Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CCN)=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].C(Cl)(=[O:24])C.O>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:17]([CH2:18][CH3:19])[C:15](=[O:24])[CH3:16])=[C:4]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cc(Br)ccc1CCN
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCN(C(C)=O)c1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In a 250 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, 15 g (58.5 mmol) of (4-bromo-2-tert-butylphenyl)ethylamine are dissolved in 150 mL of dichloromethane. 8.9 g (87.8 mmol, 12.2 mL) of triethylamine and 0.72 g (5.9 mmol) of 4-dimethylaminopyridine are added. 11.5 g (146 mmol, 2.5 mL) of acetyl chloride are added dropwise and the reaction medium is stirred for 1 hour at room temperature. The reaction medium is poured into 250 mL of water and extracted twice with dichloromethane. The organic phases obtained are combined and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a blackish oil. This oil is purified by chromatography on silica (eluent: 80/20 heptane/ethyl acetate) to give 15 g (yield=86%) of N-(4-bromo-2-tert-butylphenyl)-N-ethylacetamide in the form of an orange oil.
Reaction SMILES: C(O)(C)C.FC(F)(F)C([NH:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12])=O.[OH-].[K+]>C(O)C>[NH2:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)C(NC(=O)C(F)(F)F)c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CC(C)(O)C(N)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
180 mL of isopropanol and 180 mL of ethanol were added to 36.0 g of the 1-(trifluoroacetylamino)-1-(1-naphthyl)-2-methyl-2-propanol obtained, and 63 g of an aqueous solution of 22% by weight of potassium hydroxide was added dropwise thereto over 30 minutes at room temperature. The inner temperature of the mixture was raised to 50° C. and, at the same temperature, the mixture was stirred for 2 hours to effect reaction. The reaction mixture was concentrated, and 500 mL of chloroform and 180 mL of water were added to the resulting concentrated residue to carry out extraction treatment. The organic layer obtained was washed with 100 mL of water and the organic layer obtained was dried over dehydrated sodium sulfate and then concentrated. The resulting concentrated residue was dried at an inner temperature of 30° C. under reduced pressure to obtain 28.0 g of brown, viscous and oily 1-amino-1-(1-naphthyl)-2-methyl-2-propanol
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:3]=1.[OH:28]O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=3[CH:5]=2)=[O:28])=[CH:26][CH:25]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCSc3ccc(Cl)cc3)cc21
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-chloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(=O)[C:12]([Cl:14])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC=C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:12]([Cl:14])=[O:13])=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=C(Cl)Cl
Product: O=C(Cl)c1ccc(CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a cold (ice bath) stirred solution of 50.0 g (0.25 mole) of 1-bromo-3-phenylpropane (Aldrich) and 31.9 g (0.25 mole) of oxalyl chloride in 300 mL of trichloroethylene was added, portionwise, 33.3 g (0.25 mole) of aluminum chloride. The reaction mixture was stirred for 0.5 hr and then poured into ice water. The layers were separated and the aqueous layer was extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed twice with 200 mL portions of water and dried (magnesium sulfate). The solvents were evaporated under reduced pressure to leave 63.6 g (97%) of 4-(3-bromopropyl)benzoyl chloride as an oil. To a solution of the acid chloride in 120 mL of dry benzene was added 60 mL of absolute ethanol and the mixture was heated at reflux for 3 hr. The solvents were evaporated under reduced pressure to give 63.4 g (93.5%) of an oil. The oil was purified by chromatography (3.5×90 cm glass column, 200 g of silica gel, benzene-hexane, 1:1). Fractions containing the desired component were combined and the solvents evaporated under reduced pressure to give 60.6 g (89%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)=[O:32]
Reactant: COCC(=O)Cl
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4ncccc4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 81 h
Yield: 22.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (148 mg, 0.412 mmol) in N,N-dimethylacetamide (5 mL) was added methoxyacetyl chloride (37.8 μL, 0.413 mmol), and the mixture was stirred at room temperature for 81 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→90% ethyl acetate-hexane) to give the title compound (40.6 mg, 23%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCNCC
Product: CCN(CC)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and diethylamine. MS (ESI): 414.3 (MH+).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[F:15][CH:2]([F:1])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(CC(F)F)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)O)cn1CC(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
Ethyl 1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate (1.375 mmol, 300 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (4.12 mmol, 2.062 ml) was added and the resulting mixture was stirred for 2.5 h at RT. The pH of the mixture was adjusted to about 6 with 5 M HCl and the solvents were evaporated. Ethanol was added and filtered. The filtrate was evaporated. 176 mg of the title compound was obtained. The two isomers formed in the previous reaction were still present. Isomer 1: 1H-NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 4.67-4.80 (m, 2H), 6.09-6.44 (m, 1H), 6.94 (s, 1H). Isomer 2: 1H-NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.32-4.44 (m, 2H), 6.17-6.47 (m, 1H), 7.15 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=3)=[O:10])=[C:4]([C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[CH:3]=2)=[CH:41][CH:42]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 30 mg, 0.060 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (14.4 mg, 0.066 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) in 1 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80° C. for 3 h under Ar, and then cooled to RT. Treated with 50 μL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexane) gave 16 mg (85%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.37 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.43-7.47 (m, 3H), 7.35 (d, 1H, J=2.1 Hz), 6.84 (d, 2H, J=8.5 Hz), 5.97 (s, 2H), 5.89 (m, 1H), 3.67 (t, 2H, J=8.2 Hz), 2.25-2.34 (m, 4H), 1.77-1.90 (m, 4H), 0.98 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H35N5O2Si, 514.3 (M+H), found 514.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:9][C:8]=1[O:21][CH3:22].[CH3:26][CH:27]([CH3:30])[CH:28]=O.[Cl:31]CCl.C(O)(=O)C>CO>[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH2:26][CH:27]([CH3:30])[CH3:28])[CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: CC(C)C=O
Reactant: ClCCl
Reactant: CNC(=O)CNCCc1ccc(OCc2cccc(F)c2)c(OC)c1
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)CC(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
90 mg of 2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamide (0.235 mmol) and 19 mg (0.263 mmol) of 2-methyl-propionaldehyde were dissolved in 6 ml of a dichloromethane/acetic acid (8:2, v:v) mixture and 1.5 ml of methanol. 100 mg (0.425 mmol) of (polystyrylmethyl)trimethylammonium cyanoborohydride (loading: 4.25 mmol/g) were added and the mixture was stirred at room temperature overnight. The resin was filtered and the solvent was removed. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:0:0→100:2:0.2 gradient v:v:v). The product was dissolved in anhydrous hydrochloric acid in ethyl acetate, the solvent was removed and the residue was triturated with diethyl ether. 80 mg (77% yield) of the title compound were isolated as a hygroscopic solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+].O>O1CCCC1>[CH3:24][S:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[N:21]\[O:22][CH3:23])/[C:17]([NH:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(SC)n1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
(E)-2-[2-(6-chloropyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (1.2 g) was dissolved in tetrahydrofuran (10 ml), and sodium thiomethoxide (1 g) was added. The mixture was heated under reflux with stirring for 5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (800 mg). mp. 130°-132° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH2:32][NH:2][C@H:3]1[C@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:15](=[O:16])[NH2:17])=[CH:8][CH:7]=2)[C:12]1([CH3:14])[CH3:13])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN[C@H]1[C@H](OC)Cc2ccc(C(N)=O)cc2C1(C)C
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (0.25 g, 0.88 mmol) anhydrous ethanol (0.90 mL), triethylamine (0.14 mL, 1.32 mmol) and acrylic acid ethyl ester (0.14 mL, 1.0 mmol) were heated at 70° C. After 23 h, additional acrylic acid ethyl ester (0.04 mL, 0.3 mmol) was added and heating was continued. Five hours after the addition, the reaction was cooled to room temperature, combined with another run (0.36 mmol scale) and concentrated under vacuum. The title compound (0.61 g) was used without further purification. (m/z): [M+H]+ calcd for C19H28N2O4 349.21. Found 349.0.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:39])[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][CH2:34]Br)[C:23]=1[CH2:36][CH2:37][CH3:38])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:39])[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][CH2:34][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:23]=1[CH2:36][CH2:37][CH3:38])[CH3:16]
Reactant: CCCc1c(OCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 68.7 %

Procedure:
A mixture of 3.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.4 g of racemic-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]methylacetic acid ethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a red oil which was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to give 5.6 g (69%) of racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylacetic acid ethyl ester as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[N:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1.[Br:31]Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:31][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[Cl:7])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[N:13]=[C:12]2[NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.22 cm3 of pyridine is added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 15 cm3 of chloroform, followed by addition of 0.14 cm3 of bromine. The mixture is stirred for 24 hours at 20° C., followed by addition of 50 cm3 of dichloromethane and 50 cm3 of saturated aqueous sodium sulphate solution. After stirring for 10 minutes, the insoluble material is removed by filtration on a sinter funnel and the organic phase is washed with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/m; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 940 mg of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 130° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH2:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccccc1N
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2N)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-aminobenzylamine in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH2:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (8.0 g, 40.40 mmol, 1.00 equiv.), diphenylphosphoryl azide (11.2 g, 40.73 mmol, 1.00 equiv.), triethylamine (6.2 g, 61.39 mmol, 1.50 equiv.) in toluene (60 mL) was heated at reflux for about 1 hour and then refluxing 6N hydrogen chloride was added. The mixture was kept at reflux for 16 hours, and then cooled to ambient temperature. The resulting mixture was concentrated in vacuo, and the resulting residue was dissolved in water/ether (1:1) 200 mL). Following standard extractive workup with ether (3×100 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0)) to give the title product as a light-brown solid (6.2 g; yield=91%). 1H NMR (300 MHz, CDCl3) δ: 6.98-7.07 (m, 1H), 6.72-6.81 (m, 2H), 2.40 (m, 1H), 1.82-1.87 (m, 1H), 1.05-1.11 (m, 1H), 0.85-0.96 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:37]=[CH:36][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:36][CH:37]=1
Reactant: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
1.0 g of 4-[4-(2-oxazolin-2-yl) benzylidene]-1-tritylpiperidine in 20 ml of methylene chloride are treated slowly with 2 ml of trifluoroacetic acid at -10° C. After stirring for 1 hour at -10° C., the reaction mixture is poured into 150 ml of ice-water and immediately adjusted to pH 11.5 using 6N sodium hydroxide solution. After stirring for 10 minutes, it is extracted twice with 150 ml of ether, and the combined organic phases are washed, dried and evaporated down. The residue is purified by column chromatography on alumina (methylene chloride/methanol=40:1, v/v). 340 mg of the title compound of melting point 126° C. are obtained.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.CN(C=O)C.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([OH:31])=O.[NH2:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[CH:34]([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([NH:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[O:38])[CH:34]([CH3:35])[CH3:36])=[O:31]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
4-Dimethylaminopyridine (DMAP) (67 mg, 0.55 mmol) and 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (125 mg, 0.65 mmol) were added as solids to a DMF solution of 1,3-dimethylindole-2-carboxylic acid (95 mg, 0.5 mmol in 1 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (153 mg, 0.5 mmol in 1 mL of methylene chloride) was added and the resultant reaction mixture was first stirred for 1 hour at 0° C. and then for 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×), and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether/hexane to yield the title product as a white solid (134 mg, 56%). TLC: (ethyl acetate/hexanes, 2:1): Rf=0.42. 1H NMR (CDCl3): δ 7.59 (d, J=8.8, 1H), 7.37 (d, J=7.7, 1H), 7.29-7.24 (m, 1 H), 7.12-7.07 (m, 1H), 4.49-4.26 (m, 5H), 3.81-3.79 (m, 3H), 2.66-2.47 (m, 5H), 2.22-2.10 (m, 1 H), 1.45-1.41 (m, 9 H), 1.09-1.03 (m, 6 H).