Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](OCC)=[O:23]>C1(C)C=CC=CC=1>[C:4]1([C:1](=[O:3])[CH2:2][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CC(=O)c1ccccn1)c1ccccc1
Yield: 68.6 %

Procedure:
Acetophenone (11.6 mL, 99 mmol), was added to a suspension of potassium tert-butoxide (12.34 g 110 mmol) in toluene (150 mL) and stirred under argon. The flask was then charged with ethyl picolinate (13.4 mL, 99 mmol) and the mixture stirred overnight. The toluene was removed by rotary evaporation and 200 mL of both diethylether and deionised water added. With stirring the mixture was acidified with dilute HCl until the ether layer was dark orange˜pH 7). The ether layer was separated, washed with deionised water (3×100 mL), dried over magnesium sulfate and filtered. The solvent was removed and the solid recrystallised from hot ethanol to yield 1-phenyl-3-pyridin-2-ylpropane-1,3-dione (1) as a pale yellow crystalline solid (15.3 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: Nc1ccc(Br)nn1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(N)nn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
5-methoxybenzofuran boronic acid 1.2 mmol), 6-bromo-3-pyridazinamine (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (51 mg). 1H NMR δ ppm 7.77 (d, 1 H) 7.52 (d, 1 H) 7.35 (s, 1H) 7.19 (d, 1 H) 6.79-6.98 (m, 2 H) 6.72 (s, 2 H) 3.80 (s, 3 H); MS m/z 242 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCCO3)CS[C@H]12)c1csc(N)n1
Yield: 57.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-tetrahydrofurfurylthio-3-cephem-4-carboxylate (40 mg) was reacted with iodomethyl pivalate (38 mg), followed by purification, in the same manner as in Example 2 to give the titled compound (27 mg; 57%) as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O1CCCC1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1>C(=O)([O-])[O-].[K+].[K+].O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (1, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (108, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)-palladium(0) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (109, 670 mg, 64.0%). MS (ESI) [M+H+]+=199.4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][OH:35]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][OH:35])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (157 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare a solution. Potassium carbonate (195 mg) and 2-bromoethanol (0.1 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (147 mg, yield 83%).
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[C:7]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[NH2:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[NH2:6])C>Cl.C(O)C>[NH2:6][C:5]1[CH:4]=[N:21][C:16]2[C:15]([C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[CH:20][CH:19]=[N:18][CH:17]=2
Reactant: CCOC(OCC)C(N)=C(c1ccncc1N)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: Nc1cnc2cnccc2c1-c1ccccc1Cl
Yield: 34.6 %

Procedure:
2,2-Diethoxy-N-[α-(3-amino-4-pyridyl)-2-chlorobenzylidene]ethylamine (4.00 g, 11.17 mmol) was dissolved in 10% hydrogen chloride in ethanol (60 ml), and the mixture was refluxed for 5 hours. The mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methanol:chloroform=1:19) to give the title compound (0.99 g, 3.87 mmol) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.O[C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[C:1]1([CH:7]=[CH:8][C:9]([O:11][C:17]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: O=C(O)C=Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)O)c(OC(=O)C=Cc2ccccc2)c1
Yield: 79.4 %

Procedure:
Using the method of example 4, 14.815 g (0.1 moles) of 3-phenyl-2-propenoic acid and 20.82 g of SOCl2 (0.175 moles) followed by 15.24 g of 2-hydroxy-4-methylbenzoic acid (0.1 moles) give 22.4 g of 2-(3-phenyl-2-propenoyloxy)-4-methylbenzoic acid (yield 81.1%), m.p. 156.5°-157° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCCC4)c3)n2)n1
Yield: 71.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.300 g, 0.613 mmol) by treatment with pyrrolidine (0.131 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.230 g, 71%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 174° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=2[CH3:10])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: Cc1c(F)cccc1C=O
Product: Cc1c(F)cccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 3-fluoro-2-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:29](I)[CH3:30]>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:29][CH3:30])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: CCN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m.p. 197° C. (dec.) and MS: m/e=398.4 M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and ethyliodide.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([O:31][CH2:2][C:1]#[N:4])=[O:30])=[O:22])=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reaction time: 1.5 h
Yield: 112.8 %

Procedure:
N,N-Diisopropylethylamine (52 μL, 0.298 mmol) and subsequently bromoacetonitrile (94 μL, 1.352 mmol) were added to a solution of (S)-6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk40) (114 mg, 0.270 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk41) (140.2 mg, quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
A mixture of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate, 100 g of potassium carbonate and 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with hexane to give 63.3 g of the title compound, melting at 98-99° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH3:7]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1ccccc1
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 65.3 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 5 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 65.3%. 1H NMR (DMSO-d6): δ 0.95 (t, J=7.5 Hz, 3H), 1.36-1.41 (m, 2H), 1.64-1.69 (m, 2H), 3.78 (t, J=7.2 Hz, 2H), 7.19 (t, Hz, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.49 (td, J=1.2 Hz, J=7.8 Hz, 1H), 7.60-7.73 (m, 4H), 7.90-7.92 (m, 2H), 13.90 (br, s 1H). 13C NMR (DMSO-d6): δ 14.06 (CH3), 20.04 (CH2), 29.56 (CH2), 39.49 (CH2), 110.69 (CH), 119.66 (C), 121.26 (CH), 123.69 (CH), 127.88 (CH), 129.67 (CH), 132.22 (CH), 132.43 (C), 133.40 (CH), 137.40 (C), 143.43 (C═N), 161.58 (C═O), 163.34 (C═O). HRMS (ES+) calcd for C19H20N3O2 (M+H+), m/e, 322.1548; found, 322.1550.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:25][CH:26]=1.CS(Cl)(=O)=O.[Br:41][C:42]1[N:46]2[CH:47]=[CH:48][CH:49]=[C:50](O)[C:45]2=[N:44][C:43]=1[CH3:52].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(N(CC)CC)C>[Br:41][C:42]1[N:46]2[CH:47]=[CH:48][CH:49]=[C:50]([O:9][CH2:8][C:7]3[C:2]([Cl:1])=[C:3]([N:11]4[CH:15]=[CH:14][CH:13]=[C:12]4[CH2:16][NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]4[CH:22]=[N:23][C:24](/[CH:27]=[CH:28]/[C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:25][CH:26]=4)[CH:4]=[CH:5][C:6]=3[Cl:10])[C:45]2=[N:44][C:43]=1[CH3:52]
Reactant: Cc1nc2c(O)cccn2c1Br
Reactant: O=C(/C=C/c1ccc(/C=C/c2ccncc2)nc1)NCc1cccn1-c1ccc(Cl)c(CO)c1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(/C=C/c5ccncc5)nc4)c3Cl)cccn2c1Br
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 1-(2,4-dichloro-3-hydroxymethylphenyl)-2-[(E)-3-[6-[(E)-2-(pyridin-4-yl)vinyl]pyridin-3-yl]acryloylaminomethyl]pyrrole (70 mg) and triethylamine (28 mg) in N,N-dimethylformamide (1 ml) was added methanesulfonyl chloride (16.7 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture were added 3-bromo-8-hydroxy-2-methylimidazo[1,2-a]-pyridine (31.4 mg) and potassium carbonate (95.7 mg) at ambient temperature, and the mixture was stirred at the same temperature overnight. Water was added thereto, the resulting precipitates were collected by filtration. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[3-(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yloxymethyl)-2,4-dichlorophenyl]-2-[(E)-3-[6-[(E)-2-(pyridin-4-yl)vinyl]-pyridin-3-yl]acryloylaminomethyl]pyrrole (76 mg) as yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:10])([C:7]([F:9])=[O:8])[C:3](OC)=[O:4].[F:11]S(O)(=O)=O>>[F:10][C:2]([F:1])([C:3]([F:11])=[O:4])[C:7]([F:9])=[O:8]
Reactant: O=S(=O)(O)F
Reactant: COC(=O)C(F)(F)C(=O)F
Product: O=C(F)C(F)(F)C(=O)F
Yield: 37.1 %

Procedure:
A mixture of 624 g (4.0 mol) of methyl difluorofluoroformylacetate, 348 g (3.5 mol) of fluorosulfonic acid and 25 ml of HSbF6 (0.3 mol) was charged to a 1 liter Teflon® pot fitted with a Teflon® condenser connected to a trap cooled to -80°. The mixture was stirred and heated at 80° to 110° for about 24 h. Then, 187 g (65% yield) of crude difluoromalonyl fluoride was collected which, after trap-to-trap distillation, was analyzed by NMR at -30°. NMR (CCl4): 19F 21.0 (t, JFF 10.9 Hz, 2F, COF) and -112.4 ppm (t, JFF 10.9 Hz, 2F, CF2) with a very small amount of impurity showing at -162.1 ppm. Distillation of a 140 g sample gave 118 g of pure FCOCF2COF, b.p. -4° to -5°. Dimethyl difluoromalonate was also formed.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.O>[C:31]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(C)=O)C4)cc2)C(=O)O1
Yield: 51.1 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (80 mg, 0.23 mmol) in DCM (2 mL) were added triethylamine (0.13 mL, 0.92 mmol) and acetyl chloride (0.02 mL, 0.34 mmol) at 0° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.83:9.17 MeOH:CHCl3) to provide the title compound (42 mg, 51%) as white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.BrC1C2OC(C)(C)C(=O)NC=2C=CC=1.NC1C=CC=C(Br)C=1O.BrC(C)(C)C(Br)=O.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52]>>[Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][N:7]([S:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[F:44])(=[O:53])=[O:52])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CNc2cccc(Br)c2O1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: CC(C)(Br)C(=O)Br
Agent: CC1(C)Oc2c(Br)cccc2NC1=O
Agent: Nc1cccc(Br)c1O
Product: CC1(C)CN(S(=O)(=O)c2ccccc2F)c2cccc(Br)c2O1

Procedure:
Using the above procedure, but starting with 8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (prepared by reducing 8-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, which in turn was prepared from 2-amino-6-bromophenol and 2-bromo-2-methylproprionyl bromide via the procedure described by Van Hes et al., WO 01/14330) and 2-fluorobenzenesulfonyl chloride, 8-bromo-4-(2-fluorobenzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine was obtained as a white solid. MP.: 108.0-110.1°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:10][CH:9]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[S:12][C:11]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[N:10][CH:9]=3)[N:3]=2)[CH:25]=1
Reactant: Brc1cccc(-c2cnc(-c3cccnc3)s2)n1
Reactant: Cc1ccnc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccnc4)s3)n2)c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A sealed tube was charged with 2-bromo-6-(2-pyridin-3-yl-thiazol-5-yl)-pyridine (125 mg, 0.392 mmol), 2-amino-4-methylpyridine (51 mg, 0.471 mmol), Pd(OAc)2 (1.8 mg, 8.01 μmol), BINAP (7.4 mg, 11.9 μmol), Cs2CO3 (255 mg, 0.782 mmol), and anhydrous and degassed toluene (2 ml) and heated to 110° C. with stirring for 48 h. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate 100/0 to 0/100. The solid obtained was then triturated in methanol, filtered and dried to afford the title compound as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ=9.74 (s, 1H), 9.15 (d, J=2.1 Hz, 1H), 8.68 (m, 1H), 8.59 (s, 1H), 8.31 (m, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.93 (s, 1H), 7.72 (dd, J=8.2-7.6 Hz, 1H), 7.66-4.40 (m, 3H), 6.77 (d, J=4.9 Hz, 1H), 2.37 (s, 3H). (APCI+) m/z 346 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]([OH:31])[CH2:5][S:6]([N:9]2[CH2:30][CH2:29][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Ca+2].[CH3:38]I>[Ag]=O>[CH:1]1([CH:4]([O:31][CH3:38])[CH2:5][S:6]([N:9]2[CH2:10][CH2:11][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:29][CH2:30]2)(=[O:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC(O)C1CC1)CC2
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: COC(CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
A mixture of 8-(2-cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, 30 mg, 0.07 mmol), dry calcium sulfate (33 mg, 0.26 mmol) and silver oxide (60 mg, 0.26 mmol) in methyl iodide (1 mL) was stirred at room temperature for 48 h. The reaction mixture was filtered through Celite® and washed with methylene chloride. The filtrate was concentrated to dryness under reduced pressure to give the crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) which afforded the desired product as a white solid (12.5 mg, 40%). MS (ESI): 477.2 (MH+).