride (1.8 g, 48.55 mmol) in tetrahydrofuran (20 ml). The reaction was stirred at 0° C. for 20 min and at 25° C. for 2 h. After such time, ethyl acetate (1 ml) and a few crystals of sodium sulphate decahydrate were added with caution. After stirring at 25° C. for 1 h saturated sodium chloride solution was added and the product extracted with ethyl acetate (3×100 ml). The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (4.09 g, 76%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.79-1.90 (m, 1H, CH), 2.15-2.26 (brs, 1H, OH), 3.69-3.81 (m, 2H, 2×OCH of 2×OCH2), 3.74 (d, J=6.8 Hz, 2H, OCH2), 3.96-4.05 (m, 2H, 2×OCH of 2×OCH2).
Reaction SMILES: Br[C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([C:19]([O:21][CH3:22])=[O:20])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:25][C:26]1[C:27]([OH:33])=[N:28][CH:29]=[N:30][C:31]=1[NH2:32].Cl>CCO>[NH2:32][C:31]1[C:26]2[N:25]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]45[CH2:18][CH2:17][C:14]([C:19]([O:21][CH3:22])=[O:20])([CH2:15][CH2:16]4)[CH2:13][CH2:12]5)=[CH:9][CH:10]=3)[C:2]([CH3:23])([CH3:24])[O:33][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: COC(=O)C12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: Nc1ncnc(O)c1N
Agent: Cl
Solvent: CCO
Product: COC(=O)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 25 °C

Procedure:
To a solution of methyl 4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]octane-1-carboxylate (Intermediate 26; 507 mg, 1.29 mmol) in abs EtOH (10 mL) was added 5,6-diaminopyrimidin-4-ol (179 mg, 1.42 mmol) followed by 1M HCl (1.4 mL). The suspension was heated under reflux overnight, the reaction mixture was allowed to cool to ambient temperature and then evaporated to dryness. The residue treated with 2M potassium carbonate solution to adjust the pH to 10 and then the mixture was extracted into EtOAc (4×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave the title compound as a yellow gum which was purified on a 12 g Redisep silica cartridge, dry loading the sample on Merck silica (deactivated, ˜1 g) and eluting with DCM-MeOH 0-2%-5% to provide the title compound 150 mg (0.357 mmol, 27%); 1H NMR δ 1.61 (s, 6H), 1.84 (s, 12H), 3.61 (s, 3H), 6.98 (s, 2H), 7.41 (d, 2H), 7.66 (d, 2H), 7.95 (s, 1H); MS m/e MH+ 421.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:30]1)=[O:15]
Reactant: Clc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.5 mg). Calcd for C20H16Cl2 N2O2: 386.0589, found 386.0595.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:20][CH3:21])(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:21][O:20][C:10](=[O:19])[CH2:11][CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([O-:9])=[O:8].C1COCC1.CO.[Li+].[OH-].Cl>O.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: Cc1cccc(OCC(=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11-13 (0.145 g, 0.285 mmol) in 1:1 THF/MeOH (6 mL) was treated with LiOH (0.114 g, 28.5 mmol) dissolved in 6 mL of H2O. After stirring for 1 hour at room temperature the solvents were removed, the residue dissolved in H2O/EtOAc/10% KHSO4 and the layers separted. The water layer was washed with EtOAc, the organic layers were combined, dried, and filtered to give the intermediate acid as a yellow oil. This material was dissolved in EtOAc (10 mL), cooled to -78° C., the solution saturated with HCl gas and warmed to 0° C. for 0.5 hours, then concentrated and dried under vacuum to give 11-14 as fluffy solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38]1([CH3:47])[C:39]([C:44](Cl)=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:44]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[CH3:47])=[O:45])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccccc3C)CC4)nc12
Yield: 98.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.017 g o-toluoyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.047 g (94%) [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-o-tolyl-methanone as yellow solid; M.p.: 194–196° C.; MS (ISP): m/e=504 (M+H+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:15]([CH2:27][CH3:28])=[N:16][N:17]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:18]=1[C:19]([NH2:21])=[O:20]>C(#N)C>[CH2:25]([O:24][CH2:23][CH2:22][N:17]1[C:18]2[C:19](=[O:20])[NH:21][C:1](=[O:2])[NH:13][C:14]=2[C:15]([CH2:27][CH3:28])=[N:16]1)[CH3:26]
Reactant: CCOCCn1nc(CC)c(N)c1C(N)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOCCn1nc(CC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of carbonyldiimidazole (12.3 g, 76.1 mmol) in acetonitrile (123 mL) was warmed to 50° C. The 4-amino-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazole-5-carboxamide prepared in step 3 (13.2 g, 58 mmol) was added to the mixture over a period of one hour and the temperature of the mixture was increased to 75° C. during the addition. The mixture was then cooled and stirred overnight. The mixture was cooled in an ice bath and filtered. The filter cake was rinsed with water and dried to provide 12.8 g of the title compound.