Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[S:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.CN1C(=O)CCC1>O>[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:2]3[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: Nc1ccc2ncsc2c1
Reactant: N#Cc1cnc(Cl)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc(Nc2ccc3ncsc3c2)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Temperature: 150 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 6-chloro-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.108 g, 0.356 mmol), benzo[d]thiazol-6-amine (0.187 g, 1.244 mmol) and NMP (1.422 mL) was stirred at 150° C. for 1 hour in a microwave reactor. The vessel was cooled to room temperature, diluted with water and filtered. Following drying on a buchner funnel, 6-(benzo[d]thiazol-6-ylamino)-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.122 g, 0.292 mmol, 82% yield) was collected as a yellowish solid. LC-MS (m/z, M+1=418), Waters sunfire 4.6×50 mm C18 Sum 4 min/1 min hold time 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFA RT=2.06.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.NN.C1C=CC2N(O)[N:18]=[N:17]C=2C=1.CCN=C=NCCCN(C)C>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH:17][NH2:18])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: ClCCl
Product: NNC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a round-bottom flask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 23.3 mmol, 1.00 equiv, 90%) in dichloromethane (40 mL). NH2NH2 (2 mL, 2.00 equiv), HOBt (5.20 g, 38.5 mmol, 1.50 equiv), and EDCI (7.50 g, 39.1 mmol, 1.50 equiv) were added and the resulting mixture was stirred overnight at 25° C. The solids were removed by filtration, and the filtrate was concentrated in vacuo to furnish 2.50 g (74%) of (S)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[N:31]=2)=[CH:34][CH:35]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Cc1cc(C)nc(Oc2ccc(I)cc2)n1
Product: COC(=O)C(C/C=C/c1ccc(Oc2nc(C)cc(C)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 56.5 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (47 mg) was reacted with 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (56 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4,6-dimethylpyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (44 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][C:5]([NH2:6])=[C:4]([F:22])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:29]([O:31][C:32]([CH3:34])=[CH2:33])=[O:30]>CCOC(C)=O>[Br:1][C:2]1[C:8]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][C:5]([NH:6][C:29](=[O:30])[O:31][C:32]([CH3:34])=[CH2:33])=[C:4]([F:22])[CH:3]=1
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3Br)c(C)nc2n1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(Br)cc1F
Yield: 100 %

Procedure:
Treat a mixture of 4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)aniline (0.20 g, 0.527 mmol) in EtOAc (10 mL) and saturated. NaHCO3 (10 ml) with isopropenyl chloroformate (0.064 ml, 0.580 mmol) and stir the biphasic mixture vigorously at RT for 4 h. Separate the layers, extract the aqueous layer with additional EtOAc (1×), wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (assume 100% yield). MS (m/z): 463.0.
Reaction SMILES: [C:1]([C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:16]([O:18][C:19]([C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1C(=O)C(C)C
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C(=O)C(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-isobutyryl-3-methyl-benzoic acid (227) (200 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (220 mg, 1.07 mmol), HATU (441 mg, 1.16 mmol) in anhydrous DMF (10 mL) is added DIPEA (192 μL, 1.16 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in DCM (50 mL) and washed with water (1×5 mL) and brine (1×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (228) as a pale yellow solid (340 mg, 89%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].NCCC(O)=O>C(O)CCC>[N+:13]([C:16]([CH3:17])=[CH:11][C:8]1[S:9][CH:10]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)([O-:15])=[O:14]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cc(-n2ccnc2)cs1
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1cc(-n2ccnc2)cs1)[N+](=O)[O-]
Reaction time: 9 h

Procedure:
A mixture of 94 g 4-(1-imidazolyl)-thiophene-2-aldehyde (EPA 112 987), 47.7 g nitroethane, 4.9 g β-alanine and 327 ml n-butanol is stirred for 9 hours at reflux temperature. Subsequently, it is evaporated and the residue is purified by column chromatography (silica gel//dichloromethane/methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([Cl:35])=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)Cl)c(F)c3)c2CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.95 g, 4.21 mmol) in DCM (20 mL) at 0° C. under nitrogen, add three drops of DMF and oxalyl chloride (1.06 g, 8.41 mmol). Stir for 2 h and concentrate in vacuo to afford the desired intermediate as a yellow oil (1.93 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In 300 ml of chloroform, 100 g of 4-chloro-3-nitrobenzenesulfonyl chloride was dissolved, and cooled to 0° C. Thereto, a solution of 84.3 g of methyloctadecylamine in chloroform was added dropwise. Then, 39.5 g of triethylamine was added dropwise as the reaction system was kept at a temperature from 0° C. to 10° C. After the conclusion of the addition, the reaction was run for 1 hour. Then, the solvent was distilled away, and the residue was dissolved in 500 ml of methanol under heating. The solution was allowed to stand for a while in order to cool. Thereupon, crystals separated out, and they were filtered off. Yield: 109 g, Percent yield: 71.2%, Melting point: 86°-87° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]1[C@@H:46]2[C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:40][NH:39]1>O1CCCC1>[CH2:16]([C@@H:11]([CH2:12][C:13]([N:39]1[CH2:40][C@H:41]2[C@H:46]([CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:38]1)=[O:15])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of (S)-3-benzyloxycarbonyl-4-phenylbutyric acid (671 mg) in anhydrous tetrahydrofuran (15 ml) were added N-methylmorpholine (0.5 ml) and isobutyl chloroformate (0.38 ml) with stirring at -20° C. for 20 minutes. To the mixture was added a solution of cis-hexahydroisoindoline (313 mg) in anhydrous tetrahydrofuran (5 ml) with stirring at -10 - -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from dichloromethane-hexane to give 772 mg of benzyl (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate.
Reaction SMILES: [CH2:1](O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([N:22]([CH2:48][CH3:49])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[CH3:21].[OH-].[Na+]>C(Cl)Cl>[CH2:48]([N:22]([CH2:20][CH3:21])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:31]2[CH2:32][CH2:33][N:34]([CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)[CH2:35][CH2:36]2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)=[CH:26][CH:25]=1)[CH3:49]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: OCc1ccco1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccco3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a 0° C. solution of furfurylalcohol (0.19 ml; 2.24 mmol) and triethylamine (0.52 ml; 3.73 mmol) in methylene chloride (4 ml) was added methanesulfonyl chloride (0.17 ml; 2.24 mmol). The mixture was stirred 1 hour at 0° C., then compound 1 (300 mg; 0.75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight, then heated to 45° C. and stirred for 1½ hours. The reaction mixture was allowed to cool to room temperature and NaOH 2N was added untill pH was basic. The mixture was extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-25% CH3CN/H2O (TFA as the buffer) gave 197 mg of desired product (TFA salt).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:23]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([NH2:23])=[O:21])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Next, anhydrous tetrahydrofuran (7 ml) was added to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.59 g, 2.0 mmol), and the mixture was stirred at −78° C. N-Methylmorpholine (0.22 ml, 2.0 mmol) and then a solution of isobutyl chloroformate (0.38 ml, 2.9 mmol) in tetrahydrofuran (3 ml) were added to the mixture. After one hour, a 28% aqueous ammonia solution (6.0 ml, 9.8 mmol) was added thereto, and the whole was stirred for 1.5 hours. Chloroform (50 ml) was added to the reaction mixture, the temperature was raised to room temperature, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (20 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.34 g (58%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O-]S([O-])(=O)=O.[Mg+2].[NH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH2:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:16][NH:15][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CN1CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CN1CCC(NNC(=O)OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
To a solution of 1-methylpiperidin-4-one (3.0 g, 27 mmol) in DCM (60 mL) was added MgSO4 (6.5 g, 54 mmol) and tert-butyl hydrazinecarboxylate (2.9 g, 22 mmol). The reaction mixture was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:20) to give tert-butyl 2-(1-methylpiperidin-4-yl)hydrazinecarboxylate (3.2 g, 53% yield) as a colorless oil. LCMS (ESI) m/z: 228.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][C:3]2([C:2]([F:9])([F:8])[F:1])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1(C(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A 0° C. solution of (1-(trifluoromethyl)cyclopropyl)methanol (2.46 g, 17.56 mmol), TEA (2.94 mL, 21.1 mmol) and DMAP (0.215 g, 1.76 mmol) in DCM (35 mL) was treated with p-toluenesulfonyl chloride (3.38 g, 17.7 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with additional DCM, washed with 2N HCl (3×), followed by satd. NaHCO3, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (3.42 g, 66%). 1H NMR (400 MHz, DMSO-d6): δ 7.77 (m, 2H), 7.48 (m, 2H), 4.16 (s, 2H), 2.41 (s, 3H), 1.04 (m, 2H), 0.92 (m, 2H); MS (ESI) m/z: 295.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[N:8]([CH2:29][CH2:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201 mg, 1.0 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg, 3.24 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (873 mg, 3.0 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography and 10% MeOH-DCM to yield 3,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (190 mg). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.2 (s, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.3 (t, 2H), 3.6 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.5 (s, 8H), 2.4 (s, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14](Cl)[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14]([NH:2][NH2:3])[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=c1c(Cl)nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Hydrazine hydrate (2.7 ml, 55 mmol) was added to a solution of 5.9 g (14 mmol) of 1-benzyloxy-3-chloro-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in 100 ml of dichloromethane with stirring at 0° C. After 1 h the mixture was evaporated to dryness and the residue was triturated with water and dried to give 5.3 g (90%) of crude title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:21][CH2:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:7])(C)(C)C.C(N(CC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:21][CH2:22][S:23](=[O:25])(=[O:26])[NH2:24])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:19]
Reactant: CCN(CC)c1ccccc1
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.95 g. (2 mmol.) of 7β-amino-7α-methoxy-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g. (2 mmol.) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0-5° while 0.56 g. (2 mmol.) of D-O-dichloroacetylmandeloyl chloride in 10 ml. of methylene chloride is added dropwise over a 10 minute period. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml. of cold dilute hydrochloric acid and 50ml. of cold 5% aqueous sodium bicarbonate, dried (MgSO4) and evaporated to dryness. The residue is dissolved in a mixture of 10 ml. of trifluoroacetic acid and 2 ml. of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml. of ether and 50 ml. of water. The pH is adjusted to 9.3-9.5 with 5% aqueous sodium carbonate and the organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml. of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml. portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(C#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Mg]I.CC[O:20][CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21](=[O:20])[CH3:22])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (163.6 g) in ether (130 ml) was added dropwise over 0.5 hours at ambient temperature under nitrogen to stirred methylmagnesium iodide (3M solution in ether; 300 ml), then the mixture was heated under reflux for 1 hour, diluted with ether (100 ml), heated under reflux for a further 2.5 hours, then stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions at <20° C. to a stirred mixture of concentrated hydrochloric acid (410 ml) and water (650 ml). The mixture was heated at 95° C. for 0.5 hours with occasional stirring then cooled to ambient temperature. The product was extracted into dichloromethane (3×200 ml), the combined extracts were dried over magnesium sulphate, and the solvent removed in vacuo to leave 1-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone as a dark red oil (172.7 g) which was used without purification.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:14])C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([CH2:38][OH:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43]([NH2:45])=[O:44])[N:42]=[C:33]3[C:32]=2[CH:46]=1>ClCCl.O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([C:38]([OH:14])=[O:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43](=[O:44])[NH2:45])[N:42]=[C:33]3[C:32]=2[CH:46]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CO)C2
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
TEMPO (17 mg, 0.11 mmol, 0.33 equiv) and PhI(OAc)2 (255 mg, 0.79 mmol, 2.37 equiv) were added to a stirred suspension of 10-bromo-6-(hydroxymethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (113 mg, 0.33 mmol, 1.00 equiv) in dichloromethane (4 mL) and water (0.8 mL) at 0° C. After 30 min the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched by the addition sodium bicarbonate and washed with dichloromethane. The pH value of the aqueous solution was adjusted to 2 by 2N hydrogen chloride. The aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in to 85 mg (crude) of 10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-6-carboxylic acid as a white solid.