Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[CH:53]([N:56](CC)C(C)C)(C)[CH3:54].O>O1CCOCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:51])[NH:56][CH2:53][CH2:54][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])[CH:20]=4)[CH2:15]3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CCNC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-(4-chlorocarbonylphenyl)piperidine-1-carboxylic acid tert-butyl ester (125 mg) in 1,4-dioxane (2 ml) was added N,N-diisopropylethylamine (0.45 ml), and the solution was stirred for 4 hours at 90° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide (R)-4-{4-{{2-[6-(2,2-dimethylpropionyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-4,5-dimethoxyphenyl}ethylcarbamoyl}phenyl}piperidine-1-carboxylic acid tert-butyl ester (189 mg). Synthesized from this compound (60 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (29 mg) was obtained.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[C:17]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(O)C>C(OCC)(=O)C>[CH:1]1([NH:4][C:26]2[N:25]=[C:24]([CH2:23][S:22][C:17]3[C:16]([C:14]([NH:13][C:8]4[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH3:5])[CH:7]=4)=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:29]=[CH:28][N:27]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(S(C)=O)n2)c1
Reactant: NC1CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC3CC3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Cyclopropylamine (6.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-methylsulfinylpyrimidin-4-ylmethylthio)pyridine-3-carboxamide (990 mg, 2.4 mmol, Compound No. 1-27), and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was diluted with ethyl acetate (80 mL), washed twice with water (50 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by silica gel column chromatography to give 650 mg (recrystallized from ethanol) of the target compound as a colorless solid (Yield: 67%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]=O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]1[O:4][CH2:1][CH2:2][O:3]1)=[O:29])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C1OCCO1

Procedure:
Ethylene glycol (0.3 ml), p-toluenesulphonic acid (1 mg) were added to a solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (164 mg) in benzene (3 ml). The mixture was refluxed for 1 hr. The reaction solution was poured into a saturated aq. solution of sodium bicarbonate. The mixture was extracted with benzene. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (CH3OH--EtOAc--CH2Cl2) to give the title compound (79 mg) having the following physical data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[N:32]([CH2:39][CH2:40][OH:41])([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35]>C1COCC1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O-:16])=[O:15])[N:27]=1.[OH:35][CH2:34][CH2:33][NH+:32]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Reactant: OCCN(CCO)CCO
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)[O-])n1
Product: OCC[NH+](CCO)CCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid (2.0 g) and triethanolamine (0.7 g) were dissolved in 30 ml of THF, and the solution was stirred at room temperature for 12 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([OH:46])=O)[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:66][S:63]([CH:60]4[CH2:62][CH2:61]4)(=[O:65])=[O:64])=[O:46])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2d (200 mg, 0.305 mmol) was dissolved in DCM (10 ml). EDAC (70 mg, 0.366 mmol) was added and the reaction mixture was stirred at RT for 30 min. Cyclopropanesulfonic amide (41 mg, 0.336 mmol) and DBU (96 μl, 0.641 mmol) were added and the reaction was stirred at RT for 72 h. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. This material was used directly in the following step without further purification.
Reaction SMILES: C([O:7][C:8]1[C:9]([CH3:28])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27])(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2=[C:9]([CH3:28])[C:8]([OH:7])=[CH:16][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (80 mg, 0.2 mmol) in THF (1 mL) was added a solution of NaOH in MeOH/H2O (0.2 mL, 1 M). The solution turned red instantly. After 5 minutes, the reaction was quenched with EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated in vacuo to give the title compound (52 mg, 85%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[F:35][CH:36]([F:39])[CH2:37][NH2:38]>>[F:35][CH:36]([F:39])[CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: NCC(F)F
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCC(F)F)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.190 mmol) and 2,2-difluoroethylamine (300 μL, 3.92 mmol) the title compound was obtained as a white powder (57 mg, 0.100 mmol, 52.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.15 (d, J=5.1 Hz, 1H), 7.65-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.27 (q, J=7.5 Hz, 3H), 6.30 (bs, 1H), 3.63 (bs, 2H), 3.27-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI): 569.9 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][C:33]1[O:37][C:36]([C:38](O)=[O:39])=[CH:35][CH:34]=1>>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][C:38]([C:36]2[O:37][C:33]([CH2:32][N:23]3[C:24](=[O:31])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]3=[O:21])=[CH:34][CH:35]=2)=[O:39])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)o1
Product: N/C(=N\OC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)o1)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28] and 5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-2-furoic acid (see Preparation 98], to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[(5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-2-furylcarbonyl)oxy]-2-piperidinecarboximidamide as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=13)[N:7]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C.C(OCC)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(=O)NCCn1ccc2cc(C)c3ccccc3c21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1cc(C)c3ccccc3c12
Temperature: 100 °C
Yield: 17 %

Procedure:
N-[2-(5-Methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide (0.3 g) was treated with 3 ml of phosphorous oxychloride under argon and the mixture was heated to 100° C. for 30 minutes. The cooled mixture was added to 250 g of ice-water and treated with 30 ml of 28% sodium hydroxide solution. The mixture was extracted once with 100 ml of methylene chloride and twice with 50 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.14 g of brown oil, was chromatographed on 10 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. The crude product, 90 mg of yellow-brown, amorphous solid was dissolved in 1 ml of ethanol and 3 ml of diethyl ether and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 58 mg (17%) of 10,11-dihydro-5,8-dimethylbenzo[g] pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 184°-186° C. (dec.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21](O)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:51]5[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CNC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4O)no2)cc1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCc3sc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (92 mg, 0.26 mmol) that was obtained in Example 8 (8f), carbon tetrabromide (0.10 g, 0.31 mmol), triphenylphosphine (81 mg, 0.31 mmol), ethyl 3-azetidinecarboxylate hydrochloride (65 mg, 0.39 mmol), and N,N-diisopropylethylamine (0.14 ml, 0.78 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (44 mg) in a yield of 36% as a colourless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of 38.9 g (0.20 mole) of 4-fluorobenzenesulfonylchloride in 20 ml of methylene chloride was added slowly to 300 ml of a 40% aqueous dimethylamine solution during 0.5 hour period. The reaction was exothermic. After the reaction mixture was cooled a yellow solid was precipitated. The solid was collected, dissolved in 300 ml of ethyl acetate, and dried over magnesium sulfate. The solution was concentrated to 100 ml and a light yellow crystal formed. The crystal was collected and air-dried to afford 39 g of the product, mp 40°-43° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45](=O)[CH2:46]Br)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:49][C:50]([NH2:52])=[S:51].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45]1[N:49]=[C:50]([NH2:52])[S:51][CH:46]=1)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)C(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
To a solution of benzhydryl 7-(2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (2.5 g) in tetrahydrofuran (25 ml) was added a solution of thiourea (0.78 g) and sodium acetate (0.34 g) in water (10 ml), followed by stirring at 35° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-benzyloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].O>CN(C)C=O.C(OCC)(=O)C>[N:6]1([CH2:5][CH2:4][O:3][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (3.18 g; 0.0795 mol of a powder dispersed at 60%) is added at 23° C. to a solution containing 4-(2-hydroxyethyl)morpholine (9.40 g, 0.072 mol) in dimethylformamide (60 ml). Stirring is maintained for 30 minutes then the compound 4-fluoroacetophenone (5 g, 0.0362 mol) is added. The reaction medium is stirred for one hour at 23° C. then cooled down to 0° C. and water is added. After the addition of ethyl acetate then extraction, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulphate then the solvent is evaporated off. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 6-1). An orange-coloured oil is obtained.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[OH-].[K+].[F:8][C:9]([F:22])([F:21])[C:10]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[N:12]=[N:11]1.O>C(#N)C>[O:18]1[CH2:2][CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([C:10]2([C:9]([F:8])([F:21])[F:22])[N:11]=[N:12]2)=[CH:14][CH:15]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(C2(C(F)(F)F)N=N2)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C1(c2ccc(C3CO3)cc2)N=N1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
0.95 g of trimethylsulfonium iodide and 0.52 g of potassium hydroxide were dissolved in 4 ml of acetonitrile, and agitated for 10 minutes at 60° C. in a nitrogen gas atmosphere. 1.00 g of 4-(3-trifluoromethyl-3H-diazirine-3-yl)benzaldehyde were added together with 5.3 ml of acetonitrile, then 0.02 g of water were added. This was agitated for one hour at 60° C. in a nitrogen gas atmosphere. After extracting with ethyl ether, the resulting substance was washed twice with water and once with saturated saline solution, then dried with anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the resulting substance was purified by silica gel chromatography (hexane:chloroform=1:2, V/V) to obtain 0.56 g of 3-(4-oxiranylphenyl)-3-trifluoromethyl-3H-diazirine (52% yield).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH2:29]=O.[C:31]([BH3-])#[N:32].[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C.C(#N)C.C(Cl)Cl>[CH3:29][N:32]([CH3:31])[C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
To a stirred solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-amino-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 24; 30 mg, 0.072 mmol) in 2:1 acetonitrile/DCM (6 mL), was added formaldehyde (0.1 mL, 3.6 mmol), sodium cyanoborohydride (68 mg, 1.08 mmol) and acetic acid (12 μL). The reaction mixture was stirred for 3 h at room temperature. 1 M NaOH was added until the solution became basic. The mixture was taken up in DCM (5 mL), and washed with water and brine. The organic layer was removed, dried, and purified by preparative reversed-phase HPLC (acetonitrile/water, 0.05% TFA) to afford the title compound (8 mg, 0.02 mmol, 25%). MS (ESI): m/z 446 [M+H]+, 468 [M+Na]+. HPLC (reversed-phase): RT=9.14 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.61 (s, 1H), 8.22 (dd, J=7.0 Hz, 1.0 Hz, 1H), 8.18 (dd, J=8.8 Hz, 1.0 Hz, 1H), 7.63 (dd, J=8.8 Hz, 7.0 Hz, 1H), 6.95 (d, J=2.5 Hz, 7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.26 (dd, 8.7 Hz, 2.5 Hz, 1H), 3.16 (s, 4H), 2.95 (s, 6H), 1.56 (m, 2H), 1.42 (m, 4H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)C.O1CCCC1>[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:23])[CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCCCCCCCCCOc1ccccc1
Reactant: C=CC[Mg]Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)CCCCCCCCCOc1ccccc1
Temperature: 0 °C
Yield: 42 %

Procedure:
To 85 ml of a 1 M solution of allyl magnesium bromide in diethyl ether cooled in ice bath was added dropwise, under nitrogen, a solution of 20 g of 10-phenoxydecanal in 200 ml of dry tetrahydrofuran. The mixture was poured into 400 ml of ice and 30 ml of 9M sulfuric acid was added. Upon standing the mixture formed aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with 300 ml of water and 300 ml of a half-saturated aqueous solution of sodium chloride, filtered, and concentrated. The residue was flash chromatographed utilizing as successive eluents 5% diethyl ether/hexane, 10% diethyl ether/hexane, and 25% diethyl ether/hexane to give 18.51 g (42%) of 13-phenoxy-1-tridecen-4-ol as a solid, m.p. 50°-52°.