Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:19])=[O:18].[NH2:20][C:21]1[N:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=[C:23]([CH3:30])[N:22]=1>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH:15][C:16]([NH:20][C:21]3[N:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[CH:24]=[C:23]([CH3:30])[N:22]=3)=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:19])=[O:18]
Reactant: Cc1cc(C2CC2)nc(N)n1
Reactant: CC1Cc2cccc(S(=O)(=O)N=C=O)c2OS1(=O)=O
Solvent: C1COCCO1
Product: Cc1cc(C2CC2)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)C3)n1
Reaction time: 18 h

Procedure:
66.5 ml of a 10.78% solution of 3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl isocyanate in dioxane is added dropwise over 5 minutes at room temperature to a mixture of 3.72 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 100 ml of absolute dioxane. The mixture is stirred for a further 18 hours and then concentrated by evaporation. The residue is crystallised by trituration with a 1:2 mixture of ethyl acetate and petroleum, affording 11.2 g of N-(3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-cyclopropyl-6-methylpyrimidin-2-yl)urea with a melting point of 216°-217° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[NH:33][C:32]2=[O:42])[CH2:27][CH2:26]1>C1COCC1>[N:10]1([C:8]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[NH:33][C:32]4=[O:42])[CH2:29][CH2:30]3)[CH:7]=[CH:6][N:5]=2)=[O:9])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2ccccc21
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ccn1)N1CCc2ccccc21

Procedure:
110 mg (0.43 mmol) (4-chloro-pyridin-2-yl)-(2,3-dihydro-indol-1-yl)-methanone, 150 mg (1.0 mmol) potassium carbonate and 100 mg (0.41 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 mL THF were refluxed for 3 days. Then the reaction mixture was evaporated down using the rotary evaporator, taken up in 20 mL xylene and refluxed for a further 3 days. The solid was filtered off and the filtrate evaporated down i. vac. The residue was dissolved in DMF and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:27]([NH:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2NC(C)=O)c1

Procedure:
3-{5-Amino-6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (16 mg), acetyl chloride (3.5 mg), triethylamine (0.02 ml) were stirred in methylene chloride (0.2 mL) at room temperature for overnight. The product (2.8 mg) was purified by preparative thin layer chromatography. MS (m/z): 399 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[C:17](=O)([O-])O.[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[OH:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ccc2cc1O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
6.55 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid were dissolved in 20 ml of dimethylformamide, treated with 5.5 g of sodium hydrogen carbonate and 4.0 ml of dimethyl sulfate and stirred at 90° C. under argon for 10 minutes. Subsequently, the reaction mixture was poured on to ice-water and extracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate and concentrated. The thus-obtained residue was recrystallized from ethyl acetate/hexane. Methyl 3-hydroxy-7-methoxy-naphthalene-2-carboxylate with m.p. 138° C. was thus obtained.
Reaction SMILES: [ClH:1].CC(C)(OC([NH:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C>CCOC(C)=O>[ClH:1].[NH2:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)c1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.[Ni]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:12]=[N:13][N:14]=[CH:15]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2cnnc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnc2)ccc1N

Procedure:
A solution of 4-(3 methyl-4-nitrophenyl)-1,2,4-triazole (1.0 g) in acetic acid (25 cm3) was hydrogenated at 25° and 60 p.s.i. (4.13×105Pa) pressure over Raney nickel (0.2 g) for 2 hours. The mixture was then filtered through "Solkafloc" (Trade Mark for a cellulose based filtering agent), the solvent was evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and aqueous sodium carbonate solution (20 cm3). The aqueous phase was further extracted with chloroform (3×50 cm3) and the combined and dried (MgSO4) organic extracts were concentrated to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:ethyl acetate, 1:9. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from ethyl acetate/hexane to give 4-(4-amino-3-methylphenyl)-1,2,4-triazole, m.p. 152°-154° (0.67 g).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C(F)(F)F)ccc1Cl
Yield: 77.7 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2-chloro-5-trifluoromethylaniline (4.25 g, 21.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (6.49 g, 70%) was obtained.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:33]1[CH:32]=[CH:31][C:30]([OH:35])=[C:29]([C:28]([NH:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])=[O:36])[CH:34]=1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
2′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid and EPA starting materials. for C35H42F2N2O3=576.72; found: [M+H]+=577.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:14]2[C:13]([CH3:23])=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, colorless oil, MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-2-sulfonyl chloride.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>>[C:12]([O:15][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: ClC[C@@H]1CN2CCC[C@H]2CO1
Agent: [K+]
Product: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Yield: 96.9 %

Procedure:
(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylfomamide (25 mL) at 140° C. for 20 h. The mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H), 3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C10H17NO3: 200 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:26].[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:26])=[CH:19][CH:20]=2)[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 63.7 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-2,2-dimethyl-5-(4-methylsulfanyl-phenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (6 g, 16.91 mmol) in ethanol (300 mL) is cooled to 0° C. followed by addition of K2CO3 (4.665 g, 33.80 mmol) and m-CPBA (2.90, 16.90 mmol) at 0° C. and resulting reaction mixture is stirred at 0° C. for 10 h. After completion, reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by CombiFlash using 120 g column with 100% ethyl acetate in hexane as an eluent to afford title compound (4 g) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.50 (s, 3H), 1.62 (s, 3H), 2.74 (s, 3H), 3.82-3.89 (m, 1H), 4.46-4.57 (m, 1H), 4.81 (m, 1H), 5.15 (d, J=7.28 Hz, 1H), 7.65-7.72 (m, 4H). LC-MS (m/z): M+H=372.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[NH2:34][C:35]1[CH:36]=[C:37]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:38]=[CH:39][CH:40]=1>CC(O)C>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:41][C:37]1[CH:36]=[C:35]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH:22]=[CH:23][CH:24]=4)=[N:10][N:11]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: COc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1

Procedure:
N-{3-[3-(2-chloro-4-pyrimidinyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (0.26 g, 0.58 mmol) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine dihydrochloride (0.18 g, 0.70 mmol) were combined in i-PrOH (4 mL)) and microwaved for 15 min. at 160° C. The reaction mixture was concentrated to dryness to afford N-{3-[3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}-6-(methyloxy)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide as a brown solid. The solid was dissolved in THF (5 mL) and water (0.5 mL) and treated with 1N NaOH (3 mL) and stirred for 16 h at rt after which time the reaction was incomplete by LC/MS. 1N NaOH (1 mL) was added and the mixture heated at 40° C. for 2 h and then cooled to rt and diluted with DCM and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the title compound as crude yellow solid (320 mg, >100%), which was used as such in Step C. ES-LC/MS m/z=496 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[N:5]1.C(N(C(C)C)CC)(C)C.[C:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[I-].[K+]>CC#N>[CH3:16][O:15][C:13]([C:6]1[CH:7]=[C:8]2[C:9](=[O:11])[N:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]3)[CH2:2][CH2:3][N:4]2[N:5]=1)=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O

Procedure:
A solution of 3-2 (14.0 g, 48.0 mmol), diisopropylethyl amine (25 ml, 144 mmol), Boc-4-aminoethylpiperidine (12.0 g, 52.6 mmol), and potassium iodide (2.39 g, 0.3 mmol) in 250 ml CH3CN was refluxed under N2 for 4.5 h then cooled, filtered and evaporated at reduced pressure. The resulting yellow residue was chromatographed on silica gel using EtOAc as eluent to give 3-3 as an off-white crystalline solid.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl.C(OCC)C>[C:1]1([CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[O:32][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCCCCCCCC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C(CCCCCCCCC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.53 g of 11,11-diphenylundec-1-ene in 25 mL of dichloromethane was added 1.5 g of 50-60% by wt of m-chloroperbenzoic acid and the mixture was stirred at room temperature for 16 hrs. The solution was diluted with diethyl ether and washed with 10% by wt aqueous solution of sodium hydrogen sulfite, saturated aqueous sodium hydrogen carbonate solution, and brine. The organic layer was dried over sodium sulfate and concentration in vacuo gave 1.5 g of 11,11-diphenylundec-1-ene oxide which is characterized by:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>O1CCCC1>[C:17]([NH:20][NH:21][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Reactant: CC(=O)NN
Solvent: C1CCOC1
Product: COc1cc(C(=O)NNC(C)=O)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.438 g, 1.93 mmol) in tetrahydrofuran (10 mL) at room temperature was added 1,1-carbonyldiimidazole (0.343 g, 2.12 mmol) in one portion and the mixture was stirred at room temperature for one hour, then at 70° C. for two hours, whereupon acetic hydrazide (0.157 g, 2.12 mmol) was added. The resulting was stirred at room temperature for thirty minutes, then at 70° C. for two hours. After cooling to room temperature, the mixture was poured onto ice-water (100 mL) and the precipitate was filtered off and washed with water. 3,4-Dimethoxy-5-nitro-benzoic acid N′-acetyl-hydrazide was obtained as a white solid (0.296 g, 54%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:17]1[CH:22]=[C:21]2[C:23]([CH:26]=O)=[CH:24][S:25][C:20]2=[CH:19][CH:18]=1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:26]([C:23]2[C:21]4[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=4[S:25][CH:24]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3]1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: O=Cc1csc2ccccc12
Product: O=c1[nH]c(-c2csc3ccccc23)nc2ccc(N3CCOCC3)cc12

Procedure:
Compound 31 was synthesized from 5-morpholinyl-2-aminobenzamide (13) (1.6 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.6 g (60%); brown crystals; mp>300° C.; 1H NMR (DMSO-d6) δ 2.47 (4H, t, J=4.7 Hz, CH2NCH2), 3.75 (4H, t, J=4.7 Hz, CH2OCH2), 7.44-7.59 (4H, m, 4×ArH), 7.67-7.72 (1H, m, 1×ArH), 8.03-8.07 (1H, m, 1×ArH), 8.67 (1H, s, 1×ArH), 8.96-9.00 (1H, m, 1×ArH), 12.31 (1H, br s, NH) ppm; MS (ESI) m/z 363; Anal. (C20H17N3O2S): C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH3:17])=[C:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(-c2ccccc2)[nH]c2cc(Br)ccc12
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 6-bromo-3-methyl-2-phenyl-1H-indole (1.284 g, 4.489 mmol) was reacted with k-t-butoxide (0.529 g, 4.711 mmol) and benzyl bromide (0.809 g, 4.711 mmol) in DMF (10 ml) to give the product (1.440 g, 3.827 mmol, 85%) as a white solid, mp 97-101° C. 1H NMR (DMSO-d6)δ 2.20 (s, 3H), 5.32 (s, 2H), 6.79-6.80 (m, 2H), 7.14-7.21 (m, 4H), 7.36-7.39 (m, 2H), 7.43 (t, J=7.2 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 376/378 (M+H)+.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[CH:6]1([CH2:12][C@H:13]2[CH2:15][O:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Na+]>CN(C=O)C>[CH2:1]([S:5][CH2:15][C@@H:13]([OH:14])[CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: C1CCC(C[C@H]2CO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSC[C@@H](O)CC1CCCCC1
Yield: 77.3 %

Procedure:
Butanethiol (765 μL, 7.1 mmol), the product from Example 1308C (500 mg, 3.6 mmol) in DMF (3.0 mL), and NaH, 60% dispersion in mineral oil, (305 mg, 7.6 mmol) in DMF (40 mL) were allowed to react in a manner similar to that described in Example 1310A. The residue was chromatographed (silica gel; EtOAc/hexanes 1:40) to afford a clear oil (641 mg, 77%). 1H NMR (CDCl3, 300 MHz) δ0.80-1.00 (m, 2H), 0.92 (t, J=7 Hz, 3H), 1.08-1.34 (m, 4H), 1.37-1.75 (m, 10H), 1.81 (m, 1H), 2.42 (dd, J=9, 13.5 Hz, 1H), 2.53 (t, J=7 Hz, 2H), 2.72 (dd, J=3, 13.5 Hz, 1H), 3.76 (m, 1H); MS (CI/NH3) m/z: 231 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1)=[O:19]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: Cc1csc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 66 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 66% of theory.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21](=O)[CH2:22]Br)[C@H:4]2[S:3]1.[NH2:29][C:30]([NH2:32])=[S:31]>C(O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21]3[N:29]=[C:30]([NH2:32])[S:31][CH:22]=3)[C@H:4]2[S:3]1
Reactant: NC(N)=S
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1
Solvent: CCO
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (0.51 g.) in ethanol (10 ml.) was added thiourea (0.068 g.), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water with stirring, and the ethyl acetate layer was separated. The remaining aqueous layer was adjusted to pH 7 and extracted with ethyl acetate. The ethyl acetate layer and extract were combined together, washed with water, dried over magnesium sulfate and then concentrated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), mp 175° to 178° C. (dec.).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:34][O:35]C1C=CC(C(O)=O)=CC=1>>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:35][CH3:34])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(F)cc3)cc2)cc1
Product: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OC)cc3)cc2)cc1

Procedure:
3d was prepared by the same procedure as 3b except that 4-methoxybenzoic acid was used instead of 4-fluorobenzoic acid.