Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][C:19]1[CH:65]=[CH:64][C:22]([O:23][CH2:24][C@@H:25]([OH:63])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:62]=[CH:61][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[O:53])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:55]([NH:54][C:52](=[O:53])[NH:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:61]=[CH:62][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:63])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:65][CH:64]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])=[CH:50][CH:49]=1)[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 75.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)aniiino]-N-(4-{[(hexylamino)carbonyl]amino}benzyl)-1-piperidinecarboxamide (0.143 g, 0.159 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.077 g, 0.12 mmol).
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])#[N:2].O.OO.C(=O)([O-])[O-:24].[K+].[K+]>CS(C)=O>[C:1]([C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])(=[O:24])[NH2:2]
Reactant: CC(C)ON=C(C#N)C(=NOC(C)C)n1cncn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)ON=C(C(N)=O)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To 2 ml of a dimethyl sulfoxide solution containing 4.0 g (15.1 mmol) of 1-(2-cyano-1,2-diisopropoxyiminoethyl)-1H-1,2,4-triazole were added, with ice-cooling, 3.5 ml of hydrogen peroxide water and 2.30 g (16.6 mmol) of potassium carbonate, followed by stirring at room temperature for 10 hours. The resulting crystal was washed with water and isopropyl ether in this order, to obtain 3.28 g (yield: 77%) of a title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@@H](CC(=O)O)c1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2ccccc2F)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 150 °C
Yield: 91 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-(2-fluoro-phenyl)-propionic acid (86 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1800) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 91% yield. LC-MS ESI+: 472 (M+1)+; ESI−: 470 (M−1)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15](N(C)OC)=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([CH:15]=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N[C@@H](CC1CCCCC1)C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N[C@H](C=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To 57 mg (200 μmole) (16) was added 1.8 mL of dry THF, and the solution was cooled to 0° C. Then 9.5 mg of lithium aluminum hydride (250 μmole, 1.25 eq H-) was added, and the reaction was monitored by TLC. After 45 min the reaction was quenched with ca. 20 mL ethyl acetate and the solution stirred for 40 min. The organic layer was washed 1× with 5% citric acid and 1× with 5% NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated. The residue was pumped on high vacuum overnight to give the title compound. NMR (300 MHz, CDCl3): δ 9.52 (s, CHO, 1H), 4.27 (br m, Cha-α, 1H), 4.04 (q, CH3CH2OCO, 2H), 1.80-0.80 (m, cHxCH2, 13H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[C:3]([F:9])=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: Nc1cccc(Br)c1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(C2CC2)c1F
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-2-fluoroaniline (200 mg, 1.05 mmol), cyclopropylboronic acid (118 mg, 1.37 mmol), potassium phosphate (782 mg, 3.68 mmol), and tricyclohexylphosphine (29.5 mg, 0.105 mmol) in toluene (2.4 mL) and water (120 μL) was added Pd(OAc)2 (11.8 mg, 0.05 mmol). The reaction mixture was degassed by repeating alternating application of vacuum and positive nitrogen pressure (3×), and then heated at 100° C. under nitrogen overnight. The mixture was cooled to RT, diluted with water, and extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 93-7). TLC, Rf hexane/EtOAc 2:1)=0.7; MS (UPLC/MS): 152.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:27][CH2:28][CH3:29])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[CH:8]=1)[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Yield: 93 %

Procedure:
2-Ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylic acid ethyl ester (3.69 g; 8.50 mmole) was hydrogenated for 3.5 hours at atmospheric pressure in ethyl acetate (70 ml) and acetic acid (0.5 ml) using Pd/C as catalyst and then filtered through hyflo. The solvent was evaporated in vacuo, dichloromethane and water were added and the phases were separated. The organic phase was dried (sodium sulfate), filtered and evaporated in vacuo to give 3.45 g (yield 93%) of 2-ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:5]=1[F:20].[Li+].[OH-]>O1CCOCC1>[F:20][C:5]1[C:6]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:7][C:8]([C:10]([F:13])([F:11])[F:12])=[CH:9][C:4]=1[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoro-3-(2-oxopyrrolidin-1-yl)-5-trifluoromethylbenzoic acid methyl ester (D24) in dioxane (10 ml) was treated with 1M LiOH solution (1.75 ml) and stirred at room temperature for 2 h. The dioxane was then removed under vacuum and dil. NaHCO3 and ethyl acetate were added. The aqueous phase was separated, washed with ethyl acetate, acidified with 1M HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and evaporated to dryness to afford the title compound
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].ClCCNC(N)=O.CO>O1CCCC1.O>[CH3:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:5]1[O:6][CH2:2][CH2:3][N:4]=1
Reactant: Cc1cccc(N)c1C
Reactant: O=C=NCCCl
Agent: NC(=O)NCCCl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(NC2=NCCO2)c1C
Temperature: 25 °C
Yield: 22.3 %

Procedure:
Chloroethylisocyanate (Compound 5, Aldrich, 346 mg, 3.3 mmol) was added to a stirred solution of 2,3-dimethylaniline (Aldrich, 400 mg, 3.3 mmol) in tetrahydrofuran (5 ml) at room temperature. After 30 minutes a white precipitate formed. The solid chloroethylurea was collected by vacuum filtration, yield: 477 mg (64%): mp 145°-146° C. 1HNMR (300 MHz, CDCl3) & 7.00 (m, 3H); 6.72 (br, 1H); 5.19 (br, 1H), 3.59 (m, 2H); 3.49 (m, 2H); 2.30 (s, 3H); 2.18 (s, 3H); Mass spectrum m/e 226.0872 (C11H15ClN2O requires 226 0872). The chlorethylurea (199 mg, 0.88 mmol) was suspended in H2O (4 ml) and CH3OH (4 ml) and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with IN NaOH (to pH 13). The organic layer was dried over Na2CO3 and concentrated in vacuo to yield 140 mg (84%) of the title compound as a white crystalline solid: mp 112°-113.5° C.; 1H NMR (300 MHz, CDCl3) & 7.19 (m, 1H); 7.09 (m, 1H), 6.91 (m, 1H); 5.00 (br s, 1H); 4.40 (t, 2H); 3.70 (t, 2H); 2.30 (s, 3H); 2.15 (s, 3H); Mass spectrum m/e 190.1104 (C11H14N2O requires 190.1106).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)N1CCCC1
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:35][CH:32]1[CH2:34][CH2:33]1)=[O:13]
Reactant: NC1CC1
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)NC3CC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and cyclopropylamine (44 mg, 0.7719 mmol) were dissolved in methylene chloride (5 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (146 mg, 0.7616 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]cyclopropylamine (71 mg, 0.1536 mmol, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[C:13]1=[O:29].O1CCOCC1.[OH-].[Na+]>O>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[C:13]1=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CC(=O)O)c1=O
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
The crude product solution of diethyl [1-(2,6-dimethyl-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]malonate in dioxane (maximum 108 mmol) was introduced as initial charge in 350 ml of water, and 35 ml of concentrated sodium hydroxide solution were slowly added. The reaction mixture was stirred for 90 min at 45° C. After cooling to RT, 100 ml of water were added, followed by washing three times with dichloromethane, and the aqueous phase (pH=14) was admixed with 270 ml of dichloromethane. At 10-15° C., 59.5 ml of concentrated hydrochloric acid were slowly added until the pH=1. Even at a weakly acidic pH, carbon dioxide started to evolve. The reaction mixture was warmed to RT and stirred for 1 h, until the gas stopped evolving. Following phase separation, the organic phase was dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was stirred with 200 ml of methyl tert-butyl ether for 30 min. The crystalline solid was filtered off with suction, washed with methyl tert-butyl ether and dried in vacuo. 14.8 g (47% over 2 stages) of the desired product were obtained. The mother liquor was largely concentrated, the post-precipitation was filtered off with suction, after-washed and dried in vacuo. A further 5.3 g (17% over 2 stages) of the desired product were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])C1C=CC=CC=1.C(O)=O>CCOC(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:13]1[C:12](=[O:37])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:19]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24]2)[C:14]1=[O:25]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCSCC3)c2=O)cc1OC

Procedure:
A mixture of 0.200 g of the compound obtained in Step 3.2, and 1.22 g of formic acid is irradiated in a microwave field for 2 minutes at 180° C. The reaction mixture is taken up in EtOAc and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a CH2Cl2/MeOH mixture from (100/0, v/v) to (97/3, v/v) to give the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: N#CCc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#CCc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of 4-aminobenzyl cyanide (7.5 g, 56.7 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (11.4 g, 4.98 mL, 56.7 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 10.5 g (95%) of the title compound as a pale-orange solid, mp 127°-135° C. (decomp): 1H NMR (DMSO-d6) δ10.45 (s, 1H), 7.59 (d, J=9.2, 2H), 7.31 (d, J=9.2, 2H), 4.03 (s, 2H), 3.98 (s, 2H); 13C NMR (DMSO-d6) δ164.83, 137.98, 128.60, 126.42, 119.61, 119.26, 30.31, 21.81; MS (EI, m/z) 252 (M+).
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]\1=O.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=1>CCO>[CH2:12]([O:11][C:8]1[C:9]2[N:23]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[N:22]=[CH:3][C:4]=2[CH2:5][CH2:6][CH:7]=1)[CH3:13]
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CCOC1=CCC/C(=C\N(C)C)C1=O
Solvent: CCO
Product: CCOC1=CCCc2cnc(-c3ccc(OC)cc3)nc21

Procedure:
6-[1-Dimethylamino-meth-(E)-ylidene]-2-ethoxy-cyclohex-2-enone (WO 2004/104007) (1 g; 5 mmol) and 4-methoxybenzamidine (0.92 g; 6.1 mmol) are refluxed in EtOH (20 ml) for 14 hours. The reaction mixture is evaporated to dryness, taken up in CH2Cl2 and purified via chromatography (SiO2; acetone/hexanes 5:95) to yield the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 8.58 (s, 1H); 8.31 (d, 2H); 7.07 (d, 2H); 5.64 (t, 1H); 3.93 (q, 2H); 3.84 (s, 3H); 2.78 (t, 2H); 2.40 (m, 2H); 1.40 (t, 3H). MS (m/z) ES+: 283 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=O.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>[Cl-].[Na+].O>[CH3:13][O:12][C:11]1[C:10]([N+:22]([O-:24])=[O:23])=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:14](=[O:15])[O:16][C:7]2=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c([N+](=O)[O-])c1OC)C(=O)OC2=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4,5-Dimethoxy-phthalic acid (1.0 g) was cooled in ice-water bath. A cooled mixture of sulfuric acid (3.0 ml) and fuming nitric acid (3.0 ml) was added dropwise. The mixture was stirred for 10 minutes and left standing for 10 minutes. A mixture of brine and ice was added (1:1). The solid was filtered off, washed with water and recrystallized from ethanol.
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OCC3C=CC=CC=3)=O)=C(OS(C(F)(F)F)(=O)=O)CC[C@H]12.C(N(CC)CC)C.C1(C([NH:55][C:56]2[S:57][CH:58]=[C:59]([C:61](=[N:92][O:93][CH3:94])[C:62]([NH:64][C@@H:65]3[C:90](=[O:91])[N:67]4[C:68]([C:80]([O:82]CC5C=CC=CC=5)=[O:81])=[C:69]([O:72][S:73]([C:76]([F:79])([F:78])[F:77])(=[O:75])=[O:74])[CH2:70][CH2:71][C@H:66]34)=[O:63])[N:60]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(#N)C>[NH2:55][C:56]1[S:57][CH:58]=[C:59]([C:61](=[N:92][O:93][CH3:94])[C:62]([NH:64][C@@H:65]2[C:90](=[O:91])[N:67]3[C:68]([C:80]([OH:82])=[O:81])=[C:69]([O:72][S:73]([C:76]([F:78])([F:77])[F:79])(=[O:74])=[O:75])[CH2:70][CH2:71][C@H:66]23)=[O:63])[N:60]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(N)n1

Procedure:
syn-2-(2-Triphenylmethylthiazol-4-yl)-2-methoxyiminoacetyl chloride is reacted in acetonitrile with benzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate in the presence of triethylamine and the acylation product, benzyl 7β-[2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is treated with formic acid to remove the triphenylmethyl group and with aluminum chloride in anisole to remove the benzyl ester group to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]([O:5][C@H:6]1[C@@H:11]2[C:12]([CH2:15]OC(=O)C(C)(C)C)=[CH:13][CH2:14][C@@H:10]2[C:9]([C:23]([O:25][CH3:26])=[O:24])=[CH:8][O:7]1)=[O:4].C([O-])=O.[NH4+]>O1CCCC1.[C].[Pd]>[CH3:15][C:12]1[C@H:11]2[C@H:6]([O:5][C:3](=[O:4])[C:2]([CH3:28])([CH3:27])[CH3:1])[O:7][CH:8]=[C:9]([C:23]([O:25][CH3:26])=[O:24])[C@H:10]2[CH2:14][CH:13]=1
Reactant: COC(=O)C1=CO[C@@H](OC(=O)C(C)(C)C)[C@@H]2C(COC(=O)C(C)(C)C)=CC[C@H]12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1=CO[C@@H](OC(=O)C(C)(C)C)[C@@H]2C(C)=CC[C@H]12
Temperature: 80 °C
Yield: 76.3 %

Procedure:
Methyl (1S, 4aS, 7aS)-1, 4a, 5, 7a-tetrahydro-1-trimethylacetoxy-7-(trimethylacetoxymethyl)cyclopenta[c]-pyran-4-carboxylate (200 mg, 0.00051 mol) obtained in Example 14 was dissolved in 15 ml of tetrahydrofuran, and 10% palladium carbon (10 mg) was suspended. After ammonium formate (320 mg, 0.0046 mol) was added, the reaction mixture was refluxed at 80° C. Twelve hours later, celite filtration was carried out, and 50 ml of ethyl acetate was added to the filtrate. After this organic layer was washed with saturated sodium chloride solution (30 ml), it was dried by adding magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane ether=8:2 eluent was concentrated. A colorless oily substance was thus obtained, i.e., methyl (1S, 4aS, 7aS)-1, 4a, 5, 7a-tetrahydro-7-methyl-1-trimethylacetoxycyclopenta[c]pyran-4-carboxylate (114.5 mg, yield=72.8%). This methyl (1S, 4aS, 7aS)-1, 4a, 5, 7a-tetrahydro-7-methyl-1-trimethylacetoxycyclopenta[c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:22]2[C:9](=[CH:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14]4)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]2[CH:21]=[C:22]3[C:2]([CH3:23])([CH3:1])[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]3=[CH:10][C:11]=2[CH:12]=[C:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3cc4ccccc4cc3cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3cc4ccccc4c(Br)c3cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
13,13-dimethyl-13H-indeno[1,2-b]anthracene (10 g, 0.034 mol) and N-bromosuccinimide (7.68 g, 0.034 mol) were dissolved in carbon tetrachloride (200 ml), and the reaction mixture was stirred for 8 hours at 60° C. After the reaction was terminated, the reaction solution was extracted with distilled water, and purified by column chromatography to give 11-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (9 g, yield=71%).