Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=[O:36])[NH:33][N:32]=2)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:32][N:33]=[C:34]([O:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:35]=2)=[CH:29][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccc(Cl)cc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Yield: 72.9 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (140 mg, 0.415 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-one (202 mg, 1.04 mmol) in the presence of sodium hydride (41.5 mg, 1.04 mmol, prewashed with THF) in DMF (2.5 ml) to give 4-(5-(4-chlorophenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 73%).
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](COCCOC)[C:29](=[O:37])[O:28][N:27]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:40][C:41]([C:43]1[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47]C)=[O:46])=[O:42].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:37])[O:28][N:27]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:40][C:41]([C:43]3[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=3[C:45]([OH:47])=[O:46])=[O:42])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1C(=O)CBr
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3C(=O)O)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
To a mixture of 6-ethyl-1-[(2′-{4-[(2-methoxyethoxy)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}biphenyl-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), methyl 2-(bromoacetyl)benzoate (1.06 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (0.18 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, tetrahydrofuran (15 mL), methanol (15 mL) and 1N aqueous sodium hydroxide solution (10 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), N,N′-carbonyldiimidazole (0.2 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.18 g, 30%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(C)NS(=O)(=O)c1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)CC(C)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A mixture of β-[[(3-methoxypheyl)sulfonyl]amino]-butanoic acid, ethyl ester (7.8 g, 25.7 mmol) and ethanethiol (8 g, 0.13 mol) in methylenechloride (200 ml) was cooled in ice-bath. Aluminum chloride (17.2 g, 0.13 mol) was added to above soultion. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with 3N HCl (200 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (2×100 ml). Combined organic solution was concentrated and dried to give the title compound (7 g, 94%). The material was used for the next reaction without further purification. 1H NMR (300 MHz, CD3OD) □|□d, 3H, J=6.73 Hz), 1.23 (t, 3H, J=7.11 Hz), 2.31-2.49 (m, 2H), 3.66-3.74 (m, 1H), 4.01-4.16 (m, 2H), 7.00-7.04 (m, 1H), 7.27-7.41 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1

Procedure:
The colourless oil, (E)-ethyl 3-(4′-tert-butyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 4-tert-butylphenylboronic acid by a procedure analogous to that described in example 52a
Reaction SMILES: CO.[Li+].[BH4-].C([O:7][C:8]([C:10]1[CH:18]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[N:11]=1)=O)C>C1COCC1>[N:11]1[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[CH:18][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCCC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2n(n1)CCCC2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
MeOH (0.29 mL) was added to the THF (19 mL) solution of LiBH4 (cont. 90%) (174 mg) under a nitrogen atmosphere at room temperature, then 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (862 mg) was added to the suspension and stirred for 1 h at room temperature and 1.5 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to afford titled compound as pale yellow oil (691 mg, 95%).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[Br:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester (120 mg, 0.495 mmol) in THF was added a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 3 hrs at room temperature. The resulting residue was dissolved in H2O, then washed three times with Et2O, and neutralized with 1N HCl to pH 5˜7. The resulting solid filtered and washed with H2O and then dried in vacuo to give 3-(6-bromo-pyridin-3-yl)-acrylic acid (100 mg, 88%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](Cl)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=1[C:17]([OH:19])=[O:18].N1C=CC=CC=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:14][C:15]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=3[C:17]([OH:19])=[O:18])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(F)cc(F)c1C(=O)O
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To a solution of commercially available benzo[1,3]dioxol-5-yl-acetyl chloride (3.70 g, 18.70 mmol) in anhydrous dichloromethane (20 mL) was added 2-amino-4,6-difluoro-benzoic acid (2.20 g, 12.5 mmol). After the addition of pyridine (5 mL), the mixture was heated under microwave condition at 120° C. for 5 minutes. The solvent was evaporated and the residue was diluted with 2 N HCl solution to induce the precipitation of a brown solid which was filtered, washed with water and dried under vacuum at 50° C., to afford the title compound (3.34 g, 80% yield).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:48])[C@:29]([C:32]3[CH:37]=[C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH:35]=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[F:48][C@H:28]1[CH2:27][O:26][C:25]([NH2:24])=[N:30][C@@:29]1([C:32]1[CH:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:45][CH3:46])[CH:35]=[CH:34][C:33]=1[F:47])[CH3:31]
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1Nc1ccc(F)c([C@@]2(C)N=C(N)OC[C@@H]2F)c1
Reaction time: 15 h
Yield: 82.7 %

Procedure:
A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (49.8 mg, 76.6 μmol) in dichloromethane (2 ml) was treated at room temperature with trifluoroacetic acid (89.2 mg, 59.9 μl, 766 μmol), and the mixture was stirred for 15 hours. After evaporation at reduced pressure, the dark red residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (22 mg, 82% yield) was obtained as a white foam. MS (ISP): m/z=348.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cc2c1O
Temperature: 25 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11]C(C)(C)[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([NH:42][CH2:43][CH2:44][NH:45][C:46]([NH:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[CH2:51][CH2:50]2)=[O:47])=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:28]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][NH:25][C:21]2[N:20]=[C:19]([C:40]([NH:42][CH2:43][CH2:44][NH:45][C:46]([NH:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[CH2:51][CH2:50]3)=[O:47])=[O:41])[N:18]=[C:17]3[C:22]=2[N:23]=[CH:24][N:16]3[C@H:8]2[C@H:9]([OH:13])[C@H:10]([OH:11])[C@@H:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[O:7]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-N-{2-[({[1-(2-pyridinyl)-4-piperidinyl]amino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide (Preparation 71) (20.9 g, 0.0255 moles) in absolute ethanol (200 ml) was added aqueous hydrochloric acid (76.5 ml of a 1M solution, 0.0765 moles) and the resultant solution was heated at 60–65° C. for 24 hours. The reaction mixture was allowed to cool to ambient temperature and saturated aqueous sodium bicarbonate solution (200 ml) was cautiously added. The resultant mixture was then concentrated in vacuo and the aqueous mixture was then extracted with ethyl acetate (200 ml) and then dichloromethane (200 ml). The extracts were dried over anhydrous magnesium sulphate which caused the deposition of a gum that was redissolved by the addition of dichloromethane (100 ml) and methanol (20 ml). The resultant violet solution was then concentrated in vacuo to give the crude product as a purple foam (20.86 g) that was purified by flash chromatography on silica gel (600 g) eluting with a gradient of 6% v/v methanol in dichloromethane changing to 8% v/v methanol in dichloromethane changing to 10% v/v methanol in dichloromethane changing to 15% v/v methanol in dichloromethane to give the title compound in several fractions of varying purity. The major fraction (11.4 g) was dissolved in dichloromethane (264 ml) and was filtered to remove insoluble matter. To this solution was added diethyl ether (112 ml) and the resultant cloudy mixture was stirred at ambient temperature for 1 hour. The solids were then collected by filtration and were dried in vacuo. This material was then ground using a pestle and mortar and was dried further in vacuo at 500 to give the title compound (9.9 g) as a fine colourless powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:30][CH3:31])[C:10](=[O:29])[CH2:11][N:12]2[C:20]3[C:15](=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][CH:19]=3)[N:14]([CH3:27])[C:13]2=[O:28])=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:30][CH3:31])[C:10](=[O:29])[CH2:11][N:12]2[C:20]3[C:15](=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][CH:19]=3)[N:14]([CH3:27])[C:13]2=[O:28])=[CH:5][CH:4]=1
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47.4 %

Procedure:
To a mixture of 8,9-dihydro-N-(4-methoxyphenyl)-9-methyl-N-ethyl-8-oxo-2-phenyl-7H-purin-7-acetamide (0.83 g) obtained in Example 173 and dichloromethane (10 ml) is added a 1M solution of boron tribromide in dichloromethane (4 ml) at 0° C., and the mixture is stirred at room temperature for five days. To the reaction mixture is added water, and the precipitates are collected by filtration, washed with water, and recrystallized from ethanol and diisopropyl ether to give the desired compound (0.38 g).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:4].[CH3:22][O:23][NH2:24]>>[CH3:22][O:23][NH:24][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:4]
Reactant: CON
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(I)cc1F
Product: CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(I)cc1F

Procedure:
2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester was coupled as described previously in Example 155 using O-methyl-hydroxylamine. MS ESI (+) m/z 418 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a stirred solution of compound 8 (670 mg, 1.59 mmol) in THF (15 mL) at room temperature was added a solution of LiOH.H2O (166 mg, 3.97 mmol) in water (5 mL). After 24 h, the reaction mixture was concentrated, diluted with water and acidified with 2N HCl (pH at 5-6). A precipitate formed, which was separated by filtration, rinsed with water and dried to afford the title compound 9 (600 mg, 1.47 mmol, 93% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): AB system (δA=7.87, δB=7.41, J=8.2 Hz, 4H), 7.68-7.58 (m, 1H), 7.12-6.56 (m, 5H), 5.75 (d, J=5.5 Hz, 1H), 4.53 (d, J=6.3 Hz, 2H), 3.74 and 3.72 (2s, 6H), 3.48-3.30 (m, 2H), 2.80-2.60 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[O:14].C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of benzyl bromide (6.9 g, 40.3 mmol) and 3-hydroxy-4-nitrobenzaldehyde (9.7 g, 58.0 mmol) is added K2CO3 (8.9 g, 64.4 mmol). The mixture is stirred at ambient temperature overnight, diluted with water and extracted with EtOAc. The organic phase is washed with aqueous K2CO3 and brine, dried over MgSO4, filtered and concentrated to afford 3-benzyloxy-4-nitrobenzaldehyde as a yellow solid: MS (M+H)+=258.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[CH3:52][C:53](OC(C)=O)=[O:54]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:53]([CH3:52])=[O:54])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To erythromycin A (2.674 mmol) dissolved in 100 mL of CH2Cl2 at ambient temperature and then cooled to 0° C. was added 1.1 equivalents of Ac2O (0.28 mL). The reaction mixture was allowed to warm to ambient temperature, stirred for 3 hours and extracted with CH2Cl2. The combined organic extracts were washed once with 8% sodium bicarbonate solution, tarice with water and once with brine, dried over Na2SO4 and concentrated in vacuo to afford the crude product as a white powder. Recrystallization from acetonitrile afforded the title compound.
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][CH:7]([NH2:20])[CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][CH:38]=2)=[CH:34][C:35]=1Br)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][CH:38]=2)=[CH:34][C:35]=1[NH:20][CH:7]([CH2:8][O:9][Si:10]([CH:11]([CH3:13])[CH3:12])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])=[O:30]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1Br
Reactant: CC(C)[Si](OCC(N)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1NC(CO[Si](C(C)C)(C(C)C)C(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Nitrogen was bubbled through a mixture of 2-triisopropylsilanyloxy-1-triisopropylsilanyloxymethyl-ethylamine (prepared from serinol using triisopropylsilyl chloride) (420 mg, 1.04 mmol) and 3-bromo-5-(4,4-dimethyl-cyclohex-1-enyl)-thiophene-2-carboxylic acid methyl ester (350 mg, 1.06 mmol) in dioxane (3.5 mL) containing CS2CO3 (1 g, 3.07 mmol) and Pd2(dba)3 (96 mg, 0.1 mmol) for 6 min. 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (105 mg, 0.17 mmol) was added and the mixture was stirred at 80° C. for 24 h. It was diluted with DCM, filtered through celite and evaporated. 5-(4,4-Dimethyl-cyclohex-1-enyl)-3-(2-triisopropylsilanyloxy-1-triisopropylsilanyloxymethyl-ethylamino)-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc-95:5) (500 mg, 72%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:20][CH:21]=1)#[CH:15]>CCO>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:21]=[N:20][C:19]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:18][CH:17]=2)[N:3]=[N:2]1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#Cc1ccc(CN2CCOCC2)nc1
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(CN3CCOCC3)nc2)nn1
Temperature: 140 °C
Yield: 80 %

Procedure:
A suspension of 87.5 mg (0.494 mmol) of 3-azido-4-methyl-benzoic acid and 100 mg (0.494 mmol) of 4-(5-ethynyl-pyridin-2-ylmethyl)-morpholine were suspended in 200 μL of EtOH and heated to 140° C. for 1 h in a microwave reactor. After cooling, the mixture was concentrated to provide 150 mg of 4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid, and its triazole isomer 4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid in a 2:1 ratio