Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[C:10]([F:17])[C:9]=1[F:18])C>O1CCOCC1.O>[F:18][C:9]1[C:10]([F:17])=[C:11]([CH2:14][CH2:15][OH:16])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH:5]=[O:4]
Reactant: CCOC(COc1ccc(CCO)c(F)c1F)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=CCOc1ccc(CCO)c(F)c1F
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2-diethoxyethoxy)-2,3-difluorophenyl)ethanol (example 77, step c) (0.49 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The mixture was carefully diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound, which was used directly. Yield 0.31 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[NH2:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(NN)cc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentrated hydrochloric acid was stirred at −10 to −5° C. in an ice-acetone bath as a solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, a small amount of insoluble solid was removed by filtration into a cold receiving flask. The filtrate was then added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about −5° C. A gummy material separated during the addition. After completion of the addition, stirring was continued at −10 to −5° C. for 1 hour. The aqueous phase was decanted, and the residual gum was dissolved in 250 mL of ethyl acetate. The ethyl acetate solution was treated cautiously with 250 mL of saturated aqueous sodium bicarbonate solution and shaken in a separatory funnel. The ethyl acetate layer was washed with 50 mL of saturated aqueous sodium chloride solution. The entire mixture was filtered before separation of the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 2.59 g (65%) of an oil. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure and indicated that only minor impurities were present.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]#[N:11].[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:11][C:10]1[C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: N#Cc1ccc(Cl)c(C#N)c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2ccc(C#N)cc2c1N
Yield: 37 %

Procedure:
4-Chloroisophthalonitrile (5.69 g, 35 mmol), prepared by the method of Markley et al, J. Med. Chem., 29: 427 (1986), was treated with 1 equivalent methyl thioglycolate and 1 equivalent Na2CO3 in methanol by the procedure described in Example 41A to yield the title compound (3.00 g, 37%). m.p. 248° C. 1H NMR (300 MHz, DMSO) δ 8.71 (s, 1H), 8.09 (d, 1H), 7.86 (dd, 1H), 7.30 (br s, 2H), 3.81 (s, 3H). MS (DCI/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: [Na].[CH:2]([C:5]1[CH:9]=[C:8]([CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH:11]2[C:18]([O:20][CH3:21])=[O:19])[O:7][N:6]=1)([CH3:4])[CH3:3].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>O1CCCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:22]([C:13]1[C:14](=[O:16])[CH2:15][CH:10]([C:8]2[O:7][N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:9]=2)[CH:11]([C:18]([O:20][CH3:21])=[O:19])[C:12]=1[OH:17])(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)C1C(=O)CC(=O)CC1c1cc(C(C)C)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC(=O)C1=C(O)C(C(=O)OC)C(c2cc(C(C)C)no2)CC1=O
Reaction time: 15 h

Procedure:
15.1 g of the sodium salt of 5-(3-isopropylisoxazol-5-yl)-4-methoxycarbonylcyclohexane-1,3-dione was suspended in 150 ml of tetrahydrofuran; 6.4 g butyryl chloride was added while cooling with ice. After the mixture had been stirred for 15 hours it was filtered and concentrated. The residue obtained was taken up in methylene chloride, 2 g of 4-(N,N-dimethylamino)-pyridine was added, and the mixture was stirred for 3 days. After shaking with 10 wt % hydrochloric acid and then with water, the mixture was dried over sodium sulfate and concentrated. 15 g of 2-butyryl-3-hydroxy-5(3-isopropylisoxazol-5-yl)-4-methoxycarbonylcyclohex-2-en-1-one was obtained as an isomer mixture, and was then stirred with 300 ml of 10 wt % strength sodium hydroxide solution at 25° C. for 16 hours. The pH of the solution was then adjusted to 2 concentrated hydrochloride acid, and stirring was carried out for 2 hours at 85° C. After cooling the product was filtered off, washed with water and recrystallized from isopropanol. There was obtained 2-butyryl-3-hydroxy-5(3-isopropylisoxazol-5-yl)-cyclohex-2-en-1-one of m.p. 105°-107° C. (compound no. 64).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]2[C:26]([C:27]3[N:35]=[CH:34][N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4C3CCCCO3)=[CH:25][CH:24]=[CH:23][N:22]=2)[C:14]=1[F:42])(=[O:11])=[O:10]>>[N:35]1[C:27]([C:26]2[C:21]([NH:20][C:15]3[C:14]([F:42])=[C:13]([NH:12][S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=3[F:19])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1Cl
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccccc1Cl
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the 2-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH3:24])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Cl:14][C:15]1[CH:22]=[C:19]([CH3:20])[C:18]([OH:23])=[C:17]([CH:16]=1)[CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(Cl)cc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1cc(Cl)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(5-Chloro-2-hydroxy-3-methyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-hydroxy-3-methylbenzaldehyde (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, CDCl3) δ 2.19 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.67 (m, 6H), 5.40 (s, 1H), 6.80-6.81 (m, 1H), 7.03-7.04 (m, 1H), 7.85 (s, 1H), 10.60 (br s, 1H), 12.45 (br s, 1H). Mass spectrum (ES) MH+=335.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CCO>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:31][CH2:30][CH2:29][NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: NCCNc1ccccn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(F)c(NCCNc3ccccn3)c(F)c(F)c2c1=O
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A solution of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.70 g, 12.3 mmol), N-2-pyridyl-1,2-ethanediamine (1.77 g, 12.9 mmol) and triethylamine (3.50 mL) in EtOH (50 mL) was stirred at room temperature for 3 h, and refluxed for 1 h. The reaction mixture was cooled at room temperature. The resulting precipitate was combined by filtration. The cake washed with EtOH and collected by filtration and then dried to give 1-cyclopropyl-1,4-dihydro-5,6,8-trifluoro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (2.90 g, 56%) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[N:17]3[C:18]([N+:21]([O-])=O)=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>C(Cl)Cl.[H][H].[C].[Pd]>[NH2:21][C:18]1[N:17]2[C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[CH:13][CH:14]=[CH:15][C:16]2=[N:20][CH:19]=1
Reactant: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc(N)n23)CC1
Yield: 132.6 %

Procedure:
To a solution of 5-[1-(methylsulfonyl)-4-piperidyloxy]-3-nitroimidazo[1,2-a]pyridine (70 mg, 0.226 mmole) in methylene chloride (10 ml) was added 10% palladium-carbon (50 ml) and the mixture was stirred in hydrogen atmosphere at room temperature for 1.5 hours. After the reaction mixture was treated with Cellite, the solvent was distilled off. To the residue was added chloroform, which was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: chloroform/methanol (15:1)] to obtain 93 mg of the desired product (30.0%, brown oily product).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:28]([O:30][C:31]([CH:33]=[P:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29].CCO>C(OCC)(=O)C>[CH2:28]([O:30][C:31]([C:33](=[P:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:32])[CH3:29]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N12
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 22 h

Procedure:
A solution of t-butyl 3-bromomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (5.0 g., ca. 10.56 mmole.) in ethyl acetate (90 ml.) was treated with a solution of ethoxycarbonylmethylenetriphenylphosphorane (9.18 g, 26.4 mmole) in ehtyl acetate (110 ml.) and the mixture stirred at 27° for 22 hours, in the dark. The mixture was cooled to ca 3° and stirred for 2 hours after which time precipitated material was collected by filtration and treated as described in Example 1c to give the ylid (3.85 g, 49%) as photosensitive white prisms (from ethyl acetate), m.p. (darkening at ca 155°) ca 178° (decomp.), [α]D27 + 61.5° (C 1.6, CHCl3), λmax. (EtOH) 266 nm. (ε 10,360) and 272 nm. (ε 10,000); the infrared and p.m.r. spectra resembled those of material described above in Example 1c.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]([NH2:30])([CH3:29])[CH3:28].CN(C=O)C>O>[CH:27]([NH:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:29])[CH3:28]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C
Yield: 65.9 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.69 g of potassium carbonate, 0.30 g of isopropylamine and 3 ml of DMF was stirred while heating at 50° C. for 1.5 hours and at 80° C. for 4 hours. To the mixture, 0.30 g of isopropylamine was added and stirred while heating for further three hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of isopropyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine (hereinafter, referred to as “active compound 85”).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.[C:47](#[N:50])[CH2:48][CH3:49]>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:44]=[CH:43][CH:42]=[CH:41][C:3]=2[CH2:49][CH2:48][C:47]#[N:50])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:41]([Cl:46])=[CH:42][C:43]([CH3:45])=[CH:44][C:2]=2[Cl:1])=[CH:13][CH:12]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: CCC#N
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCC#N)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 342-bromophenyl)propanenitrile (V.6) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1>[Cl:12][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1cnnc(Cl)c1Cl
Yield: 90 %

Procedure:
4,5-dichloropyridazin-3(2H)-one (10.0 g, 60.6 mmole) in POCl3 (60 mL, 642 mmole) was stirred at 110° C. for 18 hours. Toluene was added and the solvents removed under reduced pressure. EtOAc (200 mL) and water were added to the resulting residue and the organic layer washed with water and brine and then dried over MgSO4. Concentration under reduced pressure provided the desired product as an off white solid in 90% yield, 10 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:25]([O-])=[O:26].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are dissolved in 15 ml of formic acid, and 2.1 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for 30 minutes. 100 ml of etherhexane (1:1) are added to the reaction mixture. The resultant oil is washed with ether. Then, 100 ml of ethyl acetate-methanol (10:1) are added to said oil, and insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and the residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=O.Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[C:22]([F:23])=[CH:21][C:17]=1[C:18]([NH:34][O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Carbonyldiimidazole (6.1 g, 37 mmol) was added to a suspension of 4,5-difluoroanthranilic acid (5.40 g, 31 mmol) in 250 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-benzylhydroxylamine hydrochloride (4.95 g, 31 mmol) and triethylamine (5.2 mL, 37 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 6.0 g of the title compound as a solid, mp 125-126° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH:10]([CH3:12])[CH3:11].O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 96 mg of 60% sodium hydride was suspended in 6 ml of N,N-dimethylformamide, and 388 mg of 4-iodo-1H-pyrazol was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Subsequently, 0.21 ml of 2-bromopropane was added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 328 mg of the objective compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([C:9]1[CH:10]=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[O:16][C:15](=[O:17])[CH:14](O)[C:13]=2[CH:19]=1)([CH3:8])([CH3:7])[CH3:6].[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>O>[C:5]([C:9]1[CH:10]=[C:11]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:13]=2[CH:19]=1)([CH3:6])([CH3:8])[CH3:7]
Reactant: c1ccccc1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccccc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
73.3 g (0.55 mol) of ground aluminium trichloride are added over 25 minutes to a solution of 131.2 g (0.50 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 250 ml (2.82 mol) of benzene and the reaction mixture is heated for 1.5 hours to reflux temperature and then refluxed for 1.5 hours. The reaction mixture is cooled to room temperature and then, cautiously with cooling, 200 ml of water are added, followed by the addition of concentrated hydrochloric acid until a homogeneous two-phase mixture forms. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 97.8 g (64%) of 5,7-di-tert-butyl-3-phenyl-3H-benzofuran-2-one, m.p. 116°-119° C. (compound (108), Table 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:36])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[N:24][C:23]=3[Cl:35])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.Cl>[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O>[C:42]([C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:36])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:25]=[N:24][C:23]=3[Cl:35])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)(=[O:44])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (500 mg, 0.814 mmol), tetraethylammoniumchloride (409 mg, 2.442 mmol) and dichlorobistriphenyl phosphinepalladium(II) (57.1 mg, 0.081 mmol) was added tributyl[1-(ethyloxy)ethenyl]stannane (0.302 mL, 0.894 mmol) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc and washed with water. The solvent was evaporated and the residue was dissolved in THF (7.00 mL) and HCl (1.0 M solution) (4 mL, 4.00 mmol) was added. The resulting mixture was stirred for 4 hours at RT. EtOAc was added and the organics were separated. The solvent was removed and the crude material was purifed via silica gel chromatography to give N-({3-[(3-acetyl-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (384 mg, 0.665 mmol, 82% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.33-7.49 (m, 3H), 5.59 (s, 2H), 4.61 (s, 2H), 3.49 (t, 2H), 2.60 (s, 3 H), 0.83 (t, 2H), −0.12-0.01 (m, 9H).