Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CN(C=O)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([Br:4])=[CH:6][CH:7]=1)[CH3:3]
Reactant: CNC
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2M Ethanolic dimethylamine solution (30 ml) was added to a solution of 4-bromobenzyl bromide (5 g) in DMF (20 ml). The mixture was stirred at ambient temperature for 18 h and was then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, evaporated and purified by column chromatography, eluting with a gradient of 0 to 5% methanol in DCM to yield the product as a clear oil. MS (M+H)+ 214. 1H NMR (CDCl3) 2.21 (s, 6H), 3.35 (s, 2H), 7.18 (d, 2H), 7.43 (d, 2H).
Reaction SMILES: C([O:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2sc(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2sc(C)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Ethyl 7-(acetyloxy)-2-methyl-1-benzothiophene-5-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was crystallized from ether/hexane mixture (1:5) to give the desired product 10 g (42 mmol, 84%) as a cream solid. 1H NMR (DMSO-d6): δ ppm 1.30 (t, 3H), 2.50 (s, 3H), 4.30 (qt, 2H), 7.20 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H); MS (APCI, pos): 237.1.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[C:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CCO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: C=CC(=O)Nc1c(C(=O)NCC)noc1-c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCO
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1NC(=O)CCN1CCOCC1

Procedure:
A solution of 4-acryloylamino-5-(2,4-bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide as described in example 7 (step viii), (170 mg, 0.32 mmol) and morpholine (1 ml) in EtOH (5 ml) was heated under reflux for 1 h.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.Cl[CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1.O>CO>[C:15]1([N:14]2[C:13](=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]2[S:4][CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccnc(CSc2nc3ccccc3c(=O)n2-c2ccccc2)c1
Reaction time: 5 h
Yield: 30.7 %

Procedure:
8.7 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethyl-4-methylpyridine hydrochloride in methanol, and the stirring was continued at room temperature for 5 hours. The reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous solution of sodium carbonate and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with 8% ethyl acetate in chloroform was collected and crystallized from ethyl acetate to give 2.17 g (30.7%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:21][CH2:22][CH2:23][CH3:24])[CH2:19][CH3:20]>>[CH2:18]([N:21]([CH2:22][CH2:23][CH3:24])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH3:20]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Each of two samples of the treated 1-chloro-2,6-dinitro-4-(trifluoromethyl)benzene was reacted with di-n-propylamine, yielding N,N-di-n-propyl-2,6-dinitro-4-(trifluoromethyl)aniline. Each product was analyzed for N-nitroso-N,N-di-n-propylamine by each of three different analytical laboratories (twice, in the GC-TEA method). The results were as follows.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:19])=O>C(#N)C.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5]([Cl:19])=[O:6]
Reactant: CON=C(C(=O)O)c1cc2sccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CON=C(C(=O)Cl)c1cc2sccc2s1

Procedure:
A solution of 400 mg of α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetic acid in 50 ml of acetonitrile containing 15 ml of oxalyl chloride and two drops of N,N-dimethylformamide was stirred at 0° C. for two hours. The reaction mixture was concentrated to dryness by evaporation under reduced pressure to provide α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetyl chloride as an oil. The oil was dissolved in 10 ml of fresh acetonitrile and added to a stirred acetonitrile solution of 707 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid silylated with 2.56 g of bis(trimethylsilyl)trifluoroacetamide (BSTFA). The reaction mixture was stirred at 25° C. for sixteen hours. The reaction mixture was concentrated to dryness to provide an oil which was sonicated for fifteen minutes with 300 ml of saturated aqueous sodium bicarbonate. The mixture was acidified to pH 2.3 by addition of 1N hydrochloric acid. The acid layer was extracted several times with ethyl acetate, and the combined extracts were dried and the solvent was removed by evaporation to provide 970 mg of 7-α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br.C1(O)C=CC=CC=1>ClCCl>[C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Br
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
A mixture containing 3-(S)-(+)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (49 g--see Preparation 6(B)), 48% aqueous hydrobromic acid (500 ml) and phenol (50 g) was heated under reflux for 1.25 hours then allowed to cool to room temperature. The mixture was extracted with ether (50 ml) to remove an upper layer of purple oil, then with 2:1 ether/hexane (150 ml). The aqueous layer was extracted with dichloromethane (4×100 ml), the dichloromethane extracts were combined, washed with 10% aqueous sodium hydroxide (3×50 ml), then dried (MgSO4) and concentrated in vacuo to give an oil. The original ether extract was concentrated in vacuo to give an oil which was dissolved in dichloromethane (100 ml) and washed with 10% aqueous sodium hydroxide (3×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was combined with that obtained from the initial dichloromethane extraction. The combined oils were then dissolved in dichloromethane (200 ml) and washed with 10% aqueous sodium hydroxide solution (2×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 24.3 g, [α]D25 +6.0° (c 1.0, CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)=[O:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30]([C:29]2[CH:33]=[CH:34][C:26]([C:24]([NH:23][C:20]3[CH:21]=[N:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:25])=[N:27][CH:28]=2)=[O:31])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COc1ccc(NC(=O)c2ccc(C(=O)O)cn2)cn1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. Crude methyl 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 196 mg of 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid via Procedure G. The crude product was recrystallized to yield pure N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(6-methoxypyridin-3-yl)pyridine-2,5-dicarboxamide. MS (Q1) 460 (M)+.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:2]1=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:27][CH2:28][C:29](=[O:31])[CH3:30]>>[O:31]=[C:29]([CH3:30])[CH2:28][CH2:27][O:13][C:12]([C:4]1[C:2](=[O:3])[O:1][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:14]
Reactant: CC(=O)CCO
Reactant: O=C(O)c1cc2ccccc2oc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CCOC(=O)c1cc2ccccc2oc1=O

Procedure:
Coumarin-3-carboxylic acid (25.0 g, 131 mmol) is dissolved into 100 mL of 4-hydroxy-2-butanone with ˜0.050 g of para-toluene sulfonic acid in a round bottom flask equipped with a stir bar and condenser packed with molecular sieves. The pressure is reduced to ˜15 mmHg and the system is refluxed for 10 hours. The solvents are removed by rotary evaporation. The solid organic residue is purified by column chromatography using 3:1 ethyl acetate:hexanes to yield 2-oxo-2H-chromene-3-carboxylic acid 3-oxo-butyl ester.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[S:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[S:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cccc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 52.2 %

Procedure:
3-Trifluoromethylphenylboronic acid (62.7 mg, 0.33 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (44.6 mg, 0.11 mmol) was reacted using Pd(PPh3)2Cl2 (10.5 mg, 0.015 mmol), Cs2CO3 (143.4 mg, 0.44 mmol) as described above to give the title compound (29 mg, 44%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7]Br.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OCCBr)cc1Cl
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc(CNCCOc2ccc(Cl)c(Cl)c2)cc1

Procedure:
2.70 Grams (10.0 mmol) of 2-(3,4dichlorophenoxy)ethyl bromide was dissolvedin 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 4-chlorobenzylamine. The mixture was heated and refluxed on an oil bath for 7 hours. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].Cl[CH2:58][O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:58][O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: ClCOCc1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 2 ml methylene chloride) was added disopropylethylamine (99.4 μl) followed by benzyl chloromethyl ether (34.2 μl neat) and the mixture stirred at room temperature. After 24 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (92 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47](Cl)[C:42]=3[CH:41]=2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47]([O:11][C:4]4[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=4)[C:42]=3[CH:41]=2)=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: CN1CCCC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ncnc21
Temperature: 130 °C
Reaction time: 24 h
Yield: 76.5 %

Procedure:
After adding 248 mg of 3-fluoro-4-nitrophenol, 0.208 ml of 2,6-lutidine and 1 ml of N-methylpyrrolidine to 490 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 130° C. for 24 hours. After returning it to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (ethyl acetate) to obtain 472 mg of the title compound.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]2)[CH2:13][C@H:12]1[NH:28]C(OCCCC)=O>C1(C)C(C)=CC=CC=1.[C].[Pd]>[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:13][C@H:12]1[NH2:28]
Reactant: CCCCOC(=O)N[C@@H]1CN(C2C=CCCC2)c2ccccc2NC1=O
Agent: [Pd]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Product: N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Nitrobenzene (22.16 g) and 10% palladium carbon (6 g) were added to a solution of (3R)-2-oxo-3-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (12.87 g) in xylene (200 ml), the mixture was refluxed for one hour and 30 minutes. The reaction mixture was allowed to cool, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (30 ml), 4N HCl-dioxane (20 ml) was added, the resultant mixture was stirred at 50° C. for one hour. After allowed to cool, crystals so precipitated were collected by filtration, the crystals were washed with 2-propanol, to thereby obtain hydrochloride of the title compound. The compound was dissolved under heating in the mixed solvent of methanol and water, allowed to cool, saturated sodium bicarbonate was added for neutralization, crystals so precipitated were collected be filtration, the crystals were washed with water and dried, to thereby obtain 5.55 g of the title compound (Yield: 86%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccccc1B(O)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: COCCOC
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C=O)cc1
Temperature: 85 °C
Yield: 91.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (218 mg, 1.18 mmol) and 2-methoxybenzeneboronic acid (188 mg, 1.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (1.6 mL) and Pd(PPh3)4 (63 mg, 0.055 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. overnight. The mixture was then cooled and diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography with silica gel (Hexanes/Et2O, 80:20) afforded the title compound (230 mg, 92%) as a clear oil. 1H NMR (CDCl3) δ 3.84 (s, 3H), 7.01–7.09 (m, 2H), 7.33–7.39 (m, 2H), 7.71 (d, 2H, J=6 Hz), 7.93 (d, 2H, J=6 Hz), 10.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:15]1.C(O)(C(F)(F)F)=O>>[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]3[C:7]4[NH:6][C:5]5[C:12](=[CH:13][C:2]([F:1])=[CH:3][CH:4]=5)[C:8]=4[CH2:9][CH2:10][NH:11]3)=[CH:17][C:16]=2[O:15]1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c3c(c2c1)CCNC3c1ccc2c(c1)OCO2
Yield: 84.7 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL, 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([OH:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:38].[N:39]1([CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:38].[CH3:37][C:2]1([CH3:1])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([O:30][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-eicosyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[C:50]2[C:41]=1[O:42][C:43]1[C:44]([CH2:60][C:61]([O:63][CH3:64])=[O:62])=[C:45]([O:58][CH3:59])[CH:46]=[CH:47][C:48]=1[C:49]2([CH3:57])[CH3:56])=[O:37])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[C@@H:18]([CH3:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])[CH3:13])=O)C1C=CC=CC=1>O1CCOCC1.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[C:50]2[C:41]=1[O:42][C:43]1[C:44]([CH2:60][C:61]([O:63][CH3:64])=[O:62])=[C:45]([O:58][CH3:59])[CH:46]=[CH:47][C:48]=1[C:49]2([CH3:57])[CH3:56])=[O:37])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[C@@H:18]([CH3:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:15])[CH3:13]
Reactant: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C)C2(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)OC(C)(C)C)C(C)C)C2(C)C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
A solution of 70 mg of methyl 5-[(N-benzyloxycarbonyl-L-alanyl-O-tert-butyl-L-threonyl-L-valyl-glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate in 20 ml of dioxan was treated with 47 mg of palladium/charcoal (10%) and stirred under hydrogen for 19 hours. After filtering off the catalyst the filtrate was concentrated, whereby 59 mg of colourless methyl 5-[(L-alanyl-O-tert-butyl-L-threonyl-L-valyl-glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate was obtained; IR 3300, 2970, 1741, 1680, 1658, 1631, 1523, 1494 cm-1.