Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C)=CC=1C(O)=O.CC1C=CC(C)=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: Cc1ccc(C)c(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C)c(C(=O)Cl)c1
Agent: Cc1ccc(C)c(C(=O)O)c1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,5-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 91%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([NH:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCCCCCCN
Solvent: CCOCC
Product: NCCCCCCCCNC(=O)Nc1ccccc1

Procedure:
22 grams (0.139 moles) 1,8 diaminooctane in 300 cc ether was reacted with 7.0 gms (.059 mole) phenylisocyanate. The precipitate was filtered and washed with ether, yielding 10.9 gms. Recrystallized from dimethylformamide and recovered 7.8 gms having a melting point of 200°-217°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:24]O>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH:14]([CH3:18])[C:15]([O:17][CH3:24])=[O:16])([O-:3])=[O:2]
Reactant: CO
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 81 %

Procedure:
To a solution of 3-(2,4-dinitrophenyl)-2-methylpropanoic acid (1.6 g, 5.0 mmol) in MeOH (10 mL) was added H2SO4 (0.85 mL, 16 mmol) and the mixture was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in DCM (100 mL). The organic solution was washed with saturated aqueous NaHCO3 and the layers were separated. The organic solution was dried over anhydrous Na2SO4 and filtered. The organic solution was directly purified by preparative TLC (1.0 mm plate), eluting with 5:1 pet ether/EtOAc to give methyl 3-(2,4-dinitrophenyl)-2-methylpropanoate (1.1 g, 81%): LC/MS (Table 2, Method f) Rt=1.95 min; MS m/z: 267 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[OH:24][CH2:25][CH:26]1[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH2:36])=[CH:35][C:29]=2[O:28][CH2:27]1.C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:36][C:34]3[CH:33]=[CH:32][C:30]4[O:31][CH:26]([CH2:25][OH:24])[CH2:27][O:28][C:29]=4[CH:35]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: Nc1ccc2c(c1)OCC(CO)O2
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2ccccc2Br)Cc2cnc(Nc3ccc4c(c3)OCC(CO)O4)nc21
Temperature: 140 °C

Procedure:
1.2 g 3-(2-bromo-phenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 1.54 g 2 hydroxymethyl-6-amino-1,4-benzodioxane (starting material b)) were mixed in 20 ml NMP. 0.348 g TFA were added and the mixture was heated to 140° C. for 7 hrs. The mixture was poured into 10% aqueous HCl and extracted with ethyl acetate. The aqueous phase was adjusted to pH>9 and extracted with CH2Cl2. The organic phases were combined and evaporated. The residue was suspended in CH2Cl2 at room temperature and solid impurities were filtered off. The filtrate was washed again with water to remove remainders of NMP, then evaporated. The residue was triturated with water, filtered and dried to give 0.6 g of the title product (mp: 156–158° C.). NMR (CDCl3, δ in ppm): 2.03 (broad s, 1 H); 3.48 (s, 3H); 3.89 (dd, 1H); 3.95 (dd, 1H); 4.15 (dd, 1H); 4.28 (m, 1H); 4.33 (dd, 1H); 4.55 (d, 1H); 4.71 (d, 1H); 6.89 (m, 1H); 6.98 (m, 2H); 7.25 (m, 1H); 7.40 (m, 3H); 7.71 (d, 1H); 7.98 (s, 1H). MS (APCI+): 498 (M+1), 420 (M-Br)
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O.C[O-].[Na+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].Cl>CO>[CH2:26]([NH:30][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OC
Reactant: CCCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(O)CCCCCCCCCCC(=O)NCCCC

Procedure:
50 g of methyl 12-hydroxystearate, 300 ml of methanol and 20 ml of a 28% methanol solution of sodium methoxide were mixed, and 50 ml of n-butylamine was added thereto. The resulting mixture was heat-refluxed for 6.5 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid, and the precipitated crystals were filtered to obtain 47 g of N-butyl-12-hydroxystearic acid amide having a melting point of 100°-102° C.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:31]=[C:32]([CH2:34][O:35]COCC)[CH:33]=1)[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]([CH3:30])[CH2:23][CH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[CH:19]=[CH:20][CH:21]=1)C>CO.C1COCC1>[OH:28][C:26]([CH3:27])([CH3:29])[CH2:25][CH2:24][CH2:23][CH:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]1[CH:12]=[C:11]([OH:10])[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=1)[CH3:30]
Reactant: CCOCOCc1cc(COc2cccc(C(C)CCCC(C)(C)O)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCCC(C)(C)O)c1cccc(OCc2cc(O)cc(CO)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.4 ml of concentrated sulphuric acid in 5 ml of methanol with 860 mg (1.8 mmol) of 6-[3-(3-ethoxymethoxy-5-ethoxymethoxymethylbenzyloxy)phenyl]-2-methylheptan-2-ol in 5 ml of methanol and 5 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), a colourless oil (m=510 mg. Y=79%) is obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]Br)=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][S:31][C:29](=[O:32])[CH3:30])=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(Nc1ccc(CCCBr)cn1)P(=O)(OCC)OCC
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(Nc1ccc(CCCSC(C)=O)cn1)P(=O)(OCC)OCC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of [(5-(3-bromopropyl)-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[C:4]([F:10])[CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(Br)cc2F)C[C@H](C)O1
Yield: 6.8 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzyl bromide (1.0 g, 3.7 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in THF (37 mL) was added cis-2,6-dimethylmorpholine (0.43 g, 3.7 mmol). The reaction mixture was heated under reflux for 6 h and then cooled, the solid removed by filtration and the filtrate was evaporated. The resultant residue was loaded onto a 10 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound (76 mg, 7%). 1H NMR (CDCl3, 300 MHz): 7.28-7.19 (m, 3H), 3.73-3.59 (m, 2H), 3.49 (d, J=1.5 Hz, 2H), 2.71-2.64 (m, 2H), 1.86-1.73 (m, 2H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=2.84 min, M+H+=302.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1.O.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.O>C(O)C.C1(C)C=CC=CC=1.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>[NH2:27][C:28]1[CH:33]=[C:32]([C:8]2[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:9]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Aqueous sodium carbonate solution (2 M, 1.55 ml) was added to a solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.50 g), 3-aminobenzeneboronic acid monohydrate (0.26 g) and tetrakis(triphenylphosphine)palladium(0) (0.045 g) in ethanol (1.72 ml) and toluene (6.9 ml). The mixture was stirred at reflux under a nitrogen atmosphere for 3 hours and then, cooled to room temperature. The reaction mixture was poured into water and then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give the title compound (0.43 g) as an which was recrystallised from isohexane:ethyl acetate to give a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)=[CH2:2].[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].[K+].[Br-]>C(#N)C.C(OCC)C>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:2][CH2:1][C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: C=CC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: CCCN(CCC)CCC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Vinyl-cyclohex-2-enone (0.75 g, 6.1 mmol) (prepared according to Nasarow's method) was dissolved in acetonitril (1 mL) and dipropylamine (1.5 g, 16 mmol) was added followed by Cs2CO3 (50 mg). After stirring the mixture at rt for 3 h it was diluted with diethylether (100 mL), filtered and evaporated to dryness. The residue was destined in vacuo (175° C., 0.01 mm Hg) to give a slightly yellow oil which was converted to the hydrochloride salt. Recrystallization from isopropyl ether/isopropyl alcohol yielded: 1.2 g, 4.6 mmol (75%), mp 95-97° C. IR (KBr) 2962, 2613, 1667; 1H-NMR (CDCl3) δ 5.84 (d, 1H), 2.65 (m, 2H), 2.27-2.60 (m, 9H), 1.99 (m, 2H), 1.39-1.51 (m, 5H), 0.86 (t, 6H) ppm; 13C-NMR (CDCl3) δ 198.2, 163.5, 124.9, 54.2, 50.1, 35.7, 33.7, 28.4, 21.2, 18.5, 10.4 ppm; MS (EI) m/z 223 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15]([O:19][C:20]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[F-].[K+].C1COCC1>CCOC(C)=O.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[F:11][C:9]1[CH:10]=[C:2]([C:23]2[N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:26]=[CH:25][CH:24]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A vial was charged with 5-bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.0 g, 3.5 mmol), 1-tert-butoxycarbonyl-2-pyrroleboronic acid (1.12 g, 5.3 mmol), KF (0.67 g, 11.5 mmol), and Pd2(dba)3 monochloroform adduct (54 mg, 0.053 mmol) and placed under a nitrogen atmosphere. THF (8 mL) was added and the mixture was purged with nitrogen for 5 min. P(t-Bu)3 (10% wt. solution in hexane 0.370 mL, 0.126 mmol) was added via syringe and the mixture was stirred at 25° C. for 16 h. The mixture was diluted with EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (500 mL 25% hexane/CH2Cl2 then 500 mL 100% CH2Cl2 then 500 mL 5% ethyl acetate/CH2Cl2) afforded the title compound (1.06 g, 88%) as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[S:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=4)=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:41]([O:43]/[N:44]=[C:45](/[C:49]1[N:50]=[C:51]([NH:54]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:52][CH:53]=1)\[C:46](Cl)=[O:47])[CH3:42].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:45](=[N:44]/[O:43][CH2:41][CH3:42])/[C:46]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]4[S:15][C:14]([C:16]5[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=5)=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:50]=1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12
Reactant: CCO/N=C(\C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Yield: 7 %

Procedure:
1 equivalent of 7-amino-3-[2-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-5-ylthiomethyl]ceph-3-em-4-carboxylic acid was silylated with 4 equivalents of bistrimethylsilylacetamide in anhydrous dichloromethane at room temperature for three hours. To this solution, cooled to 0° C. under argon, was added 1 equivalent of 2-[(Z)-ethoxyimino-2-(tritylaminothiazol-4-yl) acetic acid chloride (prepared from the corresponding acid (1 equivalent), 1 equivalent PCl5 and 1 equivalent TEA in dichloromethane at 0° C. for 2 hours followed by evaporation of the solvent and all POCl3, and redissolution in dichloromethane). After a few minutes at 0° C., the solvent was evaporated, and all the protecting groups removed by treating the crude reaction mixture with TFA/water for 1 hour at room temperature. The solvents were evaporated and the crude product dissolved in MeOH and precipitated in ether. Further purification was achieved by MPLC, to yield the title compound (7%), NMR (DMSOd6, AcOD, TFA), 1.25 (t,3H); 3.7 (m,2H); 4.2 and 4.25 (2d,2H); 4.4 (q,2H); 5.15 (d,1H); 5.75 (d,1H); 6.85 (d,1H); 7 (s,1H); 7.15 (d,1H); 7.3 (s,1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[BH4-].[Li+].O>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 4-cyclopropylbenzaldehyde (0.71 g) in methanol (10 mL) was added lithium borohydride (2 mol/L tetrahydrofuran solution, 3.7 mL), and the mixture was warmed to room temperature and stirred for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 mol/L hydrochloric acid solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 4-cyclopropylbenzyl alcohol (0.69 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@@H:16]([C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)[C@H:15]([OH:26])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OC)(O[CH3:31])(=O)=O.O>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][C@H:15]([O:26][CH3:31])[C@@H:16]([C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)[CH2:17]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.149 g, 3.73 mmol) was suspended in anhydrous tetrahydrofuran (20 ml) to which, after cooling to 0° C., was subsequently added dropwise a dry tetrahydrofuran (20 ml) solution of 1-benzyloxycarbonyl-3-(S)-hydroxy-4-(R)-(1-ethoxycarbonylcyclopropyl)pyrrolidine (0.98 g, 2.92 mmol) over a period of 5 minutes. After 15 minutes of stirring in an ice bath, dimethyl sulfate (0.441 ml, 4.66 mmol) was added dropwise to the reaction solution which was cooled in the ice bath. The reaction solution was stirred at room temperature for 4 hours and then mixed with water (0.5 ml), followed by evaporating tetrahydrofuran under reduced pressure. The thus obtained residue was dissolved in ethanol (40 ml), and a 1 M sodium hydroxide aqueous solution (8.76 ml) was added dropwise to the resulting solution at room temperature. The reaction solution was heated under reflux for 2 hours and then ethanol was evaporated under reduced pressure. The resulting residue was cooled in an ice bath, acidified by adding dropwise a 1 M hydrochloric acid aqueous solution (15 ml) and then extracted with ethyl acetate (50 ml×3). All of the organic layers were combined, washed with a 1 N hydrochloric acid aqueous solution (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.935 g (quantitative) of the title compound as a colorless amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5](Br)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1B(O)O.C(Cl)Cl>C(COC)OC.O.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>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([C:16]3[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=3[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
Part B: In a mixture of 270 ml dimethoxyethane and 45 ml water, after bubbling through nitrogen gas for 30 minutes, a quantity of 5.0 g ( 19.5 mmol) of 2-methyl-4-chloro-8-bromo-quinoline, 3.5 g (21 mmol) of 2,4,6-trimethyl phenylboronic acid, 13.2 g (42 mmol) Ba(OH)2.8H2O and 0.69 g (0.6 mmol) tetrakis(triphenylphosphine)palladium were subsequently dissolved. After heating to 80° C. for 16 hours and subsequent cooling, 250 ml of water and 500 ml of CH2Cl2 were added. After separation the organic layer was dried over sodium sulphate and concentrated in vacuo. The product was purified on a silicagel column using dichloromethane as eluent. A total of 5.1 g of 2-methyl-4-chloro-8-(2,4,6-trimethylphenyl)-quinoline was obtained (88% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.CC[N+](CCCN(C)C)=C=N.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]1)=[O:33])=[CH:26]2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-1H-indole-2-carboxylic acid (96.3 mg, 0.538 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide (EDC)(124 mg, 0.645 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (87 mg, 0.645 mmol) in dichloromethane/DMF (4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then filtered to give title compound (161 mg).