Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[CH:14]2[OH:17])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc2c(c1)C(=O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)C(O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2

Procedure:
0.77 g of (3S,5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone are dissolved in 15 ml of glacial acetic acid, 0.4 g of 10% palladium/charcoal are added and the mixture is hydrogenated for 24 hours at ambient temperature under 3 bars of hydrogen pressure. The catalyst is filtered off, the filtrate is evaporated down and purified by chromatography over silica gel (eluant: methylene chloride/methanol/glacial acetic acid =3:1:0.1). The crude product obtained is triturated with ether, filtered off and taken up in 50 ml of a mixture of glacial acetic acid and water (1:2). This solution is concentrated until crystallisation begins (about 5 ml). The crystals precipitated are washed with water, acetone and ether.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:22]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: O=C1CCCCC1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Nc1ncnn2c(C3(O)CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1.20 g, 5.63 mmol) was dissolved in THF (25 mL) under argon at room temperature. Chlorotrimethylsilane (1.43 mL, 11.27 mmol) was added, and the mixture was stirred at room temperature for 3 h. Then, it was cooled to 0° C., 2-propyl magnesium chloride (11.8 mL of a 2.0 M solution in THF, 23.7 mmol) was added, and stirring was maintained for another 3 h while the reaction mixture was allowed to warm to room temperature. Then, cyclohexanone (0.88 mL, 8.45 mmol) was added, and stirring was continued for 16 h. The reaction was quenched with a mixture (1:1) of concentrated aqueous ammonium chloride solution and ice until the pH reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The product thus obtained was used without further purification (purity 68% by HPLC). Yield: 1.87 g (97% of th.).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1>C1(C)C=CC=CC=1.C(O)C.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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
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: CCO
Solvent: Cc1ccccc1
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc(F)cc(F)c2)C1=O
Temperature: 95 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a stirred solution of 4-bromo-2-ethyl-2-methy-5-{4-(methylsulfonyl)-phenyl}-3(2H)-furanone (200 mg) in 15 ml toluene and 5 ml ethanol, were added 34 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 110 mg of 3,5-difluorobenzeneboronic acid. Then the reaction solution was stirred at 95° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo. The resulting crude product mixture was purified by column chromatography (hexane/ethylacetate=2:1) to obtain 80 mg of 4-(3,5-difluorophenyl)-2-ethyl-2-methyl-5{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 122-124° C. NMR: δ0.95 (t, J=7.5 Hz, 3H), 1.54 (s, 3H), 1.97 (m, 2H), 3.10 (s, 3H), 6.81 (m, 3H), 7.84 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). IR (cm−1): 2975, 2928, 1698, 1627, 1321, 1150, 990, 769, 552.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:17]([NH:24][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCCC2NCc1ccccc1

Procedure:
A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.19 g), benzylamine (14.7 ml) and p-toluensulfonic acid (7.6 g) in 250 ml of xylenes were refluxed with removal of water for eighteen hours.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: CCCCCC1=C(C)C(=O)CC1
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC1=CCC(c2cccc3cccnc23)=C1C
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 6.8 g (32 mmol) of 8-bromoquinoline in 90 ml of tetrahydrofuran was cooled to −90° C., and 12.8 ml of n-butyllithium (2.5 M in hexane, 32 mmol) were subsequently added while stirring. After stirring for 15 minutes at this temperature, 5.3 g (32 mmol) of 2-methyl-3-pentylcyclopent-2-enone (dihydroisojasmone) were added while stirring. The mixture was stirred at this temperature for a further one hour, allowed to warm to room temperature and then refluxed for one hour. After cooling to room temperature, a mixture of 30 g of ice and 30 g of concentrated hydrochloric acid was added and the resulting mixture was refluxed for 2 hours. The mixture was allowed to cool to room temperature while stirring and ammonia solution was added until a pH of 12 had been reached. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was dissolved in 5 ml of toluene and then admixed with 80 ml of hexane. The precipitate formed was filtered off and dried. The residue obtained in this way was distilled at >110° C. and 1×10−2 mbar to give 2.6 g of 2-methyl-3-pentyl-1-(8-quinolyl)cyclopentadiene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[N:22]3[CH:21]=1)=O>>[CH3:32][C:23]1([CH3:33])[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]13)[CH:29]=[CH:28][CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Product: CC1(C)CCc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)O)C2c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To a stirring solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (1.5 g, 4.2 mmol) (Intermediate 2) and one drop DMF in 10 mL of toluene at 0° C. was added thionyl chloride (8.6 mL, 11.8 mmol). The reaction was allowed to warm to room temperature and then heated to 73° C. for 2.5 hours. The solvent and excess thionyl chloride were evaporated at reduced pressure to leave 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (1.6 g, 100% crude yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[O:31])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](Cn2ccccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (370 mg) in DMF (8.0 mL) were added 2(1H)-pyridinone (87 mg) and potassium carbonate (158 mg), and the mixture was heated at 80° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (44 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following Example 156e, 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (1.76 g, 8 mmol), azetidine (550 mg, 9.6 mmol), di-isopropylethylamine (1.75 mL, 10 mmol) and methylene chloride (40 mL) were stirred at room temperature for 3-5 h. Work-up and concentrated under reduced pressure to afford 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole 200a (quant.) as yellow oil, which was used without further purification for the next step. MS (ESI+) m/z 197.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([NH:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]([CH3:17])[CH2:24][CH:23]([OH:22])[CH2:25][O:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1C2CCC1CN(Cc1ccccc1)C2
Reactant: N#Cc1ccc(OCC2CO2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CN(CC(O)COc1ccc(C#N)cc1)C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (Preparation B; 3.72 g, 16.1 mmol) in dichloromethane (80 mL) at 25° C. under nitrogen was added trimethylaluminum (8.05 mL of 2.0 M in hexane, 16.1 mmol). After stirring at 25° C. for 30 min, 4-(2-oxiranyl-methoxy)benzonitrile (see step (i) above; 2.83 g, 16.1 mmol) was added in one portion, and the mixture was stirred overnight. The mixture was quenched with 6 N NaOH (13.5 mL) and stirred 1 h. Water (100 mL) was added, and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford an oil. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 4.30 g (66%) of the sub-title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH2:17][CH3:18].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCCCO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 99 %

Procedure:
Ferulic acid (5 g) and then n-butyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for about 2 hours. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×8.5 cm; 70 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (6.25 g, 99%) as colorless oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C[O:16][B:17]([O:20]C)[O:18]C.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:16][B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reaction time: 0.33 h

Procedure:
Into a Solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (121.3 g) in tetrahydrofuran (730 mL), n-butyllithium (2.64M hexane solution; 182 mL) was dropped at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of trimethoxyborane (61.7 mL) intetrahydrofuran (20 mL) at −78° C. The temperature was raised until the inner temperature of the reaction mixture reached −10° C., a saturated ammonium chloride aqueous solution (730 mL) was added, and the mixture was further stirred for 15 minutes. To the resulting reaction mixture was added ethyl acetate, extraction with ethyl acetate was performed, and the resulting organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate (2:3), 90.4 g of a title compound was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:16]=C.C[OH:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:16]=[O:19]
Reactant: CO
Reactant: C=Cc1cc2c(nc1OC)C(C)(C)C(=O)N2C
Solvent: ClCCl
Product: COc1nc2c(cc1C=O)N(C)C(=O)C2(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A 65 mg (0.28 mmol) solution of 5-methoxy-1,3,3-trimethyl-6-vinyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one in 16 ml of methylene chloride and 4 ml of methanol was cooled to −70° C. Ozone (via an ozone generator) was bubbled into the solution until a blue color was achieved. The reaction mixture was stirred at −70° C. for 30 minutes and warmed to room temperature. Approximately 0.5 ml of dimethyl sulfide was added and the reaction was evaporated. This residue (0.6 g) was used directly in the next step. 1H NMR (CDCl3) δ 10.20 (s, 1H). Mass spectrum: m/e =235 (p+1).
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Br[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: BrCCCN1CCOCC1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCOCC3)cc2c1
Yield: 68.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(3-bromopropyl)morpholine (310 mg, 1.49 mmol) were converted to the title compound (180 mg, 69%). 1H NMR (DMSO-d6) δ 9.53 (br s, 1H), 8.06 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.73-7.68 (m, 1H), 7.55 (dd, J=8.4, 1.5 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 4.20 (t, J=5.8 Hz, 2H), 4.00 (d, J=11.0 Hz, 2H), 3.65 (t, J=11.6 Hz, 2H), 3.51 (d, J=12.3 Hz, 2H), 3.37-3.32 (m, 2H), 3.17-3.07 (m, 2H), 2.23-2.16 (m, 2H); MS (ESI+) m/z 350.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:15][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:9]=2)[CH:4]=1)=[O:14]
Reactant: COC(=O)c1cc2cc(O)ccc2cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)ccc2cc1O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A suspension of methyl 3,7-dihydroxy-2-naphthoate (2.2 g; 10 mmole), benzylchloride (Merck) (1.26 mL; 11.0 mmole), potassium iodide (1.8 g; 11.0 mmole) and potassium carbonate (2.0 g; 15 mmole) in acetone (30 mL) was refluxed for 7 hours and then cooled to room temperature. The inorganic precipitate was filtered off and washed with acetone, whereas the filtrate was evaporated to dryness The solid residue was dissolved in ethyl acetate and the resulting solution was washed with 1M hydrochloric acid. After drying with sodium sulfate the organic layer was evaporated and the dry residue was recrystallized from methanol, whereat 1.2 g (39%) of methyl-7-benzyloxy-3-hydroxy-2-naphthoate were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:21])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:4][CH2:3]1.[C:22]([C:24]1[N:29]=[C:28]([NH:30][CH2:31][CH:32]2[CH2:39][CH2:38][C:35]3([CH2:37][CH2:36]3)[CH2:34][CH2:33]2)[C:27]([C:40](O)=[O:41])=[CH:26][N:25]=1)#[N:23].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:21][C:40]([C:27]3[C:28]([NH:30][CH2:31][CH:32]4[CH2:39][CH2:38][C:35]5([CH2:37][CH2:36]5)[CH2:34][CH2:33]4)=[N:29][C:24]([C:22]#[N:23])=[N:25][CH:26]=3)=[O:41])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Oc2ccc(N)c(-c3ccccc3)c2)CC1
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCC3(CC2)CC3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(NC(=O)c3cnc(C#N)nc3NCC3CCC4(CC3)CC4)c(-c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-methylpiperidin-4-yloxy)biphenyl-2-ylamine (0.27 mmol, step 58.2) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.33 mmol) in DMF (2 mL) are added EDCI-HCl (0.54 mmol) and HOAt (0.54 mmol) at 0° C. After stirring at the ambient temperature overnight, the reaction mixture is purified by RP-HPLC to give the title compound as a white solid; 1H NMR (CDCl3), δ 0.18-0.21 (2H, m), 0.27-0.30 (2H, m), 0.90-0.94 (2H, m), 1.14-1.25 (2H, m), 1.58-1.78 (5H, m), 1.85-1.92 (2H, m), 2.02-2.06 (2H, m), 2.32 (3H, s), 2.70 (2H, br s), 3.41-3.44 (2H, t), 4.35 (1H, m), 6.89 (1H, d), 6.97 (1H, dd), 7.35-7.37 (2H, m), 7.45-7.52 (3H, m), 7.65 (1H, s), 7.92 (1H, s), 8.06 (1H, d), 8.90 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](=O)[CH2:15]Br)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]2[CH:15]=1)=[O:18])[CH3:11]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(C=O)cn1
Solvent: CCO
Product: CCOC(=O)c1cn2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
An ethanol solution (8.0 ml) containing the compound (318 mg) obtained in Example 30-1 was added with 3-bromo-2-oxo-propionic acid ethyl ester (0.33 ml) and the whole was stirred at room temperature for 18 hours. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (230 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccncc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccncc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-15; 0.8 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9 mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product was triturated from Et2O, mp 140-155° C. MS (APCI): 470 (M+H).