Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:12]3[CH:13]=[C:14]([F:15])[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:20])[CH:11]=3)[N:23]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: OB(O)Oc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)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
Product: CCN1CCN(c2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Yield: 199.2 %

Procedure:
4-Benzyloxy-3,5-difluorophenylboric acid (1.97 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (5.20 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.50 g) in toluene (250 ml) and a 10% aqueous solution of sodium carbonate (150 ml) in nitrogen atmosphere for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added thereto, and the mixture was heated under reflux for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added to the resulting mixture, and then heated under reflux overnight. The organic layer was separated and extracted with 2N hydrochloric acid twice. The resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give l-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3,5-difluorophenyl)isoquinoline (6.44 g) as a brown viscous oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:5]1[N:10]=[C:9](CS([O-])(=O)=O)[CH:8]=[CH:7][N:6]=1)[CH3:4].[CH3:16][N:17]([CH3:27])[S:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:16][N:17]([CH3:27])[S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C@H:3]([O:2][CH3:1])[CH3:4])[N:10]=2)[CH2:23][CH2:22]1)(=[O:19])=[O:20]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: CO[C@H](C)c1nccc(CS(=O)(=O)[O-])n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@H](C)c1nccc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Yield: 59 %

Procedure:
To a solution of (R)-2-(1-methoxyethyl)-pyrimidin-4-yl-methanesulfonate (prepared according to the method of Example 1, Step E, 2.11 g, 9.1 mmol) in tetrahydrofuran (20 mL) was added dimethylsulfamoyl piperazine (prepared according to the method disclosed in U.S. Pat. No. 2,748,129, 1.94 g, 10 mmol) followed by triethylamine (1.4 mL, 10 mmol). The reaction was refluxed for 15 h, and evaporated to an oily residue. This was extracted with ethyl acetate (20 mL) and the extract was washed first with a saturated aqueous solution of sodium bicarbonate and then with water (10 mL). The ethyl acetate extract was dried over sodium sulfate, filtered, and the filtrate was evaporated to a crude product, which was chromatographed over silica gel. Elution with a mixture of 9:1 ethyl acetate and methanol and evaporation of the solvents gave the title compound of Example 1, Step F (1.75 g, 59%); mp, 65-70° C., [α]D+54.4° (c=1, methanol); 1H NMR (CDCl3, 300 MHz) δ1.48(d, 3H), 2.89(s,6H, 3.31(m, 4H), 3.37 (s, 3H), 3.78(m, 4H), 4.34(q, 1H), 6.41(d, 1H), 8.30(d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.N1C(C)=CC=CC=1C.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:41]>ClCCl>[CH2:43]([O:42][C:40]([NH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:41])[CH2:44][CH2:45][CH3:46]
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCOC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4C)ccc32)c1
Reaction time: 3 h

Procedure:
The amine (Example 4) (0.17 g) was dissolved in dichloromethane (5 ml) and 2,6-lutidine (50 μl) and stirred as n-butyl chloroformate (55 μl) was added over 2 minutes. The reaction mixture was stirred for 3 hours, diluted with dichloromethane and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-5% ethyl acetate in dichloromethane, yielded N-{1-[3-(n-butoxycarbonylamino)benzyl] indol-5-ylcarbonyl}-2-methylbenzene sulphonamide as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22]>C(Cl)Cl.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([S:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CS
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)CSC(CCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
To a suspension of the alcohol (0.23 g) (Step VI) in CH2Cl2 (5 mL) and methyl thioglycolate (80 μL) was added ZnI2 (10 mg). The mixture was stirred 2 hrs, buffer (pH 7) was added. The mixture was extracted with ethyl acetate, which was dried and evaporated. Flash chromatography using 5% ethyl acetate in toluene afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]3[C:13]([NH2:16])=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl>O>[NH2:16][C:13]1[C:12]2[C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:21]4[CH:26]=[C:25]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)[N:24]=[C:23]([NH2:33])[N:22]=4)=[CH:3][C:4]=3[F:19])=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
70 mg (0.27 mmol) of 4-(4-amino-2-fluorophenoxy)-1,2-benzisoxazole-3-amine (from example VII) and 55.8 mg (0.27 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 4 ml of water, and 0.02 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a lightly colored precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5]Cl.[K].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>CN(C=O)C>[C:12]1(=[O:22])[N:16]([CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[C:9]([CH3:10])=[CH:8][CH:7]=2)[C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(CCl)cc1C
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C

Procedure:
92.8 g of 3,4-dimethylbenzyl chloride and 116.7 g of potassium salt of phthalimide were dissolved in 600 ml of DMF and the solution was heated under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was dissolved in chloroform, washed with 0.1 N aqueous sodium hydroxide and then with water, and concentrated. 140 g of 4-phthalimidomethyl-o-xylene was obtained by recrystallization from a chloroform-ether mixed solvent.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([NH:17][S:18]([CH:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])(=[O:20])=[O:19])[N:10]=1.IC.O>CN(C)C=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:1])[S:18]([CH:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])(=[O:20])=[O:19])[N:10]=1
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)C)S(=O)(=O)N(C)c1nc(OC)cc(OC)n1
Reaction time: 2 h
Yield: 55.2 %

Procedure:
Potassium tert-butoxide (1.4 g) was added with stirring and cooling to the product of Example 1 (4.0 g) in dimethylformamide (25 ml). Iodomethane (1.78 g) was added portionwise, stirring was continued for 2 hours and the reaction mixture was allowed to stand at room temperature for 8 days. Addition to water and isolation through ethyl acetate gave the crude title product as a yellow oil. Purification by flash chromatography on silica gel in 10% ethyl acetate/dichloromethane gave 2.3 g (55%) pure product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:25]([C:31](=[O:34])[NH:32][CH3:33])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=3)[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=2)=[C:12]([O:39][CH3:40])[CH:11]=1)(=[O:8])[O:5]CC)[CH3:2].[I-].[Na+]>N1C=CC=CC=1>[Br:30][C:27]1[N:26]=[C:25]([C:31](=[O:34])[NH:32][CH3:33])[C:24]([NH:23][C:21]2[C:20]([C:35]([F:38])([F:36])[F:37])=[CH:19][N:18]=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:5])([OH:8])[O:3][CH2:1][CH3:2])=[CH:11][C:12]=3[O:39][CH3:40])[N:22]=2)=[CH:29][CH:28]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Temperature: 120 °C
Yield: 93.3 %

Procedure:
A solution of {4-[4-(6-bromo-2-methylcarbamoyl-pyridin-3-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-benzyl}-phosphonic acid diethyl ester (Compound 38D, 610 mg, 0.94 mmol) in pyridine (9.57 mL) was treated with Sodium iodide (847 mg, 5.65 mmol) and heated at 120° C. for 16 hrs overnight. The reaction solution was concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [5%→95% MeOH in Water over 25 CV] to afford 543 mg of the title compound (93%). 1H NMR (400 MHz, CD3OD) 8.99 (br. s, 1H), 8.80 (d, J=4.6 Hz, 1H), 8.34 (s, 1H), 7.55 (d, J=9.1 Hz, 1H), 7.10 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 3.83-3.95 (m, 5H), 3.04 (s, 1H), 2.99 (s, 1H), 2.93 (d, J=5.1 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H). MS (ESI): m/z 619.42/621.44 [M+H]+. UPLC: tR=1.24 min (UPLC-TOF: polar—2 min).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]23[CH2:19][CH2:18][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[C:20]1([C:15]23[CH2:18][CH2:19][C:12]([CH2:11][C:27]#[N:28])([CH2:17][CH2:16]2)[CH2:13][CH2:14]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC12CCC(c3ccccc3)(CC1)CC2
Temperature: 100 °C
Yield: 92 %

Procedure:
A stirred mixture of 4-phenylbicyclo[2.2.2]oct-1-ylmethyl toluene-4-sulfonate (2.5 g, 6.75 mmol) and sodium cyanide (0.5 g, 10.20 mmol) in DMSO (20 mL) was heated at 100° C. under nitrogen for 5 h. After cooling overnight the mixture was poured into water (100 mL) then extracted with DCM (2×100 mL) then methyl t-butyl ether (3×100 mL). The DCM and methyl t-butyl ether phases were separately combined, washed with water (50 mL) and dried (MgSO4). The organic phases were then combined and the solvents evaporated to give the crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate 19:1 to give the title compound as a white solid (1.4 g; 93%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[C:20](OCC)(=O)[CH3:21]>C(O)C>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:20][CH3:21])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2nn[nH]c2c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1H-1,2,3-benzotriazole-6-carboxylic acid (6.0 g, 36.8 mmol) in ethanol (27.8 mL) was added sulfuric acid (1.5 mL, 28.1 mmol). The mixture was heated to 60 C. After 18 h, the mixture was cooled to ambient temperature. Aqueous sodium hydroxide (3N) and ethyl acetate was added and solid crashed out of the solution. The solid was filtered and dried under hi-vac to give the title compound (5.14 g): LC-MS [M+1]=192.1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][C:14]=3[F:23])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.ClC1C=CC(CNC(C2C=NC3C(C=2O)=CC(CCl)=CC=3F)=O)=CC=1.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[CH:15][C:14]=3[F:23])=[O:9])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCl)cc2c1O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example No. 141 (500 mg), collidine (0.21 mL), and DMAP (28.3 mg) in 25 mL DMF is cooled to 0° C. Methanesulfonyl chloride (0.12 mL) is added dropwise. The reaction is stirred at room temperature and monitored by mass spectroscopy for complete conversion to N-(4-chlorobenzyl)-6-(chloromethyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide (approx. 2-3 hrs and reaction mixture turns yellow). Morpholine (0.24 mL) is added. The reaction is monitored by mass spectroscopy for complete conversion. The product is precipitated by addition of 25 mL H2O. The white solid is filtered and collected to afford 459.3 mg (78%) of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1B(O)O>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: COc1cccc(F)c1B(O)O
Reactant: FC(F)(F)CNc1cnccc1I
Product: COc1cccc(F)c1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2-fluoro-6-methoxyphenylboronic acid after a reaction time of 18 hours. The compound was purified by silica gel column chromatography eluting with a gradient of n-hexane:EtOAc (20:80 to 0:100). Yellow liquid (62%). LC-MS (ESI): m/z=301.6 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:33])[CH2:17][CH2:18][N:19]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[K+]>ClCCl>[C:11]([O:15][C:16](=[O:33])[CH2:17][CH2:18][N:19]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:20][CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)CCN(CCO)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN(CC=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of 4.53 ml (35.65 mmol) of oxalyl chloride in 76 ml dichloromethane at −50 to −60° C. was added a solution of 5.81 ml (74.40 mmol) dimethylsulfoxide in 16 ml of dichloromethane within 20 min. The solution was stirred for 5 min and a solution of 10.03 g (31.0 mmol) 3-[benzyloxycarbonyl-(2-hydroxy-ethyl)-amino]-propionic acid tert-butyl ester in 67 ml dichloromethane was added within 20 min. The mixture was stirred for 15 min and 21.6 ml (155 mmol) of triethylamine were added within 25 min. The suspension was stirred for 2 h and slowly warmed to 0° C. The reaction was neutralized with cold 10% aq. potassium dihydrogenphosphate solution (adjusted with solid potassium dihydrogenphosphate to pH 4-5) and extracted with diethyl ether (3×). The organic phases were washed with 10% aq. potassium dihydrogenphosphate solution, sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to yield 9.94 g (99.8%) of the titled compound as yellow oil. MS: 322.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=1)=[O:48])[CH3:45])=[O:4].N1C=CC=CC=1.[C:66](OC(=O)C)(=[O:68])[CH3:67]>C(Cl)Cl>[C:66]([O:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=1)=[O:48])[CH3:45])=[O:4])(=[O:68])[CH3:67]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)S[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred solution of 4(R)-hydroxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-azetidin-2-one (418 mg, 0.5 mmole) in CH2Cl2 (5 ml) was sequentially treated with pyridine (162 mg) and acetic anhydride (90 mg) and then stirred at room temperature for six hours.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[I-].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Zn+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Cc1ccccc1[Zn+]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [I-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccc4C)cc3C)c(C)nc12
Yield: 46 %

Procedure:
Using the procedure analogous to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 g, 0.38 mmol) and PdCl2(dppf) (0.014 g, 0.019 mmol) and 0.5M solution of 2-methylphenylzinc iodide in THF (3 mL, 1.53 mmol) furnish the title compound (0.069 g, 0.17 mmol, 46%). 1H NMR (CDCl3) δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.19 (s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.55 (s, 3H), 3.32-3.40 (m, 1H), 6.68 (s, 1H), 7.02 (s, 1H), 7.22-7.30 (m, 3H), 7.48-7.53 (m, 1H). LC/MS (m/z): calcd. for C25H29N3S (M+H)+: 404.3; found: 404.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:25].O.O>C1COCC1>[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:25]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(N)=O)C1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1-L 3-necked round-bottomed flask was charged with a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 42.79 mmol, 1.00 equiv, 98%), TEA (5.2 g, 50.46 mmol, 1.18 equiv, 98%) in THF (100 mL). To this mixture was added isobutyl carbonochloridate (6.8 g, 49.00 mmol, 1.15 equiv, 98%) drop wise at 10° C. The resulting solution was stirred for 15 minutes at 10° C. in a water/ice bath. Then, to the mixture was added NH3.H2O (25%, 60 mL) and allowed to stir for 10 minutes at 10° C. Then, it was treated with water (40 mL) to afford off-white solids after filtration. The solid was dried in an oven under reduced pressure affording tert-butyl 3-carbamoylpiperidine-1-carboxylate as white solid (7 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]=[C:12]=[S:13])=[C:9]([F:14])[CH:8]=[C:7]([Cl:15])[C:5]=2[N:6]=1.Cl.[NH2:17][C:18]1[NH:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH:22]=1.[OH-].[Na+].BrBr>ClCCl.O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]=[C:12]3[S:13][N:17]=[C:18]4[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][N:19]34)=[C:9]([F:14])[CH:8]=[C:7]([Cl:15])[C:5]=2[N:6]=1
Reactant: CC1(C)C=C(N)NC1
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1N=C=S
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)Cc2nsc(=Nc3c(F)cc(Cl)c4nc(Cl)sc34)n2C1
Temperature: 2 °C
Reaction time: 3 h

Procedure:
A solution of 2 g 2,4-dichloro-6-fluoro-7-isothiocyanatobenzothiazole in 10 ml dichloromethane was added, dropwise, at 0° C., to a suspension of 1.1 g 2-amino-4,4-dimethylpyrroline hydrochloride in 20 ml dichloromethane. A solution of 0.3 g sodium hydroxide and 6 ml water was added, dropwise, at 2° C. to this mixture which was stirred for 3 hours, whereby the temperature rose to 20° C. The mixture was cooled to -10° C. and a solution of 1 g bromine in 10 ml dichloromethane was added, dropwise, slowly and the mixture stirred for I hour whereby the temperature rose to 10° C. The solution was washed with water and with dilute caustic soda, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether. Yield: 1.5 g=53% of theory m.p.: 134°-136° C.