Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1.Cl>C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:6]=1
Reactant: COC(=O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Lithium hydroxide monohydrate (0.062 g, 1.49 mmol) was added into a suspension of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)thieno[2,3-d]pyrimidine-6-carboxylate (0.100 g, 0.25 mmol) in THF/water (1:1; 1.0 mL) and the reaction stirred at ambient temperature for 16 hours. The mixture was cooled in an ice-bath and 1 N hydrochloric acid added drop wise until the solution reached pH 5. The precipitate was collected, washed with water and dried over P2O5 to yield off-white solid (0.060 g, 62%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:7]=1)=[NH:10]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1cccc(OC)c1CNC(=N)Nc1cccc(-c2ccc(F)cc2)n1

Procedure:
0.254 g (0.695 mmol) N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine, 0.128 g (0.913 mmol) 4-fluorophenylboric acid, 0.239 g (2.258 mmol) sodium carbonate, and 0.055 g (0.047 mmol) tetrakis-(triphenylphosphine)palladium(0) were heated to 110° C. in 1,2-dimethoxyethane/water/ethanol (7:3:2) in a reaction block (Variomag, Telemodul 40 CT) at standard pressure. Upon cooling of the reaction mixture a yellow solid precipitated, which was suctioned off and washed with water. After the yellow solid was dissolved in methanol and dichloromethane the catalyst was separated via a Millipore filter (Ø=25 mm, 0.45 μm). The target product N-(2,6-dimethoxybenzyl)-N′-[6-(4-fluorophenyl)pyridin-2-yl]guanidine was in the pure form after the removal of solvent, and the yield was 0.214 g (0.563 mmol, 81%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:14])[NH:12][CH3:13])[CH:6]=1)C.[BH4-].[Na+]>C(O)C>[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([NH:12][CH3:13])=[O:14])[CH:6]=1
Reactant: CCOC(=O)c1ccnc(C(=O)NC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of 2-methylcarbamoyl-isonicotinic acid ethyl ester (7.77 g, 37.3 mmol) in absolute ethanol (125 mL) was added sodium borohydride (2.82 g, 74.6 mmol, 2.0 eq), and the reaction mixture was stirred at RT under argon for 18 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated at reduced pressure to give 5.36 g (86.5%) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide as a colorless solid: MS LC-MS [M+H]+=153.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCN(C)C1=O>C1(C)C=CC=CC=1>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
A four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser with a water trap was charged with 554.7 g of p-phenylphenol, 607.7 g of p-chlorotoluene, 265.4 g of potassium carbonate, 8.0 g of 8-hydroxyquinoline-copper complex and 82 g of 1,3-dimethyl-2-imidazolidinone. The mixture was stirred at 140° to 180° C. under nitrogen for 5 hours while the temperature was raised gradually. The material which was collected in the trap was removed from time to time. After 15 hours of further heating at 170° to 185°C. with stirring, the ratio of p-phenylphenol and 4-biphenylyl p-tolyl ether in the reaction mixtures was found to be 1.5:98.5 as determined by GLC (gas-liquid chromatography) on the area ratio basis. Thereafter, the resulting mixture was concentrated under reduced pressure (10 mmHg) to give 270 g of a distillate composed of p-chlorotoluene and 1,3-dimethyl-2-imidazolidinone. Toluene (400 ml) was added to the residue for dissolving the reaction product. The organic layer was washed with a 10% sodium hydroxide solution, 10% sulfuric acid, and water, in that order. The toluene was then distilled off under reduced pressure to give 796 g of crude, light brown 4-biphenylyl p-tolyl ether in 95% yield. Distillation of the crude product under reduced pressure (2 mmHg) at 190° to 195° C. to give 775 g (92% yield) of white 4-biphenylyl p-tolyl ether melting at 97° to 99° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].[Cl:24]C1OC(CNCCSC2C=CC3C(=CC=CC=3)C=2Cl)=CC=1>>[Cl:24][C:21]1[O:20][C:19]([CH2:18][NH:17][CH2:16][CH2:15][S:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])(=[O:14])=[O:13])=[CH:23][CH:22]=1
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Reactant: Clc1ccc(CNCCSc2ccc3ccccc3c2Cl)o1
Product: O=S(=O)(CCNCc1ccc(Cl)o1)c1ccc2ccccc2c1Cl
Yield: 50 %

Procedure:
Prepared as described for compound 25 from N-[(5-chlorofuran-2-yl)methyl]-2-[(1 chloronaphthalen-2-yl)sulfanyl]ethanamine in 50% yield as whitish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:24][C:25]#[CH:26])[C:13]([NH:15][CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([NH3+:64])[C:60]([O:62][CH3:63])=[O:61])=[N+:50]=[N-:51].CCN(C(C)C)C(C)C>CN(C=O)C>[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([C:60]([O:62][CH3:63])=[O:61])[NH:64][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:15][C:13](=[O:14])[CH:12]([CH2:24][C:25]#[CH:26])[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:50]=[N-:51]
Reactant: COC(=O)C([NH3+])CCC(=O)NCCCN=[N+]=[N-]
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of compound 4 (11.7 g; 31 mmol) in dry DMF (100 mL) was added EDCI (7.25 g; 37.82 mmol), HOBt (5.79 g; 37.82 mmol), and the reaction mixture was stirred at room temperature for 30 min (solution A). In the meantime, to a solution of compound 9 (8.67 g: 31 mmol) in dry DMF (100 mL) kept at 0° C. was added DIEA (10.01 g; 77.7 mmol) and stirred for 30 min (solution B). Solution B was mixed with solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL) and washed sequentially with saturated sodium bicarbonate (2×75 mL), 5% HCl (2×75 mL) and brine (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, yielding a crude product which was purified using recrystallization to yield 9 as an off white solid (8.3 g; 46% yield). NMR (CDCl3) δ 8.1 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 7.5 (s, 1H) 7.3 (m, 5H), 5.0 (s, 2H), 4.3 (m, 1H), 4.1 (m, 1H), 3.3 (t, 1H), 2.8 (s, 1H), 2.4 (d, 2H), 2.2 (d, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 1H), 0.8 (d, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12](=[O:25])[C:13]3[C:17]=2[C:16](=[O:18])[NH:15][C:14]=3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(C1C=CC(C)=CC=1)(O[CH3:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][N:15]1[C:16](=[O:18])[C:17]2=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[O:11][C:12](=[O:25])[C:13]2=[C:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc([N+](=O)[O-])cc3)=C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(c3ccc([N+](=O)[O-])cc3)OC(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of furopyrrole 12 (0.9 g, 2.7 mmol), methyl tosylate (750 mg, 4.04 mmol), potassium carbonate (1 g, 7.2 mmol) and dimethyl formamide was stirred at room temperature overnight. Water was then added, and the organic component extracted with DCM. The solvent was removed, and washing with water then methanol gave the methylated compound 13 as a red solid (0.652 g, 70%), m.p. 253-255° C. δH (CDCl3) 8.55 and 8.38 (4H, AA′BB′, Ar), 7.88-7.84 (2H, m, o-Ph), 7.65-7.60 (3H, m, m/p-Ph) and 3.49 (3H, s, NCH3). λmax (abs) (DCM)/nm 482 ( 17,462)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[OH-:26].[K+].P.CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:9]1[CH:10]=[C:2]([OH:26])[C:3]2[CH:4]=[CH:5][N:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=3)[C:7]=2[CH:8]=1
Reactant: [OH-]
Reactant: Fc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)cc3)c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Oc1cc(F)cc2c1ccn2-c1ccc(OCc2ccccc2)cc1
Temperature: 85 °C
Yield: 44.6 %

Procedure:
A mixture of 4-bromo-6-fluoro-1-{4-[(phenylmethyl)oxy]phenyl}-1H-indole (D19) (200 mg, 0.505 mmol) and potassium hydroxide (113 mg, 2.02 mmol) in 1,4-dioxan (3 mL)/water (3 mL) was treated with Pd2dba3 (9 mg, 0.02 mmol) and phosphine ligand, bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (11 mg, 0.05 mmol) and the mixture was heated to 85° C. for 1.5 hours. After cooling, the mixture was diluted with dichloromethane and water and the product was extracted into dichloromethane. The combined organic layers were dried (MgSO4) and evaporated. Chromatography on silica gel (elution with 0-50% ethyl acetate in hexane) gave the title compound (D20), (75 mg).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:4].[OH-].[Li+]>>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:6]1[CH2:7][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ncccn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ncccn1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-pyrimidin-2-yl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid. MS (ESI): m/z=402.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(Cc3ccccc3)cn(-c3ccccn3)c2C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (10 mg, 0.31 mmol), benzyltributylstannane (253 mg, 0.68 mmol) and dichlorobis(triphenylphosphine)palladium (50 mg, 0.08 mmol) in hexamethylphosphoramide (1 mL) was heated at 70° C. for 48 h. The mixture was cooled to room temperature, diluted with DCM (2 mL), and the solution chromatographed on silica gel, eluting with isohexane: EtOAc (4:1). The title compound (45 mg, 43%) was isolated as a colourless solid. mp 111-113° C. Found: C, 79.7; H, 6.7; N, 8.3%. Calc. C22H22N2O: C, 79.97; H, 6.71; N, 8.48%. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 2.39 (2H,s), 2.93 (2H,s), 4.17 (2H,s), 6.61 (1H,s), 7.16-7.34 (7H,m), 7.77 (1H, d of t, J=7.7 and 1.9 Hz), 8.50-8.53 (1H,m). MS (ES+) 331 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17].O>CN(C)C=O.C(OCC)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Hydroxyquinoline (0.46 g) in dry N,N-dimethylformamide (10 ml) was added dropwise to a stirred suspension of sodium hydride (0.10 g, 80% dispersion in mineral oil) in dry N,N-dimethylformamide under an atmosphere of nitrogen at ambient temperature. The green solution was stirred at ambient temperature for 1 hour and a solution of 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.74 g) in dry N,N-dimethylformamide (10 ml) was added. The mixture was stirred at ambient temperature for 18 hours, poured into water and extracted into diethyl ether (three times). The organic extracts were combined, washed with dilute aqueous sodium hydroxide, water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give a gum. The gum was fractionated by chromatography (silica; diethyl ether) to give the required product, 0.44 g, as a colourless gum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:36])[CH3:35])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:34]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:38]=[CH:37][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH2:31][O:32][CH3:33])=[N:28]1)([CH3:36])[CH3:35]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.30 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL, 20.2 mmol) and the reaction mixture stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue azeotroped with ether. The resultant oil was triturated with diethyl ether to give 2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetate salt as a solid which was collected by filtration (103 mg, 64%). LCMS RT=3.03 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1 H, s), 8.33 (1 H, d, J=8.33 Hz), 7.90 (1 H, s), 7.00 (1 H, dd, J=8.38, 1.78 Hz), 6.85 (1 H, d, J=1.73 Hz), 5.81-5.80 (1 H, m), 4.46 (4 H, d, J=2.51 Hz), 4.33 (2 H, s), 3.34 (2 H, d, J=12.58 Hz), 3.27 (3 H, s), 2.98-2.95 (2 H, m), 2.82 (1 H, t, J=11.91 Hz), 1.93 (2 H, d, J=13.66 Hz), 1.75 (2 H, t, J=12.95 Hz), 1.44 (6 H, d, J=6.60 Hz)
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]#[N:12])=[O:4].[OH-].[Li+]>C1COCC1>[C:11]([CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])#[N:12]
Reactant: COC(=O)[C@@H]1CCCN1CC#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CCN1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-cyanomethyl-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.60 mmol) and lithium hydroxide (16 mg, 0.66 mmol) in THF (2 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under vacuum and the resulting residue dissolved in water (5 mL) and neutralized with 1M aqueous HCl. The resulting solution was freeze-dried to afford (S)-1-cyanomethyl-pyrrolidine-2-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ: 3.80 (d, 2H), 3.53 (dd, 1H), 3.25 (m, 1H), 2.85 (m, 1H), 2.40-1.94 (m, 4H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:34][C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
1.95 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 4.7 g of phenol in 15 ml of trifluoroacetic acid, and the solution is left to stand for 15 minutes at room temperature and is then diluted with an equal amount of toluene. After evaporation under reduced pressure, the residue is taken up in 100 ml of acetic acid ethyl ester and 50 ml of an aqueous 10% strength dipotassium hydrogen phosphate solution, the mixture is well shaken and the organic phase is separated off. The aqueous layer is twice washed with 100 ml portions of acetic acid ethyl ester to remove the excess phenol and then covered with 100 ml of acetic acid ethyl ester, and its pH value is adjusted to 2 by means of 20% strength aqueous phosphonic acid. The organic layer is separated off after thorough shaking, the aqueous solution is twice extracted with 100 ml portions of acetic acid ethyl ester, and the combined organic extracts are washed three times with 50 ml portions of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is triturated with acetic acid ethyl ester and yields 3-(4-hydroxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, which after recrystallisation from a mixture of acetic acid ethyl ester and methanol melts at 210°C; thin layer chromatogram (silica gel): Rf = 0.72 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.77 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.49 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 224 mμ (ε = 15800) and 276 mμ (ε = 2400), and shoulder at 282 mμ (ε = 1900); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.77μ, 5.80μ, 6.07μ and 6.62μ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([N+:26]([O-:28])=[O:27])=[CH:19][CH:20]=[CH:21][C:22]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Nc3c([N+](=O)[O-])cccc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,6-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (57%) as a dark red solid: mp, 187.0°-188.0° C.; 13C NMR (DMSO-d6) δ139.9, 135.2, 134.0, 132.0, 131.8, 127.2, 123.8, 117.0, 115.4, 112.9, 112.0, 109.3, 59.9, 45.1, 23.0; HRMS calculated for C18H19N5O 369.1439, found 369.1428. Anal. calcd. for C18H19N5O: C, 58.53; H, 5.18; N, 18.96. Found: C, 58.45; H, 4.96; N, 18.63.
Reaction SMILES: [Na+].Br[CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6].C[O-].[Na+].[CH2:12]([SH:15])[CH2:13][SH:14].Cl>CCO.O>[CH2:12]([S:15][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[CH2:13][S:14][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6]
Reactant: SCCS
Reactant: O=S(=O)([O-])CCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCSCCSCCS(=O)(=O)O
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a solution of 2-bromoethylsulfonate sodium salt (25.6 g, 125 mmol) and sodium methoxide (8.03 g, 149 mmol) in EtOH (350 mL) at 0° C. was added, dropwise, a solution of 1,2-ethanedithiol (5.00 mL, 59.4 mmol) in EtOH (25 mL). The reaction mixture was allowed to warm to room temperature, and then heated to reflux for 48 hours. Next, the mixture was cooled to room temperature, and then acidified with 2 N HCl to pH 1-2. The resulting suspension was heated to 75° C. and water was slowly added in small portions until a clear solution was obtained. The reaction mixture was then cooled to room temperature, and then to 5° C. The resulting white precipitate was filtered off, washed with cold EtOH and dried, giving 11.9 g (64.6%) of Compound 4 as a white powder. 1H NMR (500 MHz, D2O) δ 3.27 (t, J=9.3, 6.4 Hz, 4H), 3.06-2.99 (m, 4H), 2.98 (s, 4H). 13C NMR (126 MHz, D2O) δ 51.11, 31.09, 25.58.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[C:20]2[O:25][CH2:26][O:27][C:19]=12>>[Cl:24][C:23]1[C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:19]2[O:27][CH2:26][O:25][C:20]2=[N:21][CH:22]=1
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Product: ClCCCOc1ccc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2c1
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(3-chloropropoxy)quinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 89% yield; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.25 (m, 2H), 3.8 (t, 2H), 4.35 (t, 2H), 6.25 (s, 2H), 7.35 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.7 (d, 1H), 9.0 (s, 1H).