Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[Cl:30])[CH2:16][CH2:15]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)(C)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:32])[CH2:15][CH2:16]2)=[O:31])=[C:22]([Cl:30])[CH:23]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3Cl)CC2)c1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
N-tert-Butyl-3-((4-(2-chloro-4-nitrobenzoyl)piperazin-1-yl)methyl)benzamide (1.9483 g, 4.2 mmol) was added to a suspension of reduced iron powder (2.3623 g, 42 mmol) and 1M hydrochloric acid (6 mL) in isopropanol. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the remaining residue was taken up in dichloromethane and washed with water. The organic phase was dried over magnesium sulphate and concentrated under vacuum to afford the title compound (1.57 g).
Reaction SMILES: [C:1]1([CH:11]([O:15]C(=O)C)[C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:19][CH:20]([O:33]C(=O)C)[C:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:22].Cl>C(O)C>[OH:15][CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12](=[O:14])[CH3:13].[OH:33][CH:20]([CH3:19])[C:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: CC(=O)OC(C(C)=O)c1cccc2ccccc12
Reactant: CC(=O)OC(C)C(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: CC(=O)C(O)c1cccc2ccccc12
Product: CC(O)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of acetic acid 1-naphthalen-1-yl-2-oxo-propyl ester and acetic acid 1-methyl-2-naphthalen-1-yl-2-oxo-ethyl ester (2:1 mixture) (16.7 g), ethanol (300 mL) and 1M hydrochloric acid (150 mL) was heated at reflux for 4 hours. After cooling to room temperature, the ethanol was removed under reduced pressure and the aqueous phase was extracted with dichloromethane (200 mL). The organic phase was washed with water (2×150 mL), brine (2×150 mL) dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 1-hydroxy-1-naphthalen-1-yl-propan-2-one and 2-hydroxy-1-naphthalen-1-yl-propan-1-one (4:1 mixture) (12.0 g, 87%) as an orange oil, 1H NMR (DMSO-D6): 1.2 (3H, d, J=6.8 Hz), 2.0 (3H, s), 5.0 (1H, m), 5.35 (1H, d, J=6.5 Hz), 5.65 (1H, d, J=4.0 Hz), 6.15 (1H, d, J=4.0 Hz), 7.45-8.20 (10H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[N:24][N:25]=1>C(O)CCC>[CH3:26][C:23]1[S:22][C:21]2=[N:20][C:3]([C:5]3[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:7][N:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=34)=[CH:2][N:25]2[N:24]=1
Reactant: O=C(CBr)c1c(-c2ccccc2)nn2ccccc12
Reactant: Cc1nnc(N)s1
Solvent: CCCCO
Product: Cc1nn2cc(-c3c(-c4ccccc4)nn4ccccc34)nc2s1
Yield: 54.2 %

Procedure:
A mixture of 3-(2-bromoacetyl)-2-phenylpyrazolo[1,5-a]pyridine (1.87 g), 2-amino-5-methyl-1,3,4-thiadiazole (0.68 g) and 1-butanol (19 ml) was refluxed for 5 hours and 20 minutes. The reaction mixture was evaporated in vacuo and the residue was taken up methylene chloride (40 ml). The methylene chloride solution was washed with an aqueous solution of potassium carbonate and dried over magnesium sulfate. The solvent was removed and the residue was subjected to chromatography on silica gel (25 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.06 g), which was recrystallized from acetone gave crystals (0.69 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Cl:49][C:50]1[N:55]=[CH:54][C:53](O)=[CH:52][C:51]=1[CH3:57]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:16][C:53]2[CH:54]=[N:55][C:50]([Cl:49])=[C:51]([CH3:57])[CH:52]=2)[CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Reactant: Cc1cc(O)cnc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester (450 mg, 1.91 mmol) in toluene (19 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 722 mg, 2.86 mmol) at 0° C., followed by the additions of tributylphosphine (0.71 mL, 2.86 mmol) and 6-chloro-5-methyl-pyridin-3-ol (327 mg, 2.29 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (440 mg).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCC1.C(O)(=O)C>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of 3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (3.4 g), 2.7 g of 5-bromo-2-oxindole and 1.4 g of pyrrolidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed by refluxing in 30 mL of ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under vacuum to give 5.2 g (98% yield) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as a red-orange solid, mp 286-289° C.
Reaction SMILES: [Na][Na].[C:3]([NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]#[N:15])=[O:12])#[N:4].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN1CCCC1=O>[C:14]([N:13]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:3]#[N:4])=[O:16])#[N:15]
Reactant: N#CNC(=O)CCCCC(=O)NC#N
Reactant: CCCCI
Agent: [Na][Na]
Solvent: CN1CCCC1=O
Product: CCCCN(C#N)C(=O)CCCCC(=O)N(C#N)CCCC

Procedure:
Analogously to Example 3, 23.8 g (0.1 mol) of the disodium salt of adipic acid bis-(N-cyanamide) and 55.2 g (0.2 mol+50% excess) of n-butyl iodide are reacted in 50 ml of N-methylpyrrolidone at 92°-100° C. for 5 hours and 15 minutes and the mixture is worked up.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13](=[O:15])[NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O[C@H](C)C(=O)O)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(O[C@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Cool a solution 3-((R)-1-carboxy-ethoxy)-benzoic acid methyl ester (0.50 g, 1.90 mmol) in pyridine (5 mL), to 0° C., and add 4-aminobenzonitrile (0.28 g, 2.33 mmol) followed by phosphorous oxychloride (0.22 mL, 2.4 mmol). Stir the mixture at 0° C. for 1 h then dilute with water and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography to provide 0.59 g of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxyl]-benzoic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(COC)OC>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]2[CH:15]=1
Reactant: CCOc1ccc(N)nc1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: CCOc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-ethoxypyridine (1.53 g; prepared by the method of Lombardino, J. Med. Chem. 1981, 24, 39-42), 1,3-dichloroacetone (Aldrich; 1.115 g), and dimethoxyethane (7 mL) is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and ethanol (22.5 mL) is added. After the mixture is stirred for 30 min at 80° C., it is cooled and then concentrated under reduced pressure. The residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and crystallized from ether/dichlormethane/hexane to give 0.94 g of 2-(chloromethyl)-6-ethoxyimidazo[1,2-α]pyridine in three crops; mp 95-96° C.; MS m/z 210, 212; IR (mineral oil) 1192, 1263, 810, 1537, 1511 cm-1 ; 1H NMR (CDCl3) δ1.45, 3.97, 4.75, 6.98, 7.46, 7.55, 7.58.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:30]>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:37][CH:36]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: O=C(CBr)Nc1ccc(F)cc1
Product: O=C(COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1)Nc1ccc(F)cc1

Procedure:
N-(4-Fluoro-phenyl)-2-{4-hydroxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromen-6-yloxy}-acetamide was prepared in 41% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 2-Bromo-N-(4-fluoro-phenyl)-acetamide (Bioorg. Med. Chem. 11 (2003) 2769-2782).
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[C@H:7]([C:23]([N:25]([CH2:34][C:35]([OH:37])=[O:36])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH3:38][CH2:39]O.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:38]([O:36][C:35](=[O:37])[CH2:34][N:25]([C:23]([C@@H:7]1[CH2:6][C@@H:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][N:8]1[S:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=[O:12])=[O:11])=[O:24])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH3:39]
Reactant: CCO
Reactant: CC(=O)S[C@@H]1C[C@@H](C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(C)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 0 %

Procedure:
A suspension of 700 mg (1.29 mmol) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid and 0.1 ml (1.68 mmol) EtOH in 12 ml CH2Cl2 was treated at 0° C. with 273 mg (1.42 mmol) EDCI and 16 mg (0.13 mmol) DMAP. After warming up to RT (1 h), the reaction was partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated KHCO3, 10% NaCl and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 9:1 to 4:1) gave 0.254 mg (34%) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid ethyl ester, mp: 119-120° C., MS: 569 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43]Cl>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:43][CH2:42][N:41]([CH3:45])[CH3:40])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OCCN(C)C)cc2n1Cc1ccccc1
Yield: 50.7 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-dimethylamino ethyl chloride hydrochloride (20 mg, 0.20 mmol) to yield the title compound (10 mg, 53%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.[CH3:35][O:36][C:37](=[O:46])[CH:38]([P:40]([O:44][CH3:45])([O:42][CH3:43])=[O:41])[NH2:39]>CN(C)C=O>[CH3:35][O:36][C:37](=[O:46])[CH:38]([P:40]([O:42][CH3:43])([O:44][CH3:45])=[O:41])[NH:39][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])=[CH:20][C:12]=1[Cl:11]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: COCOc1cccc(CNC(=O)c2ccc(C(=O)O)c(Cl)c2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCOc1cccc(CNC(=O)c2ccc(C(=O)NC(C(=O)OC)P(=O)(OC)OC)c(Cl)c2)c1
Reaction time: 12 h
Yield: 45.4 %

Procedure:
N,N-dicyclohexylcarbodiimide (0.216 g, 1.05 mmol) and 1-hydroxybenzotriazole (0.027 g, 0.2 mol) were added to a solution of 2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoic acid (Example 124; 0.34 g, 1.0 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 197 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 12 h, then was filtered and diluted with ethyl acetate. The resulting solution was washed with water, dried (Na2SO4), evaporated and the residual material was chromatographed (50-80% ethyl acetate/hexanes) to give rac.-N-[2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (0.24 g, 45% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:22]3[NH:23][C:24]4[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].CO[CH:36](OC)[N:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C.Br>O1CCOCC1.CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:22]3[NH:23][C:24]4[CH:30]=[C:29]([CH2:31][N:32]=[CH:36][N:37]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:28]=[CH:27][C:25]=4[N:26]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(OC)N1CCCCCC1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc4ccc(CN)cc4[nH]3)[C@H]2SC1
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc4ccc(CN=CN5CCCCCC5)cc4[nH]3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 3-acetoxymethyl-7-(5-aminomethylbenzimidazol-2-yl)aminoceph-3-em-4-carboxylate (93 mg.) in dioxane (2 ml.) and methanol (3 ml.) at 20° was added dimethoxyhexahydro-1H-azepin-1-ylmethane (30 mg.) and then triethylamine. The mixture was cooled to 0° and stirred for 30 minutes. Two equivalents of HBr in methanol were added and the solvent evaporated. The residue was dissolved in the minimum CH2Cl2 and triethylamine hydrobromide precipitated by addition of ether. The product was purified by chromatography on magnesium silicate using CH2Cl2 /MeOH 98:2 v/v as eluant to give t-butyl 3-acetoxymethyl-7-(5-hexahydro-1H-azepin-1-ylmethyleneaminomethylbenzimidazol-2-yl)aminoceph-3-em-4-carboxylate having the following n.m.r. in d6DMSO: 1.63 (s, 9H); 1.7 (s, 8H); 2.17 (s, 3H); 3.3-4.0 (br, 6H); 4.67 (s, 2H); 4.75 (d, 1H); 5.1 (d, 1H); 5.38 (d, 1H); 6.0 (d, 1H); 6.8-7.5 (m, 3H); 8.43 (s, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[N:24]=[N:25][S:26][CH:27]=2)=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[N:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[N:24]=[N:25][S:26][CH:27]=2)=[O:22])=[CH:18][CH:19]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N=C=S)cc1)c1csnn1
Temperature: 0 °C

Procedure:
To a ice cooled solution of 1,1′-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl)amide (9.0 g) in tetrahydrofuran (100 mL). After approximately one hour the solvent is removed by evaporation and the residue is dissolved in ethyl acetate. Diethyl ether is added to precipitate the crude product, which is then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrous magnesium silicate. After removal of solvents, the residue is recrystallized from ethyl acetate-hexanes to provide the desired product as a slightly yellow solid.
Reaction SMILES: [CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:35]O>S(=O)(=O)(O)O>[CH2:19]([CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([O:18][CH3:35])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CO
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)OC
Temperature: 55 °C
Reaction time: 24 h

Procedure:
144 mg of 2-(tetradecyl)hexadecanoic acid was dissolved in 25 ml of methanol. After the addition of a few drops of concentrated sulfuric acid, the solution was stirred at 55° C. for one day, neutralized with 10% sodium hydroxide and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:50) to obtain methyl 2-(tetradecyl)hexadecanoate.
Reaction SMILES: [I:1][Si](C)(C)C.[CH:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[CH2:13][CH2:14][C@@H:15]([NH:16]C(=O)OCC3C=CC=CC=3)[C:9]2=[N:8][CH:7]=1.C(O)C.CCCCCC.C(O)C>ClCCl>[IH:1].[IH:1].[CH:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[CH2:13][CH2:14][C@@H:15]([NH2:16])[C:9]2=[N:8][CH:7]=1
Reactant: C[Si](C)(C)I
Reactant: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: CCCCCC
Product: I
Product: N[C@@H]1CCc2ccccc2-n2ccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
Add iodotrimethylsilane (783 mL, 5.49 mol) to dichloromethane (800 mL) and cool in an ice water bath. Dissolve benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate (610 g, 1.83 mol) in dichloromethane (1 L) and add to the iodotrimethylsilane solution. After addition is complete, remove the ice water bath and allow the reaction to stir for approximately 16 hours at ambient temperature. Stir a mixture of hexanes (6 L) and ethanol (1 L) in an ice water bath. Add the reaction mixture to the stirring hexane/ethanol mixture carefully to avoid foaming. Stir it at ambient temperature 10 minutes. Remove the resulting solid by filtration and wash the cake with hexanes (3×2 L) to give the title compound (817.1 g, 98%) as an orange, free flowing solid: MS (m/z): 200 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:35][CH2:36][O:24][C:23]([C:18]2([C:20]([O:22][CH2:36][CH2:35][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCCC1CCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC1CCCC1)(C(=O)OCCC1CCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclopentylethanol according to the procedure of Example 30 as an amber gum (HCl salt); 1H NMR (CDCl3) δ 1.32 (d, J=6.3 Hz, 3H), 1.60 (m, 20H), 2.80 (m, 1H), 2.90 (m, 2H), 3.15 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4.30 (t, J=6.9 Hz, 4H), 5.50 (bd, 1 H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 614 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C34H44ClNO7 ·HCl: C, 62.77; H, 6.82; N, 2.15; Cl, 10.90. Found: C, 64.04; H, 8.24; N, 1.62; Cl, 8.99.
Reaction SMILES: [O:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH2:2][CH3:3].[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].N1CCCCC1.O>C(O)C>[C:13]([C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:1][CH2:2][CH3:3])[CH:5]=1)#[N:14]
Reactant: COC(=O)CC#N
Reactant: CCOc1cc(C=O)ccc1O
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cc(C=C(C#N)C(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of 20 grams of 3-ethoxyl-4-hydroxybenzaldhyde and 13 grams of methyl cyanoacetate in 100 ml of ethanol was refluxed with 1 ml of piperidine for 4 hours. The crude mixture was allowed to cool down to room temperature and, with stirring, water was added until the solid began to form. This mixture was then refrigerated for 4 hours and solids was collected by suction filtration, washed with a cold mixture of ethanol and water (1:2) and suction dried to provide 25 grams of 1-cyano-2-(3-ethoxy-4-hydroxyphenyl)-1-methoxycarbonyl ethene.