Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[CH2:40][CH2:41][CH2:42][NH+:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[NH+](C)CCCCl
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
In a 2-(5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (109 mg, 205 μmol), 3-chloro-N,N-dimethylpropan-1-aminium chloride (97.4 mg, 616 μmol, Eq: 3.0) and Cs2CO3 (402 mg, 1.23 mmol, Eq: 6.00) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 158 μmol, 76.7%) as a light brown solid. MS (M+H)+=616 (>90% purity); 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.06 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.8 Hz, 1H), 5.75 (s, 2H), 4.60 (t, J=6.6 Hz, 2H), 3.53-3.74 (m, 2H), 2.33-2.42 (m, 2H), 2.29 (s, 6H), 2.14-2.27 (m, 2H), 1.65 (s, 9H), 0.90-1.07 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1>[C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: NCCCCc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
4-(4-Hydroxyphenyl)butylamine hydrobromide (4) (197 g, 0.80 mole), water (1 L), 1,4-dioxane (1 L) and sodium bicarbonate (336 g, 4 mole) were combined and stirred while cooled in an ice-methanol cooling bath. Benzyl chloroformate (141 mL, 0.96 mole) was dripped in over 5 min. at −2° C. with no appreciable exotherm observed. This was stirred and allowed to warm to room temperature as the cooling bath thawed overnight. An additional quantity of benzyl chloroformate (8 mL, 0.54 mol) was dripped in and this was allowed to stir for 2 h. The product mixture was then evaporated to approximately 500 mL and transferred to a 2 L separatory funnel with ethyl acetate while decanting away from the solids. The aqueous layer was extracted with ethyl acetate (3×1 L). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to afford 265 g of the crude product. A portion of the crude product (130 g) was chromatographed (silica gel, 5:1 hexanes/ethyl acetate) using toluene to load the column. The remaining crude material was crystallized from 1:1 toluene/heptane. This material was suction filtered to collect the solid and washed with 1:1 toluene/heptane. This material was vacuum desiccated at 45° C. for 2 h. The combined yield of compound (29) was 150 g (62%) of a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ 1.43-1.65 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 4.78 (br s, 1H), 5.09 (s, 2H), 5.77 (s, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 7.34 (s, 5). CI MS m/z=300 [C18H21NO3+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-methylbenzylamine and acetonitrile essentially as described above in example 18. Purity by LC/MS (APCI)=100%, [M+H]+=365.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][C:7]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2ccc(F)cc21
Temperature: 25 °C

Procedure:
At 130° C., 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml acetic anhydride for 3 hours. After cooling to room temperature, the precipitate is filtered off with suction, washed with 100 ml of petroleum ether and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[Na].[CH3:14][C:15](N(C)C)=O>[Cu].O>[Br:8][C:5]1[CH:4]=[C:3]([S:9]([OH:12])(=[O:11])=[O:10])[C:2]([C:2]2[C:3]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:4][C:5]([Br:8])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)c1cc(Br)ccc1Br
Reactant: CC(=O)N(C)C
Agent: [Cu]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)O
Temperature: 120 °C
Yield: 86 %

Procedure:
A modification of the published procedures of Courtot and Lin in Bull. Soc. Chim. Fr. 1931, 49, 1047 was used. Inside a glove box, a 500 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 2,5-dibromobenzenesulfonic acid, sodium salt (73 g, 0.216 moles), activated copper bronze (27 g, 0.43 moles), and DMAc (200 mL). The mixture was heated to 120° C. overnight under nitrogen. The mixture was poured into water (1 L) and the solid removed by vacuum filtration. The filtrate was evaporated and the residue dried at 100° C. under vacuum. The solids were recrystallized from acetonitrile/water (10:1) after treating with decolorizing carbon and dried under vacuum at 60-150° C. to give 48.13 g (86% yield) of 4,4′-dibromobiphenyl-2,2′-disulfonic acid, sodium salt. 1H NMR (DMSO-d6): 7.19 (d, 8.3 Hz, 2H), 7.42 (dd, 8.3 and 2.1 Hz, 2H), 7.96 (d, 2.1 Hz, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:39])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:25][CH:24]=3)[CH2:14][NH:15]C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:40]>C(Cl)Cl>[ClH:40].[ClH:40].[NH2:15][CH2:14][CH:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:24]=1)[C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:39]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(2-oxo-2-phenylethoxy)phenyl)propylcarbamate (E275) in CH2Cl2 was added HCl (4 N, dioxane) and the solution was stirred overnight. The solvents were evaporated to give pure 3-amino-N-(isoquinolin-6-yl)-2-(4-(2-oxo-2-phenylethoxy)phenyl)propanamide dihydrochloride (E277).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22]Cl)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:39])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22][N:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Yield: 69.5 %

Procedure:
N-Chloroacetyl-N-(indan-2-yl)glycine benzyl ester (3 g) and 2 g of N-benzylglycine ethyl ester are dissolved in 50 ml of methyl ether ketone, 10 g of potassium carbonate is added, and the mixture is refluxed for 24 hours with stirring. After cooling, the insoluble matter is filtered off, and the filtrate is distilled under reduced pressure to give an oil. This is purified by silica gel column chromatography to give 3 g of N-ethoxycarbonylmethyl-N-benzylglycyl-N-(indan-2-yl)glycine benzyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.CCCCCC.C([O:22][B:23](OCCCC)[O:24]CCCC)CCC>O1CCCC1>[CH3:11][C:4]1[CH:3]=[C:2]([B:23]([OH:24])[OH:22])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH3:10]
Reactant: COc1c(C)cc(Br)cc1C
Reactant: CCCCOB(OCCCC)OCCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C)cc(B(O)O)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
4-Bromo-2,6-dimethylanisole (5 g, 1 eq, Acros) in tetrahydrofuran (100 mL) was cooled to −78° C. under nitrogen. N-Butyl lithium in hexane (1.6 M, 19 mL, 1.3 eq) was added dropwise over 10 min. The mixture was stirred at −78° C. for 1 h. Tributylborate (31 mL, 5 eq) was added to the solution and stirred at −78° C. for 1 h. The mixture was allowed to warm to room temperature and stirred for 16 h. Reaction was quenched with hydrochloric acid (1M, 20 mL). The solvent was evaporated and the residual aqueous solution was acidified to pH 1 using concentrated hydrogen chloride. The mixture was extracted with diethyl ether (2×100 mL). The combined organic phase was extracted with aqueous sodium hydroxide (1M, 2×100 mL). The combined aqueous phase was acidified with concentrated hydrogen chloride to pH 1. The resulting precipitates were collected by filtration to afford 3,5-dimethyl-4-methoxybenzene boronic acid (3.43 g, 82%) as a white solid: 1H NMR (CDCl3) five peaks for 2H: 7.87 (s), 7.60 (weak s), 7.85 (s), 7.26 (s) 6.98 (weak s); five signal for 3H: 3.80 (s), 3.76 (weak s), 3.74 (s), 3.69 (weak s), 3.67 (weak s); four signals for 6H: 2.40 (s), 2.54 (weak s), 2.51 (s), 2.25 (weak s). (I.b.) 3,5-Dimethyl-benzene boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]([F:29])[CH:23]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)c(F)c2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)cc1

Procedure:
900 mg (2.20 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][3-fluoro-4-hydroxyphenyl]methanone was dissolved in 12 mL of DMF and 810 mg (4.4 mmol) of 1-(2-chloroethyl)piperidine hydrochloride was added. To the reaction mixture was added 3.3 g (10 mmol) of Cs2CO3 and heated to reflux for one hour. The reaction mixture was filtered to remove the solids. The solvents were removed by evaporation and the residue was chromatographed on a silica gel column eluted with a linear gradient of beginning with CHCl3 and ending with MeOH-CHCl3 (1:19). The desired fractions were determined by tlc, combined, and evaporated to a solid. This yielded 960 mg of the title compound as a tan amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:27])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NS(=O)(=O)c1ccc(C(=O)O)cc1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suspension of 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoic acid (2.90 g) in dichloromethane (30 mL) was added N,N-dimethylformamide (19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath. The mixture was stirred for 0.5 hour at room temperature and refluxed for 1 hour. The resulting mixture was refluxed further for 5 minutes after adding oxalyl chloride (439 mg). The volatile was evaporated off to give a white solid. The solid was triturated in diisopropyl ether to give benzyl[4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a white powder (2.40 g), which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:15]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2]>O1CCCC1.[C].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)OC)cc(C#N)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Methyl 3-cyano-5-ethynyl-4-methoxybenzoate (475 mg) was dissolved in tetrahydrofuran (10 mL), and 5% palladium-carbon (150 mg) was added to the solution, and then the mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (480 mg) as a colorless crystal.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[OH:1][N:2]=[CH:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[S:9][C:8]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: ON=Cc1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C=NO)c2s1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
7-Hydroxyiminomethylimidazo[5,1-b]thiazole (a low-polarity geometrical isomer) (831 mg) was dissolved in 25 ml of THF and 5 ml of hexamethylphosphoramide (HMPA). A 1.55 N n-butyllithium/n-hexane solution (7.67 ml) was dropwise added in an argon atmosphere at −70° C. to the solution. The mixture was stirred at the same temperature for 40 min. Tri-n-butylstannyl chloride (1.84 ml) was added thereto. The mixture was stirred for 1.5 hr while raising the temperature to −40° C. An ammonium chloride solution was a added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 to 1:1) to give 680 mg of 7-hydroxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (a geometrical isomer derived from a starting compound as a low-polarity oxime isomer).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37](Cl)=[O:38]>>[CH3:28][C:11]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:40])=[CH:7][CH:6]=2)=[O:29])[C:14](=[O:15])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: Cc1ccccc1CC(=O)Cl
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Cc2ccccc2C)cc1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and o-tolyl-acetyl chloride to yield N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-2-o-tolyl-acetamide. LC/MS at 254 nm; [M+H] 516; Rt 3.526 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Solvent: CC#N
Product: CCOC(=O)CCc1nnc(Cl)c2cc(OC)ccc12
Yield: 84.8 %

Procedure:
Operating analogously to example 114 starting from 3-(6-methoxy-4-oxo-3,4-dihydro-phthalazin-1-yl)-propionic acid ethyl ester (552 mg, 2 mmoles), prepared as described in example 119, and POCl3 (1.12 ml, 12 mmoles) in acetonitrile (5 ml), 0.5 g of the title compound were obtained (yield: 84.8%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=O)[CH:3]=1.[C:21]1([CH2:27][CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][NH:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid (0.4 g, 1.23 mmol), 2-phenylethylamine (0.16 mL, 1.23 mmol), sodium cyanoborohydride (0.189 g, 3.0 mmol), and acetic acid (2 drops) were combined in CH2Cl2 and stirred at room temperature for 10 minutes. Aqueous work-up yielded the title compound.
Reaction SMILES: C([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:42]1[CH:43]=[N:44][C:45]([NH:48][CH3:49])=[N:46][CH:47]=1>>[ClH:27].[ClH:27].[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:42]2[CH:43]=[N:44][C:45]([NH:48][CH3:49])=[N:46][CH:47]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:13][CH2:14][CH:9]([NH:8][CH3:40])[CH2:10][CH2:11]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CNc1ncc(Br)cn1
Product: CNc1ncc(-c2ccc(OC)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(NC)CC3)c2)cn1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 5 (25 mg, 43 μmol) and 5-bromo-2-(methylamino)pyrimidine (6.7 mg, 36 μmol) in accordance with Method L2.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:8][C:7]=1[CH3:36].C(O)C.Cl>>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH3:36])[CH:8]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: CCO
Product: Cc1cc(SCC=C(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(3-trifluoromethyl-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (100 mg, 0.23 mmol) was dissolved in ethanol (10 ml).1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1N HCl (3 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evapotated to give the title compound in 20 mg (5%) yield.
Reaction SMILES: C(O[C:6]([N:8](C)[O:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CN(OC(=O)CCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNOC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(tert-butoxycarbonyl(methyl)aminooxy)-4-oxobutanoic acid (96 mg, 0.389) in dioxane (3 mL) was added 4 M HCl solution in dioxane (2 mL). The reaction mixture was stirred at room temperature for 20 h and concentrated. The desired product was obtained as a white solid (72 mg, 0.389 mmol, 100%). 1H NMR (CD3OD, 400 MHz): δ (ppm) 2.53-2.57 (m, 2H), 2.68-2.77 (m, 2H), 2.94 (s, 3H).