Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:39])=[CH:36][CH:35]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)CCNC(=O)c1ccc(N)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 90 %

Procedure:
A mixture of 0.0666 g (0.22 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0628 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.0456 g (0.22 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0938 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-benzamide (I-18)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[C:29]([C:35](=[N:37]O)[NH2:36])=[N:30][CH:31]=[C:32]([F:34])[CH:33]=1>>[F:27][C:28]1[C:29]([C:35]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:3][CH:2]([OH:1])[CH2:5]4)=[O:7])[CH2:9]3)[O:26][N:37]=2)=[N:30][CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: NC(=NO)c1ncc(F)cc1F
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ncc(F)cc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 61.0 mg (0.266 mmol) of 3,5-difluoro-N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 24 mg (19% of theory).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].Br[CH:11]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:13]=2[C:12]1=O>C(O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:13]2[C:12]3[N:9]=[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[S:8][C:11]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Reactant: CC(C)(CO)NC(N)=S
Solvent: CCO
Product: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS (ESI+): 369.3
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([OH:18])=O.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25]>>[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:28]=1[NH:29][C:16](=[O:18])[CH2:15][CH:14]([C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:36])[CH3:35]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCC(CC(=O)O)c1cc([N+](=O)[O-])cc(OC)c1OC
Product: CCCCCC(CC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cc([N+](=O)[O-])cc(OC)c1OC

Procedure:
A mixture of 3-(2, 3-dimethoxy-5-nitropheyl) octanoic acid and 2, 6-diisopropylaniline was allowed to react in a conventional manner to give N-(2, 6-diisopropylphenyl)-3-(2, 3-dimethoxy-5-nitrophenyl) octanamide.
Reaction SMILES: Br[CH:2]([CH3:11])/[C:3](/OC)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)/C=C(/OC)C(C)Br
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A 200-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a distillation head, a vacuum controller, an argon inlet and an oil bath was charged with 24.7 g of crude methyl rac-(E)-4-bromo-3-methoxy-pent-2-enoate (ca. 0.107 mol), 19.91 g of benzamide (0.161 mol) and 57 ml of toluene. The orange suspension was stirred and heated with an oil bath at 120° C. At a still temperature of 111° C. low boiling componentes started to distill. The head temperature reached 103° C. after ca. 1 h and was 65° C. after 6 h. After 9 h the oil bath was removed and the reaction mixture stirred over night at rt. Thereafter the toluene was removed at 60° C. bath temperature and a pressure between 300 and 70 mbar. After cooling to rt, 80 ml of methanol and 0.60 g of p-toluenesulfonic acid monohydrate were added and the brown solution stirred at reflux (ca. 73° C.) for 2 h. Subsequently 2.5 g of charcoal and 50 ml of methanol were added, the mixture was stirred for 30 min, filtered with suction through Dicalite Speedex and rotary evaporated to dryness (50° C., 8 mbar, 30 min). The orange semi-solid residue was treated under argon with 250 ml of toluene and 55 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 0.5 h, the precipitated benzamide was filtered off with suction and the filter cake was washed three times with 50 ml portions, a total of 150 ml of ice cold toluene and with little water. The combined aqueous phases (pH=8)were extracted in a separatory funnel with 80 ml of toluene. Thereafter the combined organic phases were washed twice with 50 ml, a total of 100 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 10 mbar, 1 h) to give 21.8 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 24.7 g) as a red-brown oil, which can be used without purification in subsequent steps.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][C:26]4([OH:34])[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]4)=[CH:19][C:18]=3[CH3:35])[C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].[OH-].[Na+].Cl>CO.O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][C:26]4([OH:34])[CH2:27][CH2:28][S:29](=[O:33])(=[O:32])[CH2:30][CH2:31]4)=[CH:19][C:18]=3[CH3:35])[C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(C)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6,6′-trimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoate (133 mg, 0.22 mmol) in a mixture of methanol (0.5 mL) and tetrahydrofuran (1 mL) was added 1 M aqueous sodium hydroxide solution (0.66 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and brine was added. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (72.7 mg, yield 58%) as a colorless amorphous powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2.C12(C3C=C(NC(=O)NC4C=CC(C(OC)=O)=CC=4)C=CC=3OC)CC3CC(CC(C3)C1)C2>C1COCC1.O>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:33]([C:32]([C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:37])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:36])=[O:34])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(N)cc1O
Agent: COC(=O)c1ccc(NC(=O)Nc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.7 g (40 mmol) of methyl 2-hydroxy-4-aminobenzoate, 10 ml (0.12 mol) of pyridine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 10.5 g (40 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylglyoxyloyl chloride, prepared in 1 (c), in 100 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (30:70). After evaporation of the solvents, 7.3 g (45%) of methyl ester, melting point 146°-147° C., are collected.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(N(C)C)=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O-:51])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O:51][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:25])[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)[O-])CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)OCOC(=O)C(C)(C)C)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reaction time: 1 h

Procedure:
1 ml of pivaloyloxymethyl iodide was added, whilst ice-cooling, to 15 ml of a dimethylacetamide solution containing 196 mg of sodium 17β-{N-[1(4-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylate (prepared by reacting the compound obtained as described in Example 2 with sodium hydroxide in a conventional salification process). The resulting solution was then stirred for 1 hour, whilst ice-cooling, after which it was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a gradient elution method, with solutions of from 1 to 3% by volume of acetone in methylene chloride as the eluent, to give 157 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.[OH-].[Na+]>>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9]1
Reactant: Clc1nsc2ccccc12
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(N3CCNCC3)nsc2c1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
A 4 L suction flask was charged with anhydrous piperazine (1582 g, 18.36 moles) followed by molten 3-chloro-1,2-benzisothiazole (Example 8, 622 g, 3.672 moles). The flask was stoppered with a wired-on rubber stopper and a short length of pressure tubing was wired-on to the side tube. The flask was evacuated (house vacuum) and the pressure tubing on the side arm clamped shut. The apparatus was then oven heated at 125° with occasional swirling as melting proceeded. After 24 hours at this temperature, the orange melt was quenched in 4.8 liter of cracked ice and water. One equivalent of 50% NaOH (293 g, 3.672 moles) was added in one portion. The mixture was extracted with methylene chloride and these extracts washed with water. Concentration in vacuo gave 734 g of crude product which was recrystallized from 1800 mL of boiling ethyl acetate to yield 548 g, 68%, m.p. 88°-90°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].[K].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C(Cl)(Cl)Cl.O>CN(C=O)C>[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: C[Si](C)(C)C#CCOC(=O)CCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
3-(trimethylsilyl)prop-2-ynyl 6-bromohexanoate (0.606 g, 2 mmol, 1 eq.) was added to a solution of phthalimide potassium salt (0.4412 g, 2.4 mmol, 1.2 eq.) in 50 mL of DMF and stirred overnight under argon. CHCl3 was added to the solution flask and was transferred to a separatory funnel containing water. The aqueous layer was separated and twice extracted with CHCl3. The combined organic layers were twice extracted with water then the solvent was removed on a rotary evaporator. Remaining solvent was removed under high vacuum overnight to yield a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH3:17])[CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of methyl 3-acetyl-5-((1-(4-fluorophenyl)ethyl)-carbamoyl)benzoate (302 mg, 0.88 mmol) in a mixture of THF (1.2 mL), MeOH (2.4 mL) and H2O (6.0 mL), was added LiOH (63.3 mg, 2.64 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound which was ready for next step without further purification (278 mg, 96% yield): HPLC retention time: 1.718 min (method A). MS (ESI) (M+H)+ 329.00.
Reaction SMILES: CN(C)C=O.[SH:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:10][N:11]=1.[OH-].[K+].[F:24][C:25]([F:29])=[C:26]([F:28])[F:27]>C(Cl)(Cl)Cl>[F:24][C:25]([F:29])([S:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[N:10][N:11]=1)[CH:26]([F:28])[F:27]
Reactant: FC(F)=C(F)F
Reactant: FC(F)(F)c1cccc(-c2nnc(S)o2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(F)C(F)(F)Sc1nnc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 60 °C

Procedure:
60 ml of dimethylformamide and 7.38 g of 2-mercapto-5-(3'-trifluoromethylphenyl)-1,3,4-oxadiazole (m.p. 154°-155° C.) and 0.7 g of potassium hydroxide are stirred in an autoclave. 22 g of tetrafluoroethylene are pressed in, and the reaction mixture is heated for 19 hours at 60° C. (10-12·105Pa). After cooling and release of pressure, the solution is poured into ice-water, the product is taken up in chloroform, the chloroform solution is washed with 1n sodium hydroxide solution, and the solvent is removed in vacuo, affording as reside the title compound in the form of an oil with a refractive index nD22 of 1.4926.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[Na+].[I-]>C1COCC1>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)[CH3:51]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), ethyl 4-bromobutyrate (0.087 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, then partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 68% yield).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Br[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1>O.O1CCOCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][S:1]([OH:4])(=[O:3])=[O:2])[CH2:10]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S([O-])[O-]
Reactant: O=C(OCc1ccccc1)N1CCCC(CBr)C1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)O)C1

Procedure:
Sodium sulphite (12.6 g) in water (25 ml) was added to a stirred solution of benzyl 3-(bromomethyl)-1-piperidinecarboxylate (7.8 g) [Preparation 60] in dioxan (25 ml). The reaction mixture was stirred at reflux for 18 hrs, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous solution was separated and acidified with 2N aqueous hydrochloric acid. The product was then extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid as a hygroscopic solid (4.5 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:41][Si](CC)(CC)CC)[CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[S:13][C:12]=12)=[N+:2]=[N-:3].Cl.C(=O)([O-])O.[Na+]>C1COCC1.O>[N:1]([CH2:4][C@@H:5]([OH:41])[CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[S:13][C:12]=12)=[N+:2]=[N-:3]
Reactant: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SC[C@H](O)CN=[N+]=[N-])c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (560 mg) was dissolved in 10 ml of THF and 10 ml of water. The solution was adjusted to pH 2.5 by the addition of 1 N hydrochloric acid. The mixture was stirred at room temperature for 30 min, and was then adjusted to pH 7.0 by the addition of an aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate twice. The organic layers were combined, were washed with brine, and were dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 455 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-hydroxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][O:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1c(B(O)O)ccc2c1CCCC2
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2c(c1OC)CCCC2
Temperature: 25 °C
Yield: 20.1 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid, methyl ester, (2.06 g, 9.61 mM), 1-methoxy-5,6,7,8-tetrahydronaphthalene-2-boronic acid, (2.08 g, 10.09 mM), tetrakis(triphenylphosphine)palladium(0) (0.583 g, 0.5 mM), and 2M aqueous sodium carbonate solution (10.5 mL, 21.0 mM) in THF (50 mL) was stirred at reflux for 48 hours in the absence of light. The mixture was cooled to room temperature, the THF removed in vacuo, and the resulting aqueous residue dissolved in ethyl acetate and brine. The solvent layers were separated, the aqueous layer extracted with ethyl acetate (4×25 mL), the combined ethyl acetate extracts washed successively with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant black oil was purified by column chromatography on silica gel (elution with 5–15% ethyl acetate/hexane) to afford 0.656 g (20%) of the title compound 2-(1-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-nitrobenzoic acid, methyl ester as a yellow solid (MW 341.37, C19H19NO5).