Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl[CH:13]([CH2:18]Cl)[C:14]([O:16][CH3:17])=[O:15].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[N:30]([CH:31]=O)[CH:29](C(O)=O)[C:28]([CH3:37])([CH3:36])[S:27]2)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][C:28]1([CH3:37])[S:27][CH:26]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[N:30]2[CH:31]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:29]12
Reactant: CC1(C)SC(c2cccnc2)N(C=O)C1C(=O)O
Reactant: COC(=O)C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2c1C(C)(C)SC2c1cccnc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of p-toluenesulfonyl chloride (18 g, 95 mmol) and methyl 2,3-dichloropropionate (15 g, 95 mmol) in refluxing CH2Cl2 (125 mL) was added a mixture of 2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-thiazolidinecarboxylic acid (5.1 g, 19 mmol) and triethylamine (2.3 g, 22 mmol) in CH2Cl2 (125 mL). After one hour at reflux triethylamine (4.6 g, 44 mmol) was added and the reaction mixture was refluxed for a further 17 hours. The reaction mixture was cooled to ambient temperature and partitioned between cold 1N aqueous NaOH and ethyl acetate. The organic phase was washed with cold 1N aqueous NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in 5% aqueous HCl and the solution was extracted twice with ether. The aqueous phase was neutralized with solid Na2CO3 and extracted twice with ethyl acetate. The combined ethyl acetate extracts where washed with brine, dried over MgSO4, and concentrated in vacuo. Chromatography on silica gel (150 g, 1:1 ethyl acetate, hexanes), afforded methyl 1,1-dimethyl-3-(pyrid-3-yl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate (1.1 g, 20%) as an off-while powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:11][CH:10]([N:22]([C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=3)[CH3:37])[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13]2)=[O:15])[CH2:17][CH2:18]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Product: CCOC(=O)N1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid ethyl ester was prepared from N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using ethyl chloroformate instead of 4-fluorobenzoyl chloride and was obtained as a light brown foam. MS m/e: 630.3 [M]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[F:9][C:10]([F:20])([F:19])[CH2:11][CH2:12][C:13](N(OC)C)=[O:14].[Cl-].[NH4+]>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:13](=[O:14])[CH2:12][CH2:11][C:10]([F:20])([F:19])[F:9]
Reactant: CON(C)C(=O)CCC(F)(F)F
Reactant: BrCCC1OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCC1OCCO1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Mg (92.0 mmol, 2.2 g) in TBF (80 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-[1,3]dioxolane (80 mmol, 9.4 ml), while keeping the internal temperature below 35° C. with the aid of an ice bath. After the addition was complete, the mixture was stirred for 2 h at room temperature, then cooled to −78° C. Crude 4,4,4-trifluoro-N-methoxy-N-methyl butyramide (20 g, prepared above) in THF (40 ml) was cooled to −78° C., then the freshly prepared Grignard reagent was transferred via cannula into the amide solution at −78° C. The resulting mixture was allowed to warm to room temperature, held at room temperature overnight, then poured into saturated aqueous ammonium chloride (200 ml). The mixture was extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×75 ml) and concentrated under reduced pressure to provide crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g) 1H NMR (CDCl3) δ4.91 (1H, t, J=4.1), 3.97-3.82 (4H, m), 2.70 (2H, t, J=7.3), 2.57 (2H, t, J=7.2), 2.49-2.34 (2H, m), 2.01 (2H, dt, J=7.3, 4.1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:31]C(=O)OC(C)(C)C)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccccc3)C2)C1=O

Procedure:
A mixture comprising tert-butyl (2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylcarbamate (500 mg, 0.959 mmol) and TFA (2.215 ml, 28.8 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude was then diluted with DCM (10 mL) and washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous phase was further extracted with DCM (3×10 mL). The combined organic portions were dried (MgSO4), and concentrated under reduced pressure to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:37])=[N-]>>[O:23]([CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:31])[N:17]2[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:34][CH:33]=3)=[O:11])=[C:13]([O:32][CH3:37])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
More recently in my copending application Ser. No. 310,191 filed on Nov. 28, 1972 now U.S. Pat. No. 3,917,587 issued Nov. 4, 1974 the oxidation of 3-exomethylenecepham esters with ozone is described. The predominant product of the ozonolysis described therein is the 3-hydroxy-3-cephem ester which is reacted with a diazoalkene to provide the corresponding ester of a 3-alkoxy-3-cephem. Removal of the ester group provides the alkoxylated antibiotic compound. For example, 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester, obtained by the ozonolysis of the corresponding 3-exomethylene compound, is reacted with diazomethane to form p-nitrobenzyl 7-phenoxyacetamido-3-methoxy-3-cephem4-carboxylate. The p-nitrobenzyl ester group is removed by catalytic hydrogenolysis in the presence of 5% palladium on carbon catalyst to provide the free carboxylic acid antibiotic compound. In the same application Ser. No. 310,191, the formation of 3-exomethylenecepham-4-carboxylic ester sulfoxides and 3-hydroxy-3-cephem-4-carboxylic acid ester sulfoxides are disclosed as side products of the ozonolysis reaction of 3-exomethylenecepham esters.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:4]=2[O:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:6]2[C:5]3[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:12][C:4]=3[O:3][C:2]([CH3:26])([CH3:1])[C:7]2=[O:8])=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2)S(C)(=O)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2c1ccc(F)cc1)S(C)(=O)=O
Yield: 20.1 %

Procedure:
Tert-butyl [(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-methyl](methylsulfonyl)carbamate (compound obtained in Reference Example 48(2), 200 mg) and 4-fluorophenylboronic acid (146 mg) were treated in the same manner as described in Reference Example 1(2) to give tert-butyl {[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methyl}(methylsulfonyl)carbamate (50 mg) as a colorless powder.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31](Cl)=[C:26]3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:31]2[N:30]=[CH:29][N:28]=[C:27]3[N:23]([C:20]4[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=4)[N:24]=[CH:25][C:26]=23)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2c1cnn2-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (727 mg, 3.88 mmol), and sodium hydride (465 mg, 19.4 mmol) in THF (12 mL) was stirred for 30 min at 60° C. 1-(4-Bromo-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine was added to the mixture at room temperature and stirred for 1.0 hr at RT. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo to provide Compound A220 as a white solid (1.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.19 (d, 6H), 1.73-1.85 (m, 2H), 1.98-2.08 (m, 2H), 3.26-3.34 (m, 2H), 3.78-3.87 (m, 2H), 4.88 (h, 1H), 5.54 (h, 1H), 7.57 (d, 2H), 8.07 (d, 2H), 8.13 (s, 1H), 8.55 (s, 1H). Exact mass calculated for C20H22BrN5O3 460.3, found 462.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.O>CN(C)C=O.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=[CH:12][CH:13]=1
Reactant: CSc1nccc(C(Cc2ccc(F)cc2)=Nc2cccnc2Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
6.5 g (14.7 mmoles) of (2-Chloro-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethylidene]-amine is dissolved in 60 mL of dimethylformamide under nitrogen. 6.2 g of DABCO (52 mmoles) and 0.5 g of bis(triphenylphosphine)palladium dichloride are subsequently added to the reaction mixture which is stirred for 4 hours at 120° C. The cooled reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized in diethyl ether to afford 4 g of 3-(4-Fluoro-phenyl)-2-(2-methylthio-pyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a yellowish solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1COc1cccn2c(C)c(C)nc12

Procedure:
Starting from 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine (1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (3.1 g), sodium iodide (1.8 g) and sodium carbonate (2.7 g) in acetone (350 ml) analogously using the process of Example B1 gives, after chromatography on silica gel (eluent toluene/dioxane 5:1) and recrystallization from cyclohexane, 3.0 g (78%) of the title compound of m.p. 128-131° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C1COCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: C1CCNC1
Reactant: Brc1cnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1cnc(N2CCCC2)s1
Yield: 108.4 %

Procedure:
4 batches of 2,5-dibromo-1,3-thiazole (250 mg, 1.029 mmol), pyrrolidine (0.089 mL, 1.081 mmol) and DIPEA (0.225 mL, 1.286 mmol) in THF (2.5 mL) were heated in a microwave at 120° C. for 15 minutes. All 4 batches were combined and evaporated to dryness. The residues were purified on silica eluting with cyclohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (260 mg). LCMS (A): m/z (M+H)+ 233/235, C7H9BrN2S requires 232/234 (acidic).
Reaction SMILES: [CH:1]([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([N:7]1[C@H:4]([CH:1]([CH3:2])[CH3:3])[C@H:5]([O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]1=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H]1C(=O)N[C@@H]1C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of (±)-cis-4-isopropyl-3-triethylsilyloxy-azetidin-2-one (486 mg, 2.00 mmole), benzoyl chloride (0.255 mL, 1.1 equiv), diisopropylethyl amine (0.346 mL, 1.2 equiv) and p-dimethylaminopyridine (244 mg, 1 equiv) in dry DCM (6 mL) was left stirring at 0° C. for 6 hr. The bath was removed and the reaction was left stirring overnight. It was then diluted with DCM and washed with water, aq. HCl solution (0.1 N), saturated aq. NaHCO3 solution, brine and dried (Na2SO4). Removal of the solvent followed by silica gel column chromatography (gradient elution with 0 to 5% EtOAc in hexane) gave the title compound: 1H NMR δ (CDCl3) 0.47-0.94 (m, 21H), 2.09 (m, 1H), 4.07 (m, 1H), 4.75 (m, 1H), 7.24-7.76 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:28][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C#CCOC(=O)c1ccc(O)cc1
Reactant: ClCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C#CCOC(=O)c1ccc(OCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 3.9 parts of 3-chloro-6-[4-(2-chloroethyl) 1-piperidinyl]pyridazine, 2.64 parts of (2-propynyl) 4-hydroxybenzoate, 2.76 parts of potassium carbonate and 75 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling the reaction mixture was poured into 100 parts of water and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 5.2 parts (86.7%) of (2-propynyl) 4-[2-[1-(6-chloro-3-pyridazinyl) -4-piperidinyl]ethoxy]benzoate; mp. 122.0° C. (comp. 120).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12])(=[O:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(4-Hydroxy-2-nitrophenyl)ethanone (Carbocore, 181 mg, 1.00 mmol), ethyl 2-bromoacetate (183 mg, 1.10 mmol), potassium carbonate (138 mg. 1.00 mmol) and DMF (5 mL) were combined in a 20 mL glass vial and stirred at 60° C. for 2 hours, at which point LC-MS analysis showed a clean complete reaction. The reaction mixture was diluted with water and extracted with EtOAc, washed with sat. NaCl aq. The reaction was repeated using 1-(4-Hydroxy-2-nitrophenyl)ethanone (0.802 g, 4.43 mmol), ethyl 2-bromoacetate (0.813 g, 4.87 mmol), potassium carbonate (0.612 g. 4.43 mmol) and DMF (25 mL), and worked up in the same way. The combined EtOAc extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, affording ethyl 2-(4-acetyl-3-nitrophenoxy)acetate (TU3205-034) as a dark yellow oil MS (ESI+): calcd. 268.07. found 268.10 (MH+). H-NMR (400 MHz, CDCl3): 1.317 (3H, t, J=7.2 Hz), 2.512 (3H, s), 4.294 (2H, q, J=7.2 Hz), 4.722 (2H, s), 7.192 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.455 (1H, d, J=8.4 Hz), 7.462 (1H, d, J=2.8 Hz). C-NMR (100 MHz, CDCl3): 14.133, 29.695, 61.922, 65.499, 110.105, 119.735, 129.461, 130.154, 147.793, 159.356, 167.474, 198.352.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:17]([O:19]C)=[O:18])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2]>C(O)(=O)C.Cl>[C:1]([NH:4][C@H:5]([C:17]([OH:19])=[O:18])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:8])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(F)cc1)NC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of the title compound of Example 11a (17.9 g, 59.0 mmol) in glacial acetic acid (135 mL) and concentrated HCl (135 mL), was heated to 7 degrees C. for 2 hours. The solution was concentrated under a stream of N2 to yield the title compound as a white solid (17.0 g, quant. yield): MS MH+ calcd. for C11H12NO5SF: 290, found 290. HRMS calc. for C11H13NO5SF: 290.0499, found: 290.0520.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[C:13]([Cl:26])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:26][C:13]1[CH:12]=[N:11][C:10]2=[N:15][C:14]=1[NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([O:25][CH2:2][C:3]3[CH:4]=[C:5]([NH:9]2)[CH:6]=[CH:7][CH:8]=3)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCCc1cccc(c1)OCc1cccc(c1)N2
Yield: 64 %

Procedure:
To a solution of 3-{2-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (25.0 mg, 0.0576 mmol) in tetrahydrofuran (0.561 mL) was added a solution of sodium hydroxide in water (0.46 mL, 0.50 M). The resultant solution was stirred at rt for 16 hours until the reaction was complete. The reaction mixture was neutralized with aqueous HCl solution (3 M) to pH 7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (13 mg, 65%). LCMS for C19H18ClN4O (M+H)+: m/z=353.0. 1H NMR (400 MHz, CD3OD): δ 7.72 (s, 1H), 7.52 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J=7.6, 0.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.93 (dd, J=7.2, 0.8 Hz, 1H), 6.73 (dd, J=2.4, 0.8 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.25 (s, 2H), 3.70 (m, 2H), 2.72 (t, J=6.8 Hz, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][CH2:18][C:19](O)=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][CH2:18][C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1cccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 18.8 %

Procedure:
To a solution of 1-aminopyrrole (2.46 g) and carbobenzyloxyglycine (6.28 g) in 120 ml of dry DCM and 10 ml of dry dimethylformamide was added DDC (8.00 g). The reaction mixture was stirred at room temperature over a period of 64 hours. The precipitate was removed by filtration and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) yielding a first fraction (2.97 g) which was contaminated by DCU. A second fraction recrystallized from ethyl acetate afforded 1.54 g of the product as crystals, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1

Procedure:
Part A: Ethyl 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.80 gram, 3.94 mmol) is dissolved in methanol (20 mL) and a solution of KOH (0.65 gram (85%), 9.85 mmol) in water (20 mL) is added. The resulting mixture is heated at reflux temperature for 1 hour, poured into water and acidified with hydrochloric acid (1N solution). The formed precipitated material is collected by filtration and dried in vacuo at room temperature to give a quantitative yield of 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-thiazole-2-carboxylic acid. Melting point: 94-95° C.