Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNc3ccccn3)c2c1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine (150 mg, 0.38 mol, prepared in analogy to Example 9-16), 2-bromo-pyridine (60 mg, 0.38 mol), tri(dibenzylideneacetone)dipalladium(0) (17.4 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthe (22 mg, 0.038 mmol), cesium carbonate (247.6 mg, 0.76 mmol) and N-methylpyrrolidinone (3 mL) was heated with stirring at 150° C. for 6 hours under nitrogen. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by preparative HPLC to give 10 mg of produce as an off-white solid. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.1 (d, J=6.4 Hz, 1 H), 7.96 (dd, J=1.2, 8.0 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H), 7.54-7.39 (m, 5 H), 7.27 (dd, J=2.0, 8.8 Hz, 1 H), 6.63-6.56 (m, 2 H), 6.07 (s, 1 H), 5.10 (s, 2 H), 4.52 (brs, 2 H), 3.69 (t, J=6.4 Hz, 2 H), 3.55 (m, 4 H), 2.40 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([CH3:14])[S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[O:20][CH:19]=3)=[O:23])[CH2:49]2)=[CH:46][CH:47]=1
Reactant: c1cc(C2CCCNC2)ccc1C1=NCCN1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCCC(c4ccc(C5=NCCN5)cc4)C3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), 3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]piperidine (49 mg, 0.15 mmol) and DIPEA (0.134 mL, 0.76 mmol) in DCE (1.2 mL).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)=[CH:5][C:4]=1[CH3:30])#[N:2].[Cl-].[Li+].C(#N)C>CC(N(C)C)=O.CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])=[CH:5][C:4]=1[CH3:30])#[N:2]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)c(C)c3)c2OC)nc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)c(C)c3)c2O)nc1
Yield: 26.7 %

Procedure:
Combined 6-(4-(4-cyano-3-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (54.7 mg, 0.135 mmol) and lithium chloride (57.2 mg, 1.350 mmol) in DMA (2109 μl) and heated at 60° C. for 24 hours. The reaction mixture was then diluted with 0.6 mL DMSO and purified by preparative HPLC (35-60% acetonitrile in water under TFA conditions) and then again (15-40% acetonitrile in water under basic conditions) to give the title compound (14 mg, 0.036 mmol, 26.5%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (quin, J=6.63 Hz, 2H) 2.43 (s, 3H) 3.25 (s, 3H) 3.38-3.41 (m, 4H) 7.08 (br. s., 2H) 7.58 (d, J=8.08 Hz, 1H) 7.88 (d, J=9.35 Hz, 1H) 7.97 (s, 1H) 8.29 (dd, J=8.46, 2.40 Hz, 1H) 8.50 (d, J=8.34 Hz, 1H) 8.61 (t, J=6.06 Hz, 1H) 8.85 (d, J=1.77 Hz, 1H); MS (M+H)+392.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.03 g (10.91 mmol) of 4-bromo-2-methylaniline in 40 ml of DMF was added 2.07 g (14.98 mmol) of K2CO3 and 0.63 ml (10.12 mmol) of iodomethane, and the mixture was stirred at room temperature for 14 hours. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 20:1) to give the title compound. 1H-NMR (CDCl3) δ 2.18 (s, 3H), 2.90 (s, 3H), 3.60 (brs, 1H), 6.49 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.29 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:10]Br>CCOCC>[Br:10][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a mechanically-stirred solution of ethyl acetoacetate (59 mL, 463 mmol) in ether (75 mL) was added bromine (23.5 mL, 912 mmol) while the reaction temperature was maintained below 23° C. using an ice-water bath. The yellow-orange solution was stirred for 5 hours with cooling and then was stirred overnight at ambient temperature. Ice (60 g) was added and the reaction mixture was extracted with ether. The organic phase was washed twice with aqueous NaHCO3 saturated with NaCl and once with brine. The ether solution was stirred for 1 day over CaCl2 and then was filtered through celite. The filter cake was rinsed with dichloromethane. The filtrate was concentrated in vacuo to give ethyl 4-bromoacetoacetate (71.5 g) which was stored in the dark and stabilized with BaCO3 (300 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1H-NMR (300 MHz, CDCl3) δ7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]([NH2:40])=[O:39].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>C(Cl)Cl>[C:38]([C:34]1[S:35][CH:36]=[CH:37][C:33]=1[NH:32][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:29])(=[O:39])[NH2:40]
Reactant: NC(=O)c1sccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccsc2C(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 3-aminothiophene-2-carboxylic acid amide (160 mg, 1.1 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-thiophen-3-yl)-amide as a off white powder (15.8 mg, 6.2%). HRMS (ES+) m/z Calcd for C28H26Cl2F2N4O2S+H [(M+H)+]: 501.1195. found: 591.1191.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)N
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccccc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
t-Butylamine (2.0 eq.) was stirred in dry THF at r.t. and n-butyllithium (1.2 eq.) was added slowly. The resulting mixture was stirred for 30 min. and then bromobenzene (1.0 eq.) added, refluxed for 4 hr. After work-up, it was purified and separated by a column(silica) to elute with hexane and ethyl acetate (9:1). Yield 50%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: Fc1ccc(OCCBr)c(F)c1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1F

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-2,4-difluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.26-7.15 (m, 1H), 7.10-7.00 (m, 1H), 6.92-6.88 (m, 1H), 4.67 (t, J=5.0 Hz, 2H), 4.30 (t, J=5.0 Hz, 2H), 3.30 (s, 3H); MS (ES) m/z 347 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:11]1[C:21]2=[C:22]3[C:17](=[CH:18][CH:19]=[CH:20]2)[CH2:16][CH2:15][CH2:14][N:13]3[CH:12]=1)=[O:10])(C)(C)C.[ClH:24]>C(Cl)Cl>[ClH:24].[NH2:7][CH2:8][C:9]([C:11]1[C:21]2=[C:22]3[C:17](=[CH:18][CH:19]=[CH:20]2)[CH2:16][CH2:15][CH2:14][N:13]3[CH:12]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cn2c3c(cccc13)CCC2
Agent: Cl
Solvent: ClCCl
Product: NCC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of [2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (1.35 g, 4.30 mmol) in DCM (50 mL) was added HCl (4 M in dioxane, 11 mL, 44 mmol) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered through a filter paper, washed with DCM and dried under vacuum to give 2-amino-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone HCl salt (1.06 g, 99%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.50 (s, 1H), 8.42 (brs, 3H), 7.88 (d, J=8.0 Hz, 1H), 7.20 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.28 (m, 4H), 2.95 (t, J=5.6 Hz, 2H), 2.15 (m, 2H). LCMS: m/e 215.21 [M+H].
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:8]1[O:9][C:4]([CH2:3][CH2:2][Br:1])([CH3:5])[O:6][CH2:7]1
Reactant: CC(=O)CCBr
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(CCBr)OCCO1

Procedure:
A mixture of 75 g of 4-bromo-2-butanone, 40 g of ethylene glycol, 250 mg of p-toluenesulfonic acid acid and 500 ml of toluene is refluxed for about 4-6 hours under a Dean-Stark water trap. The mixture is cooled, poured into ethyl acetate and dilute potassium carbonate solution. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is distilled under reduced pressure to give the title product.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:41])[CH2:4][C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:42]([O-])=[O:43].[Na+]>>[Br:1][CH2:2][C:3](=[O:41])[C:4](=[N:42][OH:43])[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Reactant: O=N[O-]
Agent: [Na+]
Product: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]3SC2)s1
Yield: 88.7 %

Procedure:
By the same procedure as described in Example 1, 0.378 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate was treated with 0.048 g of sodium nitrite to obtain 0.350 g powdery benzhydryl 7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>C(OCC)C>[C:1]([O:5][C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
A 1 L three-neck flask fitted with a reflux condenser, rubber septum, addition funnel and argon inlet was charged with 200 ml of t-butanol. To the solution, n-butyl lithium (1.45N, 91.1 ml) was added dropwise using a water bath to prevent an excessive temperature rise. After stirring 30 minutes, the addition funnel was charged with p-toluoyl chloride, added dropwise. The reaction mixture was stirred overnight. At this point, the contents were transferred into a separatory funnel by using 250 ml of diethyl ether and the solution was washed with water (250 ml). The organic layer was then dried (MgSO4) and concentrated by rotary evaporation. The crude product, tert-butyl-4-toluate, was purified by fractional distillation.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[C:6]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:28][CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[C:6]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1c(NCCO)c2ccccc2n(-c2ccccc2)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(NCCBr)c2ccccc2n(-c2ccccc2)c1=O
Yield: 74.6 %

Procedure:
Dissolved in 30 ml of tetrahydrofuran were 0.352 g (1 mmol) of ethyl 4-(2-hydroxyethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate, 0.67 g (2 mmol) of carbon tetrabromide and 0.531 g (2 mmol) of triphenylphosphine, followed by a reaction at room temperature for 5 hours. The insoluble matter was filtered off, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column and then recrystallized from ethyl acetate/isopropyl ether, whereby 0.31 g of ethyl 4-(2-bromoethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate was obtained (yield: 74.7%).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:16][CH2:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH2:19][CH:20]=[CH2:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[Si:1]([O:8][C:9]([CH3:13])([CH3:14])[C@@H:10]([NH:12][CH2:16][CH2:17][C:18]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([OH:22])[CH2:19][CH:20]=[CH2:21])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCC(O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)c1ccccc1
Yield: 3.3 %

Procedure:
A mixture of (S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-amine (6 g, 27.6 mmol), 1-chloro-3-phenylhex-5-en-3-ol (4.83 g, 23 mmol) and K2CO3 (15 g, 100 mmol) in CH3CN (100 mL) was stirred and heated to reflux overnight. The solid was filtered, and the filtrate was concentrated to give the crude product which was purified by column chromatography to afford 1-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-ylamino)-3-phenylhex-5-en-3-ol (300 mg, 3%). 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.02 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 1.92 (m, 2H), 2.30 (m, 4H), 2.49 (m, 3H), 2.96 (m, 2H), 4.92 (m, 3H), 5.45 (m, 2H), 7.11 (m, 1H), 7.21 (m, 2H), 7.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.[NH2:21][C:22]1[C:30]([C:31](O)=[O:32])=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][C:23]=1[CH3:34].S(Cl)(C)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:15][C:31](=[O:32])[C:30]4[C:29]5[NH:28][N:27]=[CH:26][C:25]=5[CH:24]=[C:23]([CH3:34])[C:22]=4[N:21]=3)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid (40 g, 157 mmol) and acetonitrile (1000 mL) was added 6-amino-5-methyl-1H-indazole-7-carboxylic acid (30 g, 157 mmol). To the resulting brown suspension were added sequentially pyridine (57 mL, 706 mml) and dropwise mesylchloride (43 mL, 549 mmol). The reaction mixture was stirred for 6 h at 50° C. and 15 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was suspended in water and stirred for 15 min. The resulting yellow suspension was filtrated. The filtercake was washed sequentially with water and heptane/AcOEt 2:1 and dried to afford the title compound as beige powder, which was submitted to the next step without further purification. LC/MS: 409 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[CH3:14][C:15](C)([CH3:19])[C:16](O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].N>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][C:12]=1[C:15]([CH3:19])([CH3:16])[CH3:14]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)c1cc(Cl)nnc1Cl
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
Concentrated sulphuric acid (53.6 ml, 1.0 mol) was added carefully to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in water (1.25 l). This mixture was then heated to 70° C. (internal temperature) before the addition of trimethylacetic acid (47.5 ml, 0.41 mol). A solution of silver nitrate (11.4 g, 0.07 mol) in water (20 ml) was then added over approximately one minute. This caused the reaction mixture to become milky in appearance. A solution of ammonium persulphate (230 g, 1.0 mol) in water (0.63 l) was then added over 20-30 minutes. The internal temperature rose to approximately 85° C. During the addition the product formed as a sticky precipitate. Upon complete addition the reaction was stirred for an additional 10 minutes, then allowed to cool to room temperature. The mixture was then poured onto ice and basified with concentrated aqueous ammonia, with the addition of more ice as required to keep the temperature below 10° C. The aqueous was extracted with dichloromethane (3×300 ml). The combined extracts were dried (MgSO4), filtered and evaporated to give 55.8 g of crude product as an oil. This was purified by silica gel chromatography using 0-15% ethyl acetate in hexane as eluent to give 37.31 g (53%) of the desired compound. Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ1.50 (9H, s), 7.48 (1H, s); MS (ES+) m/e 205 [MH]+, 207 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1>>[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:5]2[N:4]=[C:3]([O:9][CH2:10][CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:2]([Br:1])=[CH:7][N:6]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2nc(Cl)ncc2Br)C1
Reactant: C[C@H]1CC[C@@H](N)CC1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1

Procedure:
Using the procedure of Example 1 Step 2, tert-butyl 3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was reacted with cis-4-methylcyclohexanamine to provide the title compound in 55% yield. 1H NMR (CDCl3, 300 MHz) 8.10 (s, 1H), 5.17 (m, 1H), 5.47 (d, 2H), 4.11-4.00 (m, 3H), 3.84-3.79 (m, 2H), 3.02-2.98 (m, 1H), 1.78-1.58 (m, 6H), 1.46 (s, 9H), 1.46-1.27 (m, 3H), 0.95 (d, 3H); MS (ESI) m/z: Calc: 454.2 (M+). Found. 456.1 (M+2).