Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCNCC1.C([Li])CCC.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=1.C([Li])(C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:28][C:16]1[CH:17]=[CH:18][C:19]([CH:21]=[O:22])=[N:20][C:15]=1[O:14][CH3:13]
Reactant: COc1cccc(C=O)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN1CCNCC1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C=O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
A solution of methylpiperazine (2.31 g) in tetrahydrofuran (20 mL) was cooled to −78° C., and n-butyllithium (2.64 M, 7.55 mL) was added dropwise in an argon gas atmosphere. After stirring at the same temperature for 15 minutes, a solution of 6-methoxypicolinaldehyde (2.5 g) in tetrahydrofuran was added and the mixture was stirred for 30 minutes. t-Butyllithium (1.59 M, 17.1 mL) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for one hour and at −40° C. for 15 minutes. The reaction solution was cooled again to −78° C. A solution of hexachloroethane (12.9 g) in tetrahydrofuran (20 mL) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→10:1) to give 5-chloro-6-methoxypyridine-2-carbaldehyde as a colorless powder (1.21 g).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[Br:10][CH2:11][C:12](Br)=[O:13]>ClCCl.O>[Br:10][CH2:11][C:12]([N:3]1[CH2:4][CH:5]2[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:13]
Reactant: O=C(Br)CBr
Reactant: C1CC2CCC1CNC2
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-azabicyclo[3.2.2]nonane (1.25 g) in dichioromethane (20 ml) and water (0.75 ml) was added dropwise a solution of bromoacetyl bromide (2.02 g) in dichloromethane (10 ml) at, 5°-10° C. The mixture was allowed to warm to room temperature and stirred for 1 hour at the same temperature. The reaction mixture was washed with a saturated sodium bicarbonate aqueous solution (10 ml) and a brine (10 ml). The organic layer was dried over magnesium sulfate. Filtration and evaporation gave N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (1.15 g). The compound was used in a following reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([F:17])[CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH:18]1[N:22]=[CH:21][N:20]([C:23](N2C=NC=C2)=[O:24])[CH:19]=1>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([NH:1][C:23]([N:20]3[CH:19]=[CH:18][N:22]=[CH:21]3)=[O:24])=[N:6][C:5]=2[CH3:7])=[CH:9][C:10]=1[F:17])(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(-c2sc(N)nc2C)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1F

Procedure:
Dry DCM (10 ml) is added to 1-[4-(2-amino-4-methyl-thiazol-5-yl)-2-fluoro-phenyl]-ethanone (0.25 g, 1.0 mmol) and CDI (0.259 g, 1.6 mmol) and the mixture is heated at reflux for 4 hours. The resulting suspension is filtered and dried under vacuum to afford the title compound.
Reaction SMILES: O1[C:3]23[C@:19]([CH3:24])([CH2:20][CH2:21][C:22](=[O:23])[CH:2]12)[C@@H:18]1[C@H:6]([C@H:7]2[C@:15]([CH3:25])([CH2:16][CH2:17]1)[C@@H:10]([C@H:11]([CH3:14])[CH2:12][OH:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4]3.[N-:26]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].S(=O)(=O)(O)O>CS(C)=O>[NH2:26][C:2]1[C:22](=[O:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one (7.7 mmole) in dimethyl sulfoxide (40 mL), under a nitrogen atmosphere, was placed in an oil bath heated at 60° C. The solution was stirred vigorously as sodium azide (8.11 g, 0.338 mole) was slowly added. After the addition of the azide was complete, concentrated sulfuric acid (0.54 mL) was added. The bath temperature was raised to 100° C. and the reaction was stirred at this temperature for 90 minutes. The reaction was removed from the oil bath and cooled to room temperature and the resulting solid mass was broken up and poured into cold water (550 mL). The mixture was stirred for 30 min and the solids were collected by filtration, washed with water and dried to a yellow solid. The crude product was purified by flash chromatography (hexane-30% ethyl acetate) to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one. IR 3462, 3390, 3346, 1652, 1616, 1592, 1564 cm-1 ; MS (CI) m/z 344 (100%, M+ +1); (EI) m/z 343 (60%, M+), 150 (100%); 1H NMR (CDCl3) δ 0.76 (3H, s, C18 -Me), 1.04+1.05 (6H, s+d, C19 -Me+C21 -Me) 2.48 (1H, dq), 2.63 (1H, dq), 3.38 (1H, dd, 1/2 C21 -CH2), 3.64(dd+v br, 1/2 C21 -CH2 +NH2), 5.97 (1H, dd) 6.30 (1H, dd); 13C NMR (CDCl3) δ 121.77, 132.08, 132.98, 136.55, 194.40.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]=O)[CH2:10][CH:9]1[CH:15]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH2:10][CH:9]1[CH2:15][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)CC1C=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC1CN(Cc1ccccc1)C2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a solution of the crude product of Example 2B (2.92 mmol) in CH3OH at 0° C. was added benzylamine (0.35 mL, 3.21 mmol) and NaCNBH3 (1.83 g, 29.2 mmol). The ice-bath was removed and the mixture stirred at 20° C. for 24 h. The solution was cooled to 0° C. and 10 mL EtOAc and 10 mL H2O were added followed by 5 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with 10 mL EtOAc. The combined organic layers were washed with 5 mL H2O followed by 5 mL brine, then were dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated and purified via flash column chromatography to give 0.68 g (2.25 mmol, 77% two-step yield) of the title compound. 1H NMR (CH3OH-d4, 300 MHz) δ 1.37 and 1.51 (s, rotamers, 9H), 1.46 (m, 1H), 1.57 (dd, J=11.2, 7.46 Hz, 1H), 1.88 (m, 1H), 1.97 (m, 1H), 2.32 (m, 2H), 2.82 (m, 1H), 3.02 (m, 1H), 3.52 (m, 3H), 3.91 (m, 1H), 7.20 (m, 1H), 7.27 (m, 4H); MS (DCl/NH3) m/z 303 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl

Procedure:
In general, the novel derivatives 31-47 were synthesized as shown in the scheme depicted in FIG. 1. Condensation of anthranilic acid hydrochloride (1) with methazonic acid (2) resulted in 2-β-nitroethylideneaminobenzoic acid (3), which was dehydrated in acetic anhydride in the presence of potassium acetate to give 3-nitro-4-hydroxyquinoline (5) [Bachman, G. B. et al. Quinoline Derivatives from 3-Nitro-4-hydroxyquinoline, J. Am. Chem. Soc., 1947, 69, 365-371]. 3-Nitro-4-hydroxyquinoline (5) was treated with phosphorous oxychloride to afford 3-nitro-4-chloroquinoline (6). This was converted to 3-nitro-4-aminoquinoline (7) with ammonia, which was subsequently reduced by catalytic hydrogenation to 3,4-diaminoquinoline (8) with 10% palladium on charcoal as catalyst. The next step involved ring-closure, which was carried out in three different ways. For example, Compound 10 was prepared by ring closure of the appropriate carboxylic acid and 3,4-diaminoquinoline (8) in polyphosphoric acid [Young, R. C. et al. Purine Derivatives as Competitive Inhibitors of Human Erythrocyte Membrane Phosphatidylinositol 4-Kinase. J. Med. Chem. 1990, 33, 2073-2080]. Compound 14 was prepared by ring-closure of 2-furoyl chloride with 3,4-diaminoquinoline (8) [Scammells P. J. et al. Substituted 1,3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors. J. Med. Chem. 1994, 37, 2704-2712]. Compound 9 was prepared by ring-closure of 3,4-diaminoquinoline (8) with formic acid in trimethylorthoformate. Oxidation with 3-chloroperoxybenzoic acid afforded 5-oxides 16-22, which subsequently could be converted with phosphorous oxychloride into the 4-chlorides 23-29. Finally, reaction with the appropriate amines afforded the desired compounds 30-47, respectively [Van Galen, P. J. M. et. al. 1-H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206].
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
Oxalyl chloride (0.63 g) in dry THF (5 ml) was added dropwise over 5 minutes to a solution of 2-chloro-4-(2'-methylpropionamido)benzoic acid (1.0 g) in dry THF (5 ml) at room temperature. After completion of the addition, dry DMF (1 drop) was added causing vigorous effervescence and a slight temperature rise. After stirring for 4 hours and addition of a further drop of DMF, the THF was evaporated to yield 2-chloro-4-(2'-methylpropionamido)benzoyl chloride as a viscous brown gum which was used without further purification. IR (liquid film): 3320, 3260, 3160, 3070, 1780, 1710, 1680, cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (1.6 g, 2.78 mmol) and (R)-2-methyl-CBS-oxazaborolidine (116 mg, 0.42 mmol) in anhydrous toluene at −40° C. was added a solution of catecholborane (355 μL, 3.34 mmol) in toluene (1.6 mL) over 15 minutes. The reaction mixture was stirred for 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at room temperature. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4×), saturated ammonium chloride solution, dried, filtered, concentrated in vacuo and purified by flash column chromatography to give the desired product.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[OH-].[Na+].Cl>CO>[C:21]([N:5]1[CH2:6][CH:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:8][C@H:4]1[C:3]([OH:28])=[O:2])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: COC(=O)[C@@H]1CC(Oc2ccnc3cc(Cl)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccnc3cc(Cl)ccc23)C[C@H]1C(=O)O
Temperature: 0 °C

Procedure:
To a solution of the product (10.57 g, 26.0 mmol) of Step 63a of Example 63 {BOC—N—P2[(4R)-(7-chloroquinoline-4-oxo) proline methyl ester} dissolved in MeOH (800 mL) cooled to 0° C. was added an aqueous 1N NaOH solution (44.5 mL, 44.5 mmol). The mixture was warmed to rt after 6 h, stirred overnite, and the pH adjusted to pH 7 using 1.0 N aqueous HCl. The solution was concentrated until only the water layer remained, the pH adjusted to 4 using 6N aqueous HCl and the mixture was partitioned repeatedly with EtOAc (3×500 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 10.16 g (100%) of the as a white solid. 1H NMR (DMSO-d6) δ 1.32, 1.34 (two s (rotamers) 9H), 2.31-2.40 (m, 1H), 2.58-2.69 (m, 1H), 3.65-3.81 (m, 2H), 4.33-4.40 (m, 1H), 5.34 (m, 1H), 7.10-7.11 (m, 1H), 7.57 (d, J=9 Hz, 1H), 7.98 (s, 1H), 8.09-8.14 (m, 1H), 8.75 (d, J=5 Hz, 1H), 12.88 (brs, 1H). 13C NMR (DMSO-d6) δ 27.82, 35.84, 51.52, 57.75, 76.03, 79.33, 102.95, 119.54, 123.86, 126.34, 127.24, 134.49, 149.32, 152.88, 153.25, 159.08, 173.74. LC-MS (retention time: 1.48, method D), MS m/e 393 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C(C(C)=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOC(=O)CN=C=O
Reactant: Oc1c(Cl)cc(Cl)c2cccnc12
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1c(Cl)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
5,7-Dichloro-8-hydroxyquinoline (21.4 g), ethyl isocyanatoacetate (21.3 g) and triethylamine (1.0 ml) were mixed together in 400 ml of methyl ethyl ketone and stirred at room temperature for about 42 hours resulting in the precipitation of a white crystalline solid. This solid was removed from the reaction mixture by filtration and was determined to be the desired ethyl N-(((5,7-dichloro-8-quinolinyl)oxy)carbonyl)glycinate, m.p. 119.5° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]4[CH2:40]COC[CH2:36]4)=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:41]N(CC#C)C.C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]([CH3:36])[CH3:40])=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([O:22][CH3:41])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)ccc1OCC(=O)O
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a degassed solution of the ester (486 mg, 0.877 mmol; prepared as described in example 38), 1-(N,N-dimethylamino)prop-2-yne (150 mg, 1.80 mmol) and diisopropyl amine (0.589 mL, 4.24 mmol) in anhydrous tetrahydrofuran (12 mL), bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol) and copper(I) iodide (14.0 mg, 0.074 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:24]3[CH:23]=[C:22]([S:19]([NH:18][CH3:17])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Product: CNS(=O)(=O)c1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-methyl-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-methylsulfamoylphenylboronic acid following general procedures as described in these Examples. MP 245-247° C., M+H=373.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:60][C:61]([F:72])([F:71])[C:62]1[CH:70]=[CH:69][C:65]([C:66](Cl)=[O:67])=[CH:64][CH:63]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:66](=[O:67])[C:65]4[CH:69]=[CH:70][C:62]([C:61]([F:60])([F:71])[F:72])=[CH:63][CH:64]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C@@H:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[C:56]([O:58][CH3:59])=[O:57]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Yield: 86 %

Procedure:
The compound of example 597 was prepared analogous to compound of example 97 by reaction of compound of example 592 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1cnn(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=O>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:16]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].IC>C1COCC1>[CH3:2][CH:26]([C:12]1([CH2:11][CH:10]([CH3:34])[CH3:9])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)CC1(C(C)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
LDA (1.5 mL, 3.0 mmol, 2.0M in heptane/THF/ethylbenzene) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (967 mg, 2.69 mmol) and THF (11.0 mL) at -78° C. The solution is stirred at -78° C. for 30 minutes and then iodomethane (0.19 mL, 3.1 mmol) is added. The solution is stirred at -78° C. for 2 hours and then allowed to slowly warm to room temperature overnight. Aqueous workup (EtOAc, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) gives 791 mg (79%) of the title compound as an oil.
Reaction SMILES: C[C@@H](N)C1C=CC=CC=1.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH:11]1[C:20]([OH:22])=[O:21]>C(O)C>[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: O=C(O)[C@H]1CCc2ccccc2O1
Yield: 13.4 %

Procedure:
A solution of (+)-(R)-α-methylbenzylamine (0.37 mol) in ethanol (100 ml) was added to a solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (0.36 mol) in ethanol (200 ml). The mixture was allowed to crystallize out. The precipitate was filtered off and dried. The residue was crystallized 4 times from ethanol. The precipitate was filtered off and dried. The residue was taken up in water, treated with HCl 10% and extracted with diethyl ether. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 8.6 g of (-)-(R)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (mp. 85.5° C., [α]20D =-6.7° (c=100 mg/10 ml in methanol)) (interm. 1).