Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.COC(Cl)=O.[Cl:19][C:20]1[C:33]2[S:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1O>C1COCC1.O>[Cl:19][C:20]1[C:33]2[S:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1[O:5][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
To a solution of iso-butyric acid (1.6 ml) in THF (10 ml) at 0° C. was added Et3N (2.7 ml) and methylchloroformate (1.5 ml). To this resulting suspension was added slowly at 0° C. a solution of 4-chloro-3-hydroxy-10H-phenothiazine in THF (10 ml). The reaction mixture was stirred at 5° C. for 12 hours, after which H2O was added and the resulting aqueous phase extracted with ethyl acetate. The organic layer was then dried and evaporated. The resulting residue was purified by chromatography on silica gel to give 2.25 g of 4-chloro-3-isobutyryloxy-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]2[O:26][CH2:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[C:24]=2[CH:23]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO>CCOCC.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:20][CH2:21][C:22]3[CH:37]=[CH:36][C:25]4[O:26][CH2:27][C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[C:30](=[O:31])[C:24]=4[CH:23]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: O=C1c2ccccc2COc2ccc(CCN3CCC(O)(c4ccc(Cl)cc4)CC3)cc21
Yield: 34.6 %

Procedure:
A mixture of 3 g (0.014 m) of 4-(4-chlorophenyl)-4-hydroxypiperdine, 4.65 g (0.014 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1, 1.96 g (0.014 m) of K2CO3, 30 ml of methanol and 30 ml of absolute ethanol was refluxed overnight. The yellow reaction mixture was filtered and evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4), filtered and evaporated to afford a solid. Trituration with ether gave 2.17 g (35%) of 4-(4-chlorophenyl)-1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-4-hydroxypiperidine, m.p. 151°-153° C.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([OH:45])=O)=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:45])=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 79 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 79% yield: mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.7 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.29-7.23 (m, 3H), 7.06-6.99 (m, 2H), 6.14 (t, J=5.7 Hz, 1H), 6.08 (s, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 162.4 (d, JC-F=246.4 Hz), 155.8, 149.2, 148.8, 142.5, 141.7, 135.5, 134.1, 131.7, (d, JC-F=3.1 Hz), 130.0 (d, JC-F=8.2 Hz), 123.6, 119.0, 115.7 (d, JC-F=21.5 Hz), 112.4, 47.4, 42.7, 41.4, 41.2, 16.1; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:7][C:6]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:9]=1
Reactant: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2c(I)cnn12
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.4 %

Procedure:
A mixture of 3-iodo-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (8.23 g, 18.7 mmol), trimethylsilylacetylene (4.67 mL, 33.7 mmol) and triethylamine (5.22 mL, 37.5 mmol) in N,N-dimethylformamide (20 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (132 mg, 1 mol %), PPh3 (49 mg, 1 mol %) and CuI (11 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (8.68 g) as a light brown solid, which was dissolved in THF (42 mL) and MeOH (98 mL), while stirring at 0° C. potassium carbonate (293 mg, 2 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (150 mL) and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4) and evaporated. The crude product was further purified by silica gel column chromatography (heptane/EtOAc 4:1) followed by trituration with heptane to give 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (4.34 g, 61%) as an orange solid. MS (EI) 337.1 [(M)+]; mp 149° C.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:20]
Reactant: CCNCC
Reactant: CC[K]
Reactant: O=C(O)C1OC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)N(CC)CC
Yield: 63.3 %

Procedure:
Following the procedure of Example 34, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and diethylamine (0.74 g) to give 0.68 g of ethyl N,N-diethyl-2,3-epoxysuccinamate (Compound No. 57) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:21])[N:13]([CH3:22])[C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:16]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
First, 2.20 g of 3-(2,4-dichloro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazin (compound 1-1009) was dissolved in 12 ml of N,N-dimethylformamide, to which 1.34 g of potassium carbonate and 0.81 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 1.11 g (yield, 48%) of 3-(2,4-dichloro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-358; m.p., 130.6° C.).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=1)=[C:8]2[CH3:33]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A solution of [8-chloro-2-difluoromethoxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.38 g) in methanol (7.0 mL) and water (0.7 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.32 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by trituration with methanol, followed by column chromatography on silica gel to afford title compound as a white solid (0.036 g).
Reaction SMILES: C([C:3]1([C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[C:6]2[C:5](=[O:17])[O:4]1)#N.[O:28]1CCCC1.[OH-].[Na+]>O>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([O:26][CH3:27])[N:19]=[C:18]([C:3]2([OH:28])[C:7]3=[N:8][CH:9]=[CH:10][C:11]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)=[C:6]3[C:5](=[O:17])[O:4]2)[N:23]=1
Reactant: C1CCOC1
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(-c4ccco4)ccnc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccco4)ccnc32)n1
Yield: 94.6 %

Procedure:
0.42 g of 7-cyano-7-(4,6-dimethoxypyrimidin-2-yl)-4-(2-furyl)furo[3,4-b]pyridin-5(7H)one was weighed out, and 14 ml of tetrahydrofuran was added thereto. The mixture was stirred under cooling with ice. 14 ml of 0.25N sodium hydroxide aqueous solution was added thereto dropwise, and the mixture was stirred at room temperature for 30 minutes. The mixture was poured into water, and the aqueous layer was washed with ethyl acetate twice, acidified with 10% hydrochloric acid and extracted with 100 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were washed with methyl alcohol to obtain 0.40 g (yield 94.6%) of the desired compound as yellow crystals. m.p.: 198°-204° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1>CO>[CH:1]1([NH:4][CH2:13][C:14]2[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(=O)c1cccc(CBr)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(CNC2CC2)c1
Yield: 34.9 %

Procedure:
Cyclopropylamine (5.71 g; 10.0 mmol) and triethylamine (1.01 g; 10.0 mmol) were dissolved in methanol (50 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (2.13 g; 10.0 mmol) in methanol (10 ml) was added dropwise. The mixture was removed from the ice bath, and stirred for 18 hours at room temperature. The solvent was evaporated under reduced pressure, and the residue was taken up in 2N hydrochloric acid (100 ml), followed by extraction with diethyl ether (100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1), to thereby yield 0.66 g of the target compound as yellow oily matter (yield: 34.9%).
Reaction SMILES: N1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](N)=O.CC[C@H](NCCN[C@H]([CH2:22][OH:23])CC)CO.Cl.CC1C2O[C@]3(C)OC=C[C@H](OC)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)C=CC=C(C)C(NC4C(/C=[N:61]/[N:62]5CCN(C)CC5)=C(O)C(C=2C3=O)=C(C=4O)C=1O)=O.OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O>O>[CH:6]1[C:7]([C:22]([NH:61][NH2:62])=[O:23])=[CH:2][CH:3]=[N:4][CH:5]=1
Reactant: NC(=O)c1cnccn1
Reactant: CC[C@@H](CO)NCCN[C@@H](CC)CO
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: Cl
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Solvent: O
Product: NNC(=O)c1ccncc1

Procedure:
Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin and Lactose through a sieve and granulate with Starch Paste prepared in Purified Water. Pass the wet mass through multimill and dry the granules at 50–60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules and isoniazid delayed release powder. Compress the blend into tablets.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:31][CH2:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CC(C)NCCCN
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)NCCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
A mixture of 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.244 g, Example 25b), N-isopropyl-1,3-propanediamine (0.211 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 h. The mixture was cooled and concentrated under reduced pressure to an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.040 g) was added portionwise and the mixture stirred at room temperature for 30 min, then concentrated under reduced pressure and the residue purified by column chromatography over silica (eluting with 9:1:0.1 dichloromethane/methanol/35% aqueous ammonia) to give the title compound (0.015 g) and a by-product (see Example 27).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:6].[C:46]([O:50][CH3:51])(=[O:49])[CH:47]=[CH2:48]>CO>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:16]2[C:17]([CH3:27])([CH3:28])[C@H:18]3[C@:13]([CH3:39])([CH2:14][CH:15]=2)[C@@H:12]2[C@:21]([CH3:26])([C@@:22]4([CH3:25])[C@H:9]([CH2:10][CH2:11]2)[C@H:8]2[C@H:40]([C:43]([CH3:45])=[CH2:44])[CH2:41][CH2:42][C@:7]2([C:5]([NH:4][CH2:3][CH2:2][N:1]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:48][CH2:47][C:46]([O:50][CH3:51])=[O:49])=[O:6])[CH2:24][CH2:23]4)[CH2:20][CH2:19]3)=[CH:38][CH:37]=1)=[O:34]
Reactant: C=CC(=O)OC
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC(=O)OC)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h
Yield: 192.5 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.033 mmol) and methyl acrylate (8.40 mg, 0.098 mmol) in methanol (1 mL) was stirred at 20° C. for 3 hours. LCMS indicated the mono-substitution. Methyl acrylate (8.40 mg, 0.098 mmol) was added to the reaction mixture again. The reaction mixture was stirred for 16 hours. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (25 mg, 98%). LCMS: m/e 787.48 (M+H)+, 2.67 min (method 1).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][S:8][C@H:3]12.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:6]2[CH2:7][S:8][C@@H:3]3[CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)[C:24](=[O:25])[N:4]3[C:5]=2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Yield: 46.6 %

Procedure:
The free base (XI) (80 mg) was treated with 2-thienylacetyl chloride (40 mg) and triethylamine (0.05 ml) in dry methylene chloride (5 ml) at -20°. After 15 minutes the solution was washed with brine, dried and evaporated. Chromatography on silica gave the cephem (X) (50 mg) which crystallised on trituration with dry ether. νmax (CHCl3) 3380, 1780, 1710, 1685 cm-1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][C:46]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:46]4[C:45]([Cl:44])=[CH:50][CH:49]=[C:48]([C:51]#[N:52])[CH:47]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cc(C#N)ccc4Cl)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 22 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross-coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-chloro-5-cyanophenylboronic acid yielded the title compound (22% yield) as a white foam.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N:31]=2)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:18][CH2:17]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCN2CCCOCC2)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: [O-][n+]1nc(NCCN2CCCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
H2O2 (70%, 1.25 mL, ca. 25.8 mmol) was added dropwise to a stirred solution of TFAA (3.6 mL, 25.8 mmol) in DCM (35 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 48 (0.85 g, 2.58 mmol) and TFA (0.43 mL, 5.50 mmol) in CHCl3 (35 mL) at 0° C. The solution was stirred at 20° C. for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (4×60 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (3-6%) of MeOH/DCM, to give 1,4-dioxide 49 (0.37 g, 42%) as a red gum: 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.45 (br s, 1H, NH), 3.82 (t, J=6.1 Hz, 2H, CH2O), 3.74 (t, J=4.6 Hz, 2H, CH2O), 3.54 (q, J=5.7 Hz, 2H, NCH2), 2.97-3.04 (m, 4H, H-6, H-8), 2.73-2.80 (m, 6H, CH2), 2.15 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=5.9 Hz, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.8, 143.3, 129.8, 120.5, 114.7, 69.3, 68.7, 57.4, 55.8, 53.6, 38.7, 33.1, 32.3, 29.9, 25.7; HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1877.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].[H][H].Cl[CH2:19][N:20]1[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]1>CN(C)C=O>[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][N:20]2[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]2)=[CH:10][CH:11]=1
Reactant: CC(C)CCOc1ccc(O)cc1
Reactant: ClCn1cnc(Cl)c1Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(OCn2cnc(Cl)c2Cl)cc1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
Under a nitrogen blanket and at room temperature, 5.8 g of 4-(3,3-dimethyl-1-proplyoxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 0.79 g of 80% strength sodium hydride in 50 ml of anhydrous dimethylformamide. After hydrogen evolution has subsided, the mixture is stirred for a further hour at 60° C. Subsequently, 6.12 g of 1-chloromethyl-4,5-dichloroimidazole in 20 ml of anhydrous dimethylformamide is dripped in at room temperature. The whole is then stirred for 3 hours at 80° C. and overnight at room temperature. The mixture is then poured into 100 ml of ice water, followed by extraction three times with methyl tert-butyl ether. The organic phases are washed with 5% strength sodium hydroxide solution and three times with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from cyclohexane. There is obtained 7.4 g of 1-[4-(3,3-dimethyl-1-propyloxy)-phenoxymethyl]-4,5-dichloroimidazole having a melting point of 105°-108° C.