Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:16])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxyindole-3-carboxaldehyde (80 g) in dimethylformamide (1 L) under nitrogen was treated portion-wise with sodium hydride (20.1 g, 60% dispersion in mineral oil) over 15 minutes. After stirring at ambient temperature for 30 minutes the mixture was treated dropwise with methyl iodide (31.3 mL) over 10 minutes and stirring was then continued for a further 2 hours. The reaction mixture was poured cautiously into water then extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulfate and then evaporated. The residue was triturated with pentane to give the title compound (76 g) as a pale brown solid, m.p. 133-134° C. 1H NMR [(CD3)2SO]: δ 9.86 (1H, s); 8.20 (1H, s); 7.60 (1H, d, J=2.6 Hz); 7.50 (1H, d, J=8.9 Hz); 6.96 (1H, dd, J=8.9 and 2.6 Hz); 3.86 and 3.80 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]#[C:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]#[C:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CC(CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 908 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added methyl 3-(4-hydroxyphenyl)hex-4-ynoate (3.8 g, 17.4 mmol), potassium carbonate (7.2 g, 52.2 mmol). The reaction mixture was brought to 0° C., was added benzyl bromide (4.47 g, 1.5 mmol) in acetonitrile (20 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. Water (20 mL) was added and extracted with ethyl acetate (60 mL). The organic layer was washed with water (20 mL) and saturated brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants to obtain product (4.2 g, yield: 78.35%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: O=Cc1cc(Cl)ccc1OCCCCCBr
Yield: 81.8 %

Procedure:
A mixture of 7.82 g (50 mmol) of 5-chlorosalicylaldehyde, 92.1 g (0.4 mol) of 1,5-dibromopentane, 22.1 g (0.15 mol) of anhydrous granular potassium carbonate, and 360 mL of acetonitrile was stirred and refluxed for 20 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and washed thoroughly with ether. The filtrate and washes were combined and concentrated under water aspirator pressure. The excess 1,5-dibromopentane was removed by distillation under high vacuum. Flash chromatography of the residue on silica gel (eluting with 4:1 hexane-ether) afforded 12.5 g (81.8%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzaldehyde as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:11][OH:12])=[CH:9][N:8](CO)[C:5]2=[N:6][CH:7]=1.[OH:15]S(O)(=O)=O>CC(C)=O.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:12])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OCc1cn(CO)c2ncc(Br)nc12
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1c[nH]c2ncc(Br)nc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a stirred solution of (2-bromo-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (0.525 g, 2.03 mmol) in 200 mL of acetone at 40° C. was added a solution of CrO3 (0.832 g, 8.32 mmol) and H2SO4 (1.32 g, 13.4 mmol) in water (3 ml). Then the reaction was stirred at 40° C. for 16 hours then filtered through Celite. The filtrate was evaporated at 40° C. under reduced pressure to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.527 g) as an off-white solid. LCMS: (M+H)+=264; 1H NMR (300 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 5.63 (s, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH3:15])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1ccccc1N
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NS(=O)(=O)c1cc(I)c2occc2c1
Reaction time: 8 h

Procedure:
7-Iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; Intermediate 56) and 2-methyl aniline (3.43 mL, 32.1 mmol) were dissolved in dichloromethane (150 mL) and pyridine (3.53 mL, 43.8 mmol) was added. The solution was stirred overnight and washed with 1 M HCl (2×100 mL), dried over sodium sulfate and evaporated to give the crude solid product that was recrystallized from methanol. Yield: 5.32 g (44%) of a beige solid.
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCOC(C)=O>[N:9]1([C:10]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=4)[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)NCCBr)c3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)N4CC4)c3)CC2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A DMF (10 ml) suspension of methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (750 mg), potassium carbonate (300 mg) and potassium iodide (361 mg) was stirred at 80° C. for 1 hour. The reaction liquid was left cooled, then EtOAc was added thereto, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain methyl 5-{[(4-{2-[3-(aziridin-1-ylcarbonyl)phenyl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (630 mg) as a colorless oil.
Reaction SMILES: [OH:1][C@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CON(C)C(=O)[C@](C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CON(C)C(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
(R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol) and 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added and stirred at ambient temperature overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (R)—N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (22.9 g, 113 mmol, 57.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45](O)=[O:46])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[O:46])[CH:28]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)cc2oc(Nc3ccccc3C)nc12
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: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(OC)c3nc(Nc4ccccc4C)oc3c2)cc1
Reaction time: 20 h
Yield: 100.8 %

Procedure:
A stirred solution of with ethyl (R) 3-(4-aminophenyl)butanoate (0.107 g, Reference Example 1) in dimethylformamide (10 mL) was treated with diisopropylethylamine (0.4 g), 2-(4-methoxy-2-o-tolylaminobenzoxazol-6-yl)acetic acid [0.105 g, Reference Example 9(a)] and then with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.14 g). The mixture was left to stand for 20 hours and then partitioned between ethyl acetate and hydrochloric acid (1M). The organic phase was washed with water, then with aqueous bicarbonate solution (5%), then with water, then with brine, then dried and then evaporated to give the title compound (0.17 g) as a cream coloured solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:19]1[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]1
Reactant: CC1CNCC(C)C1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CC(C)CC(C)C1

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 3,5-dimethylpiperidine. Yield: 0.4 g (48.1% of theory); C16H24N2O4 (M=308.38); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:14][C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13])=[O:22])([O-:17])=[O:16]
Reactant: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.3 %

Procedure:
(1R)-1-[2-(2,4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 40 g of 3,5-dinitrobenzoyl chloride were dissolved in 500 ml of methylene chloride and, with ice cooling, 24.1 ml of triethylamine was added dropwise thereinto. The reaction solution was stirred at room temperature for 3.5 hours, washed with 150 ml of water and then with 150 ml of 5% aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The crystals separated out were collected by filtration and washed with methylene chloride. The mother liquor and the washing were combined and distilled off under reduced pressure, then 25 ml of ethyl acetate and 300 ml of methanol were added to the residue and the mixture was cooled with ice. The crystals separated out were collected by a filtration and recrystallized from a mixture of 25 ml of ethyl acetate and 250 ml of methanol to give 28.7 g of [(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3]2[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (250 mg, 0.56 mmol), 4-phenoxyphenylboronic acid (133 mg, 0.62 mmol), Pd(PPh3)4 (100 mg) and Na2CO3 (150 mg, 1.41 mmol) in dioxane/H2O (40/10 ml) was stirred at 100° C. for 4 h. The reaction mixture was concentrated and purified by Pre-TLC to obtain (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (150 mg, 55% in yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>CN(C)C=O.O>[Br:1][CH2:2][C:3]1([CH2:11][O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:4][O:5][C:6]([CH3:9])([CH3:10])[O:7][CH2:8]1
Reactant: CC1(C)OCC(CO)(CBr)CO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CBr)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
409 mg (1.71 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was dissolved in 5 mL of dimethylformamide, 233 mg (3.42 mmol equivalents) of imidazole and 309 mg (2.05 mmol equivalents) of t-butyldimethylchlorosilane were added thereto, and the mixture was stirred at room temperature (25° C.) for 18 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 578 mg (1.64 mmol equivalents) of 5-bromomethyl-5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([O:19][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(N1CCC[C@@H]2c3ccc(O)cc3CC[C@@H]21)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2,2,2-trifluoro-1-(8-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-ethanone (0.98 g), 4-methoxyphenylboronic acid (1.00 g), pyridine (1.30 mL), copper(II) acetate (0.60 g), molecular sieves 3 Å (3.60 g), and dichloromethane (15 mL) is stirred in air at room temperature overnight. The mixture is diluted with dichloromethane and filtered over Celite. The filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 99:1→95:5) to give the title compound as a colorless resin-like solid. Yield: 1.05 g (79% of theory); LC (method 1): tR=5.00 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][C:39](=[O:40])[CH2:38][NH:37][C:35]([O:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:36])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCc1ccccc1)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A solution of 2.15 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide and 1.86 g of N-(benzyloxycarbonyl)-glycine in 8 ml of dimethylformamide was cooled to 0° C. and treated with 2.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature, diluted with diethyl ether and washed sequentially with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give 2.96 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-[N-(benzyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=[O:41]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:35]2=[O:41])[CH:29]=1
Reactant: NCc1ccc(F)cc1N1CCCCCC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCCCCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)-5-fluorophenyl)azepan-2-one, derived from reduction of intermediate 113, 4-fluoro-2-(2-oxoazepan-1-yl)benzonitrile. 1HNMR 400 MHz (DMSO) δ ppm: 8.80 (1H, dd, (t), J=6.0 Hz), 7.46 (2H, m), 7.36 (4H, m), 7.08 (1H, dd, J=9.8, 2.8 Hz), 7.0 (1H, m), 5.09 (2H, s), 4.43 (1H, dd, J=15.2, 7.1 Hz), 4.06 (1H, dd, J=15.2, 5.0 Hz), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t, J=5.0 Hz), 3.77 (1H, m), 3.51 (1H, m), 2.70 (1H, m), 2.51 (2H, m), 1.76 (6H, m), 1.56 (6H, s). LCMS (M+H)+ m/z 549.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Br[CH2:37][CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:39][CH2:38][CH2:37][N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1
Reactant: OCCBr
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)NC2CCN(CCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of the compound of Example 77 (200 mg, 0.399 mmol), 2-bromoethanol (42.5 μL, 0.599 mmol), potassium carbonate (248 mg, 1.80 mmol) and DMF (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-ethanol to give the title compound (68.0 mg, 33%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>C1COCC1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:10][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg, 1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL) and DMSO (2 mL) was heated at 100° C. for 20 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine (×2), dried (MgSO4), filtered and concentrated to give a crude product which was purified by column chromatography (SiO2), eluting with a gradient of ethyl acetate/petrol (2.5% to 100%) then 10% methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS (PS-A2) Rt 3.22 min [M+H]+ 504.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCOC(C)=O>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:15][CH:16]=1
Reactant: Nc1ccncc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1c(Nc2ccncc2)c(=O)c1=O
Yield: 9.9 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 4-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 4 hours then concentrated to give crude product. Chromatography (EtOAc) afforded 0.632 g (10%) of a white solid: mp 120°-125° C.