Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C1(P(=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:34][C:35]([O:37][CH3:38])=[O:36])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1NC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1ccc(NC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a solution of 4-acetamido-3-methoxybenzaldehyde (388 mg) in tetrahydrofuran (10 ml) was added methyl (triphenylphosphoranylidene)acetate (739 mg), and the mixture was stirred for 2 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1, V/V) to give methyl 4-acetamido-3-methoxycinnamate (113 mg).
Reaction SMILES: C([O:4][C@@H:5]([C@:19]12[CH2:54][C:53](=[O:55])[C:52]([CH:56]([CH3:58])[CH3:57])=[C:20]1[C@@H:21]1[C@@:34]([CH3:37])([CH2:35][CH2:36]2)[C@@:33]2([CH3:38])[C@@H:24]([C@:25]3([CH3:51])[C@@H:30]([CH2:31][CH2:32]2)[C:29]([CH3:40])([CH3:39])[C@@H:28]([O:41][C:42](=[O:50])[CH2:43][C:44]([CH3:49])([CH3:48])[C:45]([OH:47])=[O:46])[CH2:27][CH2:26]3)[CH2:23][CH2:22]1)[CH2:6][N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(=O)C.[OH-].[K+].Cl>C(O)C.C1(C)C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]([CH2:6][C@H:5]([C@:19]23[CH2:54][C:53](=[O:55])[C:52]([CH:56]([CH3:57])[CH3:58])=[C:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:39])([CH3:40])[C@@H:28]([O:41][C:42](=[O:50])[CH2:43][C:44]([CH3:48])([CH3:49])[C:45]([OH:47])=[O:46])[CH2:27][CH2:26]4)[CH2:23][CH2:22]2)[OH:4])[C:8](=[O:10])[CH3:9])=[CH:17][CH:16]=1
Reactant: CC(=O)O[C@H](CN(Cc1ccc(Cl)cc1)C(C)=O)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N(Cc1ccc(Cl)cc1)C[C@@H](O)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-(N-(4-chlorobenzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (72) (150 mg, 0.182 mmol) in ethanol (2 mL) and toluene (2 mL) was added potassium hydroxide (40.9 mg, 0.729 mmol). The reaction mixture was stirred at rt for min. The reaction mixture was neutralized with aqueous 1 N HCl to pH=7 and concentrated to obtain a residue. The residue was extracted with DCM, washed with water and dried to yield the crude product which was purified by preparative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(4-chlorobenzyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (73) (40 mg, 28%) as a white solid. Compound exists as a mixture of rotomers; 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 7.52-7.14 (m, 4H), 5.03-3.77 (m, 5H), 3.39-2.80 (m, 3H), 2.62-2.54 (m, 1H), 2.27 (t, J=17.2 Hz, 1H), 2.20-0.58 (m, 51H);
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]CN.C(O)(=O)C.C([BH3-])#[N:26].[Na+]>C(O)C>[CH3:16][O:17][CH2:18][C:14]1[CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:10][C:11]=1[CH2:12][NH2:26]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: [BH3-]C#N
Reactant: COCCN
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COCc1cc(Oc2ccccc2)ccc1CN
Reaction time: 1 h

Procedure:
A mixture of 4-phenoxybenzaldehyde (1.98 g, 10 mmol) and 2-methoxyethylamine (0.751 g, 10 mmol) in ethanol (10 mL) was stirred for 1 hour. Acetic acid (1 mL) and sodium cyanoborohydride (1M in THF, 10 mL) were added, and the reaction was stirred for 14 hours. The reaction was then partitioned between ether and 10% aqueous sodium hydroxide solution. The organic layer was further washed with water and brine, dried over anhydrous potassium carbonate, filtered and concentrated. The title compound was pure as judged by NMR and was used for next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 4 H), 7.09 (t, 1 H), 6.98 (m, 4 H), 3.80 (s, 2 H), 3.51 (t, 2 H), 3.37 (s, 3 H), 2.51 (t, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:11][CH2:12][CH3:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a −78° C. solution of 4-bromo-2-fluorobenzaldehyde (600 mg, 3 mmol) in tetrahydrofuran (10 mL) was added n-propylmagnesium chloride (2.22 mL, 4.43 mmol) dropwise over 20 minutes. The reaction was warmed to 0° C. and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), dried over sodium sulfate, filtered, and concentrated. Purification by preparatory thin layer chromatography gave (+/−)-1-(4-bromo-2-fluorophenyl)butan-1-ol (440 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.26-7.30 (m, 1H), 7.21 (d, J=8.0 Hz 1H), 7.13 (d, J=8.0 Hz, 1H), 4.90 (t, J=5.6 Hz, 1H), 1.53-1.79 (m, 2H), 1.30-1.45 (m, 2H), 0.85 (s, J=5.6 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH3:30][C@H:31]1[CH2:36][O:35][CH2:34][CH2:33][NH:32]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][O:35][CH2:36][C@@H:31]2[CH3:30])=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: C[C@H]1COCCN1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOC[C@@H]2C)c1OCCC(C)c1ccc(F)cc1
Yield: 65 %

Procedure:
Example 8a (74 mg, 0.16 mmol) was reacted with (S)-3-methylmorpholine (3.0 eq.) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 1:4) to afford the title compound as a pale yellow oil (51 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.79-3.57 (m, 4H), 3.22 (dd, J=8.7, 11.1 Hz, 1H), 3.12-2.88 (m, 2H), 2.74 (m, 1H), 2.55-2.35 (m, 6H), 2.18 (s, 3H), 2.07-1.96 (m, 2H), 1.29 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H). MS (ES+) m/z 508.2 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH:21]1([NH:24][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=2)(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC2CC2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of fuming nitric acid (8 mL) and conc. H2SO4 (16 mL), was added 4-fluorobenzenesulfonyl chloride (1.3 g, 6.7 mmol) in small portions. The mixture was stirred at RT for 2 h. and then poured onto crushed ice (60 g) and extracted with dichloromethane (2×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH2Cl2 (30 mL) cooled to −40° C. and cyclopropylamine (388 mg, 6.8 mmol), followed by DIPEA (8 mmol) were added. After stirring at −40° C. for 2 h, the mixture was poured on 5% citric acid solution and extracted with dichloromethane. The organic layer was separated, and passed through a short pad of silica gel and concentrated in vacuo to afford N-cyclopropyl-4-fluoro-3-nitrobenzenesulfonamide (1.6 g, 92%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:18])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(C)c1nccc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(C)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[butyl(methyl)amino]isoquinoline-7-carboxylic acid (130 mg, 0.5 mmol) and N,N-diisopropylethylamine (525 μL, 3.0 mmol) in methylene chloride (6.25 mL) was added HBTU (190 mg, 0.5 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (174 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1–5% methanol in chloroform) gave 1-[butyl(methyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].[C:16]([O:20][C:21](=[O:34])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH:30](Cl)[CH:31]=O)[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:30]([CH2:29][C:25]4[CH:24]=[C:23]([NH:22][C:21](=[O:34])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:28]=[CH:27][CH:26]=4)=[CH:31][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC(Cl)C=O)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (19 mg, 0.070 mmol) and tert-butyl[3-(2-chloro-3-oxopropyl)phenyl]carbamate (20 mg, 0.070 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=498.0/500.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:8]([O:7][C:5]([CH2:4][CH2:3][CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 73.8 %

Procedure:
First, 19.6 g of ethyl 4-bromobutyrate, 24.4 g of triphenylphosphine, and 70 ml of toluene were placed in a 200 ml flask. The mixture was stirred under reflux for 10 hours. After the mixture was cooled, produced crystal was recovered by filtration and washed with toluene to obtain 31.4 g of 3-ethoxycarbonylpropyltriphenylphosphonium bromide (Y: 68%). The compound thus obtained had an m.p. of 173° C. to 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccccc1Cl)c1nnc(N)s1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser was charged with 10.0 grams (0.050 mole) of 2-(2-chlorophenoxy)propanoic acid, (4.6 grams, 0.050 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (8.4 grams, 0.055 mole) was slowly added (for 25 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for 75 minutes and stood at ambient temperature for 16 hours. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane) at 60° C. and then the solution was cooled. Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off, washed with water, then dried in a vacuum oven at 80° C. to 9.8 grams of white crystals of 5-[1-(2-chlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 160°-164° C.).
Reaction SMILES: [N+:1]([CH:4](O)[CH3:5])([O-:3])=[O:2].[C:7]([OH:10])(=[O:9])[CH3:8].C1C=CC=CC=1>OS(O)(=O)=O.O>[N+:1]([CH2:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: CC(O)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)OCC[N+](=O)[O-]

Procedure:
64 g nitroethanol, 50 ml glacial acetic acid, 250 ml benzene and 5 drops conc. H2SO4 were refluxed, using a water separator for 8 hours; 12 ml of H2O were collected. The solution was evaporated and vacuum distilled (1mm at 60° C) yielding 89 g colorless nitroethylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([C:9](=[O:11])[CH3:10])=[CH:8][C:4]=2[CH:3]=1.Cl[C:15]1[C:16](=[O:34])[N:17]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[C:9]([C:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([NH:1][C:15]3[C:16](=[O:34])[N:17]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:18](=[O:26])[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:4]=2[CH:8]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cc2cc(NC3=C(c4ccccc4)C(=O)N(Cc4cccnc4)C3=O)ccc2o1
Temperature: 130 °C
Yield: 7.3 %

Procedure:
1-(5-Aminobenzo[b]furan-2-yl)ethan-1-one (0.94 mmol, 164 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min. 0.3 mL water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 15 mg (7%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.64 (d, 1H), 8.52 (dd, 1H), 8.01 (bs, 1H), 7.80-7.75 (m, 1H), 7.35 (dd, 1H), 7.31-7.23 (m, 2H), 7.08-6.93 (m, 7H), 4.77 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:3]=2)[CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(-c3ccccc3)ccc2c1

Procedure:
The title compound was prepared by reacting 2-bromo-6-methoxynaphthalene (1.97 g, 8.31 mmol) with phenylmagnesium bromide according to the method used to prepare intermedite 10 to yield 1.59 g (82%) of a white solid: mp 122-126° C.; 1H NMR (CDCl3): δ 3.94 (3H, s), 7.16-7.18 (2H, m), 7.34-7.37 (1H, m), 7.46-7.49 (2H, m), 7.69-7.72 (2H, m), 7.78-7.82 (2H, m), 7.97 (1H, s); MS (EI) m/z 234.2 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methylpyridine (example E.32) (0.075 g, 0.20 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.051 g, 0.2 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 45%). MS (ISP) 373.2 [(M+H)+] and 375 [(M+2+H)+]; mp 197-199° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13]N)=[N:11][CH:12]=1>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:13][C:10]2=[N:11][CH:12]=1
Reactant: CCC(C)=O
Reactant: NNc1ccc(Br)cn1
Solvent: CCO
Product: Cc1[nH]c2ncc(Br)cc2c1C

Procedure:
2-Butanone (715 μl) was added to a solution of 5-bromo-2-hydrazinopyridine (1000 mg) in ethanol (10 ml), and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. Diethylene glycol (10 ml) was added and the mixture was heated under reflux for 23 hours. The reaction solution was concentrated under reduced pressure and separated by adding dichloromethane and distilled water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (104 mg).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1CC[CH2:15][C@H:11]1[C:12](O)=O.CC(C)=O>CCO>[CH3:15][C:11]1[CH:12]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1ncccc1C=O
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc2cccnc2n1
Reaction time: 8 h
Yield: 887.8 %

Procedure:
To a suspension of 2-aminonicotinaldehyde (732 mg, 6 mmol) and L-proline (69 mg, 0.6 mmol) in EtOH (15 mL) was added acetone (1.74 g, 30 mmol). Then the mixture was heated at reflux and stirred for 8 h. The resulting mixture was concentrated under reduced pressure to give a residue, which was washed with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 2-methyl-1,8-naphthyridine as a yellow solid (768 mg). MS (ESI): m/z 145 [M+H]+. See e.g., Bioorg. Med. Chem. Lett., 2005, 15, 2679-84.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]=[CH:23][O:22]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][CH2:20][C@@H:21]2[O:22][C@@H:23]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:24][CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(COCC2CCC=CO2)cc1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(COC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 69.2 %

Procedure:
102 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and the 82 mg of 2-(4-chlorobenzyloxymethyl)-3,4-dihydro-2H-pyran prepared above were then dissolved in 2 ml of diethyl ether, and one drop of phosphorus oxytrichloride was then added. The mixture was then allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 121 mg of trans-6-(4-chlorobenzyloxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CBr
Yield: 49.3 %

Procedure:
5.34 g (30 millimoles) of methyl 2-methylphenylglyoxylate and 5.34 g (30 millimoles) of N-bromosuccinimide in 1,000 1 of tetrachloromethane are exposed for one hour to a 300 W Hg vapor lamp. Thereafter, the organic phase is washed once with water and three times with sodium bicarbonate solution and dried over sodium sulfate/sodium carbonate. After the organic phase has been evaporated down, the crude product is chromatographed over silica gel using 1:9 methyl tert-butyl ether/n-hexane. 3.8 g (49%) of the abovementioned compound are obtained as a yellow oil. 1H-NMR (CDCl3): δ=3.97 (s, 3H); 4.90 (s, 2H); 7.4-7.8 (m, 4H)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:17][O:16][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:9]([CH:8]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OCCCBr)c(OC)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCBr)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 931.3 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.2 g (33.0 mmol) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate (purity: 98%) obtained in Example II-16, 0.23 g (3.30 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 13.8 g (132.0 mmol) of nitric acid (60 wt. %), and the mixture was heated at 40-50° C. for 5 hours. After the reaction was complete, 30 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 10.7 g (isolated yield: 92.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(3-bromopropoxy)-2-nitrobenzoate as a white crystalline product.