Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C@@:7]([CH3:14])([CH2:11][CH2:12][CH3:13])[C:8](O)=[O:9])[CH3:6]>>[CH2:5]([C@@:7]([CH3:14])([CH2:11][CH2:12][CH3:13])[C:8]([Cl:3])=[O:9])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@](C)(CC)C(=O)O
Product: CCC[C@](C)(CC)C(=O)Cl
Temperature: 100 °C

Procedure:
121 μl (1.66 mmol) of thionyl chloride were added to 60 mg (0.42 mmol) of (-)-(2S)-2-ethyl-2-methylpentanoic acid [prepared as described in Preparation 16], and the resulting mixture was heated at 100° C. for one hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The whole of the (-)-(2S)-2-ethyl-2-methylvaleryl chloride obtained in this manner was added, directly and without purification, to a solution of 458 mg (0.83 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], 203 mg (1.66 mmol) of 4-(N,N-dimethylamino)pyridine, a catalytic amount (20 mg) of 4-dimethylaminopyridine and 232 μl of triethylamine in 2.5 ml of toluene, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was cooled to room temperature and then mixed with 10 ml of a 10% w/v aqueous solution of hydrogen chloride. The aqueous mixture was extracted three times, each time with 20 ml of ethyl acetate. The combined extracts were then washed with a saturated aqueous solution of sodium chloride, after which the washed solution was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting pale-yellow oily residue was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 88 mg (31% yield) of the title compound as a foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7](Cl)[N:8]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:8]=2)[N:3]=1
Reactant: CCCCCOc1nc(N)nc2ncc(Cl)nc12
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCOc1nc(N)nc2ncc(C=Cc3ccccc3)nc12
Yield: 72.9 %

Procedure:
A mixture of 1.5 g (5.6 mmoles) 2-amino-6-chloro-4-n-pentyloxypteridine (e.g. available following the procedure disclosed by Mohr et al. in Helv. Chem. Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o-tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles), styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was stirred in dry acetonitrile (50 ml) under reflux for 90 hours. It was evaporated and the residue purified by silica gel column chromatography with chloroform. The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange powder exhibiting, after recrystallization from a EtOAc/hexane mixture, a melting point (m.p.) range of 127–128° C.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:24][CH:23]=2)[CH:8]=1.Cl.O>CC(C)=O>[CH:2]([C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:23]=2)[CH:8]=1)=[O:1]
Reactant: CCOC(=O)COc1ccc(C2OCCCO2)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(C=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 200 ml of acetone was dissolved 8.69 g of ethyl 4-(1,3-dioxan-2-yl)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 41. To the solution was added 6 ml of 6% hydrochloric acid. The mixture was stirred at room temperature for 2 hours. After adding 30 ml of water thereto, the mixture was cooled and the precipitated crystals were taken by filtration, washed with 50% acetone to obtain 6.0 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]([NH:13][C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](O)=O)=[CH:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:27]>>[C:1]1([CH2:7][N:8]2[C:12]3=[N:13][C:14]4[C:15]([C:16]([Cl:27])=[C:11]3[CH:10]=[N:9]2)=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1Nc1ccnn1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2Cc1ccccc1

Procedure:
A mixture of N-(1-phenylmethylpyrazol-5-yl) anthranilic acid (6 g) and POCl3 (60 ml) is heated on a steam bath overnight. The reaction mixture is poured into ice waterl, neutralized with NH4OH, and the precipitate which forms is collected by filtration,washed with water and dried to afford 5 g of 1-phenylmethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, as a light brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1F.BrCC(C1C=CC=C(Cl)C=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)cs1
Agent: O=C(CBr)c1cccc(Cl)c1
Product: CCOC(=O)c1nc(-c2cccc(Cl)c2)cs1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 2A starting with 2-bromo-1-(3-chlorophenyl)ethanone. 1.51 g (73% of theory) of the title compound are obtained.
Reaction SMILES: N[C@@H:2]([CH:11](C)C)[C@@H:3]([C:5]1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].CCCCCC>CCOC(C)=O>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:5][CH2:3][CH2:2][CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCC1
Yield: 93 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenyl-ethanol. Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and a white solid (1.24 g) is obtained. The yield is 93% and the other analysis includes:
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH2:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C(O)C>[CH2:16]([C:24]1[CH:25]=[CH:26][C:27]([C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccccc1
Reactant: COC(=O)CCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1

Procedure:
Adipic acid monomethyl ester (25 g; 0.16 mole) is converted to the acid chloride with thionyl chloride (25 g) in a manner analogous to that described in Example 1. The crude product is reacted with octylbenzene (200 ml) and aluminum chloride (40 g; 0.3 mole) and the product isolated in a manner analogous to that described in Example 1. The crude product Is heated under reflux with 2N sodium hydroxide (117 ml) and ethanol (117 ml) for 2 hours and further processed as described in Example 1. The crude product is recrystallized from heptane to give 5-(4-n-octylbenzoyl)pentanoic acid (38.2 g), m.p. 96°-97° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[C:25]([F:44])[CH:24]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CCO.O>[NH2:1][C:2]1[C:7]2=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[C:25]([F:44])[CH:24]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ncnn2c(CCCCO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reaction time: 0.5 h

Procedure:
To a suspension of 1-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea in 3 ml 95:5 EtOH/H2O was added 30 μL conc. HCl. for 30 min. The reaction mixture was quenched with 5 ml saturated NaHCO3. After the solvent EtOH was evaporated, the crude was extracted with EtOAc (3×). The resulting crude organic was dried and concentrated and trituated with EtOAc and hexane to give 115 mg of pure title compound as a white solid. MS [M+H]+=521.2; LC/MS RT=2.94 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
(E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (6.58 g, 29.09 mmol) was added to a suspension of (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.02 g. 24.24 mmol) in toluene (51.1 ml) and acetic acid (2.78 ml, 48.48 mmol). The reaction was heated to 80° C. for 5 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title product (7.52 g, 68.0%) as a yellow solid. 1H NMR (400 MHz, DMSO, 100° C.) δ 1.10 (3H, d), 1.12-1.31 (6H, m), 2.28-2.72 (2H, n), 2.84-3.09 (2H, m), 3.52-3.69 (1H, m), 3.76 (3H, s), 5.30 (1H, s), 6.64 (1H, d), 6.9-7.11 (2H, m), 7.21 (1H, d), 7.32 (2H, d), 7.42 (1H, d), 7.58 (1H, d), 10.14 (1H, s). m/z: ES+ [M+H]+ 457
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].Cl.N1C=CC(CCl)=CC=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Agent: Cl
Agent: ClCc1ccncc1
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(4-pyridyl)propionate hydrochloride (prepared by the method set forth above using 4-picolylchloride hydrochloride), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.49 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[N:16][CH:17]=2)[CH3:11])=[CH:5][CH:4]=1.CO.O.[OH-].[Li+]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[N:16][CH:17]=2)[CH3:11])=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(C(C)=NOCc2ccc(C(F)(F)F)cc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(OCC(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of the product of step 3 (2.0 gm, 5.2 mmoles) in a mixture of THF (12 mL), methanol (4 mL) and water (4 mL), lithium hydroxide (440 mg, 10.5 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water, acidified with 1N HCl and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 1.7 gm (88%) of title product as white solid.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:3])[CH3:2].S([O-])([O-])(=O)=O.[Ba+2]>O1CCCC1.C(O)C.[Pd]=O>[C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C=Cc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Agent: O=[Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Reaction time: 3.5 h
Yield: 69.7 %

Procedure:
1H-NMR (CDCl3) δ: 2.69 (3H, s), 3.85 (3H, s), 6.98 (2H, d, J=10 Hz), 7.50-7.80 (6H, m), 8.36 (1H) d) 7.8 g of 3-acetyl-2-[2-(4-methoxyphenyl)-vinyl]-5-benzofurancarbonitrile obtained in the above step c) was dissolved in a solvent mixture of 600 ml of tetrahydrofuran and 500 ml of ethanol. 900 mg of palladium oxide.1H2O.barium sulfate was added to the above solution, and the mixture was subjected to catalytic hydrogenation under normal pressure for 3.5 hours. After removing the catalyst by filtration, the resulting filtrate was concentrated to dryness. The residue thus obtained was extracted with ethyl acetate, and the resulting organic layer was washed with water, and dried to distill off the solvent. Thereafter, the residue thus obtained was washed with methanol to collect precipitated crystals by filtration, thereby obtaining 5.47 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile in the form of colorless prism crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@H:9]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:34]2[CH:43]=[CH:42][C:37]3[NH:38][C:39](=[O:41])[O:40][C:36]=3[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1>COCCOC.CCO.O.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([C:34]3[CH:43]=[CH:42][C:37]4[NH:38][C:39](=[O:41])[O:40][C:36]=4[CH:35]=3)[CH:3]=[N:4]2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)oc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CCn1cc(Br)cn1)Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(-c2ccc3[nH]c(=O)oc3c2)cn1)Cc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of (S)-tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)-1-(4-chlorophenyl)butan-2-ylcarbamate (200 mg, 0.47 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (183 mg, 0.70 mmol), sodium carbonate (148 mg, 1.40 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (34.0 mg, 0.09 mmol), and bis(dibenzylideneacetone)palladium(0) (42.7 mg, 0.05 mmol) in DME:EtOH:H2O (7:2:3, 4 mL) was heated at 130° C. for 15 minutes in a Biotage Initiators microwave. After cooling to room temperature, the mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The material thus obtained was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:18]([C:17]3[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[O:8][CH2:7][C:6]=2[CH:9]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cc(Br)ccc1O
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2OCc3cc(Br)ccc3O2)cc1
Temperature: 5 °C
Yield: 69.8 %

Procedure:
An intimately ground mixture of 5-bromo-2hydroxybenzyl alcohol (4.06 g), 4-nitrobenzaldehyde (3.93 g) and benzoic acid (0.2 g) was stirred and heated to 85° C. (±5° C.) under nitrogen for 88 hours. The clear melt which formed initially gradually solidified throughout the reaction period. The resulting solidified mass was cooled and dissolved in ethyl acetate (250 ml). The solution was then washed with 20% aqueous sodium carbonate, 20% aqueous sodium bisulphite and finally with brine. After drying over sodium sulphate, the organic phase was evaporated to yield a solid residue which was purified by briefly suspending in hot ethanol (approx. 75 ml) and cooling to 0°-5° C. The pure product was obtained as pale buff-coloured crystals (4.69g, 70%), mp 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[C:15]([C:10]3[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:25][CH:24]=1
Reactant: NNc1ccc(Cl)c2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=433.1 (M+H)+
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=O)c1cccc2ccccc12
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1cccc2ccccc12
Reaction time: 8 h
Yield: 45 %

Procedure:
Hydroxylamine hydrochloride (834 mg) was added to a stirred solution of methyl 2-oxo-2-(1-naphthyl)acetate (1.72 g) in methanol. The mixture was left overnight then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The title oxime (828 mg) was obtained by recrystallisation of the residue from ethyl acetate/hexane. (Found: M+ 229.0743. C13H11NO3 requires 229.0739). νmax (CHCl3) 3311, 1725. δH (250 MHz, CDCl3), 3.84 (3H, s), 7.43 (1H, dd, J 1.21 and 7.12), 7.46-7.64 (4H, m), 7.89-7.97 (2H, m); m/z (EI) 229 (M+).
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:30][O:29]C(C)(C)[O:27]1)[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:24])(=[O:23])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[CH:8][CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:26]([OH:27])[CH2:30][OH:29])[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:23])(=[O:24])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[CH:10][CH:11]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)cc2)O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4.74 g (10 mmol) of 4-[N-(2,4,6-trifluorophenyl)sulfamoyl]- benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 50 ml of ethanol and 20 ml of water and the solution is acidified to pH 1 with dilute hydrochloric acid. It is stirred at this pH for 4 hours at 60° C. The solution is then adjusted to pH 6.3 with anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 3.4 g (7.83 mmol)=78.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.O>[CH3:9][N:10]([CH3:14])[C:11]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1)=[O:12]
Reactant: c1cc2[nH]ccn2n1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1ccn2nccc12

Procedure:
To a solution of 1H-imidazo[1,2-b]pyrazole (2 g) in tetrahydrofuran (20 ml) were added N,N-dimethylcarbamoyl chloride (3.8 ml) and triethylamine (6.2 ml) at 20° C. under stirring. After stirring, the reaction mixture was poured into a mixture of ethyl acetate (30 ml) and cold water (50 ml). The ethyl acetate layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 1-(N,N-dimethylcarbamoyl)-1H-imidazo[1,2-b]pyrazole (3.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[I-].[Mg+2].[I-]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:17](=[O:22])[CH:18]3[CH:19]([CH:25]4[O:24][CH:28]3[CH:27]=[CH:26]4)[C:20]2=[O:21])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccoc1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C=CC1=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of 2-(4-benzyloxy-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (1 g, 3.3 mmol), furan (20 ml) and magnesium iodide (50 mg) is stirred at room temperature for 5 days. The reaction mixture is diluted with methanol and silica gel is added. After evaporation of the solvent, the residue is purified by column chromatography on silica gel to give 4-(4-benzyloxy-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (0.531 g).