Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:17]2[C:18]=1[C:7](=[O:8])[CH:6]([CH3:11])[CH2:10]2
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc(C(C)C)cc(Br)c2C1=O
Temperature: -10 °C

Procedure:
To a mixture of 34.9 g (0.26 mol) of AlCl3 and 350 ml of dichloromethane, a solution of 50.9 g (0.22 mol) of 2-bromo-2-methylpropanoyl bromide in 120 ml of dichloromethane was added dropwise, while vigorously stirring, at −10° C. Then, a solution of 40.0 g (0.20 mol) of 1-bromo-3-isopropylbenzene in 70 ml of dichloromethane was added dropwise at this temperature. The resulting mixture was refluxed for 12 h and then poured onto 2000 cm3 of ice. The organic product was extracted with 4×300 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 130-135° C./1.5 mm Hg. Yield 36.2 g (67%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[Na+]>O1CCCC1.CCCCCC>[F:9][C:5]1[C:4]([F:10])=[C:3]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:2]([F:1])=[C:7]([F:8])[C:6]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(F)c(COC2CCCCO2)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -55 °C
Reaction time: 1 h

Procedure:
13 g of 2-[(2,3,5,6-tetrafluorophenyl)-methoxy]-tetra hydropyran in 200 ml of tetrahydrofuran were cooled to -60 C. and 35.1 ml of butyllithium (1,6M) in hexane were added dropwise over the course of 30 minutes. The mixture was stirred for 1 hour at -55° C. and 5 ml of dimethylformamide dissolved in 10 ml of tetrahydrofuran were added over the course of 5 minutes. The mixture was stirred for 1/2hours at this temperature and 50 ml of a saturated aqueous sodium chloride solution were added. Extraction was carried out with isopropyl ether and the extract was dried and the solvents removed under reduced pressure to obtain 14.4 g of the expected product which was used as is in the following step.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:12][C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][N+:27]([O-:9])=[CH:28][CH:29]=3)[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2csc(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of m-chloroperbenzoic acid (14.5 g) in dry methylene chloride (150 mL) was added a solution of 2-benzyl-4-(4-pyridyl)thiazole (15.1 g, 0.06 mol) in methylene chloride (125 mL) over thirty minutes. The mixture was allowed to stir overnight at room temperature then an additional portion of m-chloroperbenzoic acid (3.00 g) was added. After an additional six hours of stirring the mixture was extracted with saturated sodium bicarbonate (3×100 mL). The organic layer was dried over sodium sulfate, and concentrated to a total volume of 75 mL. Dilution with ether (200 mL) afforded 4-[2-(phenylmethyl)-4-thiazolyl]pyridine-1-oxide (15.3 g, 95%). Recrystallization from ethanol/ether afforded an analytical sample. mp. 170°-172° C.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:25]1([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]4[CH:24]=[CH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]=4)[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: c1ccc2nc(N3CCC(Oc4nccnc4N4CCNCC4)CC3)ccc2c1
Temperature: 160 °C
Yield: 30 %

Procedure:
To a mixture of 2-(4-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P2.1; 0.34 g, 1.0 mmol) and piperazine (0.83 g, 1.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.11 g, 0.30 mmol, 30% yield) as white solid. ESI-MS (M+1): 391 calc. for C22H26N6O 390.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([O:23][CH3:24])[C:11]([CH3:25])=[C:10]2[C:6]=1[C:7](=[O:26])[O:8][CH2:9]2)(=[O:3])[NH2:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C1COCC1>[C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][C:19]([O:21][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:20])=[C:12]([O:23][CH3:24])[C:11]([CH3:25])=[C:10]2[C:6]=1[C:7](=[O:26])[O:8][CH2:9]2)(=[O:3])[NH2:2]
Reactant: OCCN1CCOCC1
Reactant: COc1c(C)c2c(c(OC(N)=O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OC(N)=O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reaction time: 6 h

Procedure:
To 1.0 g of E-6-(1,3-dihydro-4-carbamoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid dissolved in 20 ml of dry THF is added 0.59 g of dicyclohexylcarbodiimide and 0.037 g of N-(2-hydroxyethyl)morpholine. The mixture is left at room temperature for 6 hours, then evaporated to dryness. The residue is chromatographed on silica gel, eluting with 50:1 dichloromethane:methanol, to give morpholinoethyl E-6-(1,3-dihydro-4-carbamoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12]1.[OH-].[Na+].C(Cl)Cl>O>[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:12]1
Reactant: Nc1cccnc1N
Reactant: CN1CCCC(C(=O)O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1CCCC(c2nc3cccnc3[nH]2)C1

Procedure:
Grams 10.9 of 2,3-diaminopyridine and 17,9 g N-methylnipecotic acid hydrochloride are heated at 190° C. for 6 hours. The reaction mixture is cooled and diluted with a small amount of water, then is made alkaline to pH 10 by addition of NaOH and extraction is repeated several times with methylene chloride. The organic extracts, collected together, are evaporated to dryness. The obtained residue, is extracted several times with diethyl ether and the ethereal extracts are evaporated to dryness. The obtained residue, crystallized from acetonitrile, provides 5 g (23% of the theoretical value) 2-(1-methylpiperidin-3-yl)-3H-imidazo-[4,5-b] pyridine melting at 141°-144° C.
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1([CH2:14][CH3:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:13])[CH3:3]>CO.O>[CH2:2]([C:4]([CH2:14][CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])[C:5]([NH2:1])=[O:13])[CH3:3]
Reactant: N
Reactant: CCC1(CC)C(=O)Oc2ccccc21
Solvent: O
Solvent: CO
Product: CCC(CC)(C(N)=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7N Ammonia in methanol (10 mL) was added to 3,3-diethyl-2(3H)-benzofuranone (Example 266a, 1.14 g) and the reaction stirred at room temperature for 16 h. 880 Ammonia (20 mL) was added and the mixture stirred for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product (1.21 g).
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)([CH2:6][CH2:7][C:8]2=[O:10])[CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:35]1[CH:36]=[CH:37][C:32]([NH:31][C:13](=[O:15])[CH2:12][CH2:11][C:5]23[CH2:6][CH2:7][C:8](=[O:10])[N:9]2[C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:33][CH:34]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CCC12CCC(=O)N1C(=O)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC12CCC(=O)N1C(=O)CC2)Nc1ccncc1
Reaction time: 16 h

Procedure:
A suspension of 21.1 g of tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-propanoic acid, 21.7 g of dicyclohexylcarbodiimide, and 100 mg of 4-dimethylaminopyridine (catalyst) in 100 ml of methylene chloride are treated with 9.4 g of 4-aminopyridine. The mixture is stirred for 16 hours and the by-product, N,N1 -dicyclohexylurea, is removed by filtration. The product is purified by chromatography over silica gel using 40% 2-propanol-methylene chloride for elution. After recrystallization from water, the product is isolated as a white solid with a melting point of 285°-287° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(N1C2C(=CC(Br)=CC=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[N:5]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)Oc2ccccc2)C[C@@H]1C

Procedure:
Phenyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and phenyl chloroformate according to the procedure outlined above for (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 389, 391 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][N:16]3[C:20]([C:21]([O:23]CC)=O)=[C:19]([CH:26]=O)[N:18]=[CH:17]3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[C:20]4[C:21](=[O:23])[N:2]([CH3:1])[N:3]=[CH:26][C:19]=4[N:18]=[CH:17]3)=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: CNN
Reactant: CCOC(=O)c1c(C=O)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cn1ncc2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of methylhydrazine (209 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-formylimidazole-5-carboxylate (6.01 g) in ethanol (10 ml) was refluxed for 2.5 hours. After cooling to room temperature, concentrated sulfuric acid (0.1 ml) was added and the mixture was further refluxed for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1) to provide the title compound as white powder (115 mg, yield 20%). H-NMR (CDCl3) δ: 3.88(3H,s), 5.81(2H,s), 7.46(4H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz), 7.97(1H,s), 8.33(1H,s).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[O:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:25])[O:18][C:19]1C=CC=C[CH:20]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(Cl)Cl>[N+:9]([C:7]1[N:8]=[C:4]2[N:5]([CH:6]=1)[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:25])[O:18][CH2:19][CH3:20])[O:12]2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: O=C(NCC1CO1)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)NCC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 11.5 %

Procedure:
2,4-Dinitro-1H-imidazole (0.678 g, 3.92 mmol) and phenyl oxiran-2-ylmethylcarbamate (1.04 g, 5.87 mmol) were dissolved in ethanol (20 ml). To the solution, sodium acetate (0.386 g, 4.70 mmol) was added followed by stirring under reflux overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and treated with diisopropyl ether to afford ethyl (6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.116 g, yield 11.6%) as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:48]=[CH:49][CH:50]=2)[CH2:33][NH:34][C:35]2[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:48]=[CH:49][CH:50]=3)[CH2:33][NH:34][C:35]3[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])=[CH:37][CH:36]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(CNc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Yield: 40.8 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol), tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)benzoate (150 mg, crude), Pd(PPh3)4 (30 mg, 0.026 mmol) and Na2CO3 (150 mg, 1.41 mmol) in 5 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (5:1) to give tert-butyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)benzoate (72 mg, 41%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 8.87 (s, 1H), 8.54-8.47 (m, 2H), 7.86-7.82 (m, 3H), 7.49-7.28 (m, 2H), 7.27-7.23 (m, 1H), 6.94 (d, 1H, J=8.7 Hz), 6.65-6.62 (m, 2H), 4.49 (s, 2H), 4.16 (s, 3H), 4.13 (s, 3H). LC-MS: 570 [M+H]+, tR=1.83 min. HPLC: 98.31% at 214 nm, 98.91% at 254 nm, tR=8.06 min.
Reaction SMILES: C([Mg]Cl)(C)C.O1CCCC1.I[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reaction time: 2.5 h

Procedure:
Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 1.5 mL, 3.00 mmol) was added dropwise to a solution of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740 mg, 2.00 mmol) in Tetrahydrofuran (12 mL, 150 mmol) at room temperature. The mixture was stirred for 2.5 hours. Tributyltin chloride (0.8138 mL, 3.000 mmol) was added and the mixture was stirred for 18 hours. The mixture was mixed with sat aq. NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and purified on 25 g silica column eluting with 15-20% ethyl acetate in heptane. Yield 160 mg (15%). MS (ESI+): 535.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: O=C(O)C1COc2ccc(O)cc2O1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: O=C(C1COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 65 %

Procedure:
That compound is obtained in a yield of 65% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cu]I.O>[CH:13]1[CH:18]=[CH:17][C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-nitroaniline (5.5 g), bromobenzene (20 ml), potassium carbonate (1.63 g) and copper(I) iodide (0.68 g) was heated to 180° for 36 h. The reaction mixture was cooled to room temperature, then ethyl acetate (200 ml) and water (300 ml) were added; the organic extracts were washed with brine (2×150 ml), dried and concentrated in vacuo to give the crude compound which was purified by flash chromatography (eluting with CH-EA 95:5) to give the title compound (3.67 g). T.l.c. CH-EA (1:1 ), Rf 0.71.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.[I:11]N1C(=O)CCC1=O>C(#N)C>[I:11][C:7]1[C:8]([OH:10])=[C:9]2[S:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1
Reactant: Oc1ccnc2ccsc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Oc1c(I)cnc2ccsc12

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (from Aldrich) (0.54 g, 3.6 mmol) and N-iodosuccinimide (0.88 g, 3.9 mmol) in acetonitrile (10 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give the desired product which was used in the next step without further purification. LCMS calculated for C7H5INOS (M+H)+: m/z=277.9. Found: 277.8.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Br)(Br)[Br:11]>C(Cl)(Cl)Cl>[Br:11][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of DL-sec-phenethyl alcohol (1.81 ml, 15 mmol) in chloroform (20 ml) was added phosphorus tribromide (15.75 ml, 15.75 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 18 hours, poured into wet ice, washed with brine (4×), dried (MgSO4), then evaporated to dryness to yield 2.62 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=C(C)C(C)=O
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (4.00 g) in N,N-dimethylformamide (40 ml) were added imidazole (2.70 g) and t-butyldimethylsilyl chloride (4.80 g). The resulting mixture was allowed to stand at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-8:2 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)-pyrrolidine (3.67 g).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[NH:14][C:11]2=[N:12][CH:13]=1)=[O:6])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:38][CH:39]([CH2:43][O:44][CH3:45])[CH2:40][O:41][CH3:42]>CN(C=O)C>[CH:1]([O:4][C:5](=[O:6])[NH:7][C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:21])[NH:38][CH:39]([CH2:43][O:44][CH3:45])[CH2:40][O:41][CH3:42])[CH:18]=3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: COCC(N)COC
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(C(=O)O)c3)nc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCC(COC)NC(=O)c1cccc(-c2nc3cc(NC(=O)OC(C)C)cnc3[nH]2)c1
Reaction time: 4 h

Procedure:
25 mg (0.07 mmol) of the acid from example 11-1 in 1 ml dry DMF were treated with 18 mg (0.11 mmol) 1,1′-carbonyl-diimidazole at room temperature for 2 hrs. 13 mg (0.11 mmol) 2-amino-1,3-dimethoxypropan were added and stirring was continued for 4 hrs. The solvent was removed under vacuum, the residue dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The dichloromethane phase was evaporated and the residue purified by chromatography on silica in dichloromethane/methanol mixtures.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH3:9])[C:6]#[N:7].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[C:8]([CH3:9])=[N:17][NH:18][C:6]=1[NH2:7]
Reactant: CC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-3-oxobutanenitrile (2.19, 9.05 mmol) in ethanol (400 mL) was added hydrazine hydrate (0.452 g, 9.05 mmol) and the resulting solution was stirred under reflux for 16 h. Then the mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1 then DCM:methanol=40:1) to provide the titled compound (1.21 g, 52%) as a yellow solid; LC/MS: MS (ES+) m/e 256 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 3.77 (s, 2H), 6.97 (dd, J=1.2, 7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.33 (dd, J=1.2, 7.8 Hz, 1H)