Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[CH:19]([CH2:29][C:30]([OH:32])=O)[S:18]2)[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47]3[C:42](=[N:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH2:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([N:33]3[CH2:34][CH2:35][CH:36]([N:39]4[C:47]5[C:42](=[N:43][CH:44]=[CH:45][CH:46]=5)[NH:41][C:40]4=[O:48])[CH2:37][CH2:38]3)=[O:32])[S:18]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)CCN1C(=O)C(CC(=O)O)SC1c1cccc(F)c1NCCN1CCOCC1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)SC1c1cccc(F)c1NCCN1CCOCC1

Procedure:
2-(2-(2-(2-Morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (420.8 mg, 0.9 mmol), 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (545 mg, 1.872 mmol), EDC (360 mg, 1.878 mmol), HOBt (282 mg, 1.841 mmol) and DIEA (730 μL, 4.191 mmol) were stirred in DMF (6 mL) at RT. The mixture was diluted with EtOAc and washed with water and saturated sodium bicarbonate solution. The aqueous layer was back-extracted, the organic layers were combined, then washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by reverse phase column chromatography with ACN/water to give 1-(1-(2-((5S)-2-(2-(2-morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:11]([O:17][CH2:18][N:19]1[CH:10]=[C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:21]=[N:20]1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C#Cc1ccc(Cl)nc1C
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Product: Cc1nc(Cl)ccc1-c1cn(COC(=O)C(C)(C)C)nn1

Procedure:
The title compound was prepared as described in Example 413 Step 2 using 6-chloro-3-ethynyl-2-methylpyridine (Example 432, Step 1) (315 mg, 2.08 mmol) and azidomethyl pivalate (327 mg, 2.08 mmol) as starting materials.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:46])CC2C=CC=CC=2C)[CH:6]=1.NCCCOC1C=C(OC)C=CC=1C(NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.[CH3:83][C:84]1[CH:91]=[CH:90][CH:89]=[CH:88][C:85]=1[CH:86]=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:46][CH2:83][C:84]2[CH:91]=[CH:90][CH:89]=[CH:88][C:85]=2[CH3:86])[CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2ccccc2C)cc1
Reactant: Cc1ccccc1C=O
Agent: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2ccccc2C)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-(3-(2-methylbenzyl)-aminopropoxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (50 mg, 0.084 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methylbenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[N:7]2[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CN1Cc2c(Br)cccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(Br)cccc2N(Cc2cccc(F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
To a solution of 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one (132 mg, 0.55 mmol) in 5 ml anhydrous dimethylformamide was added sodium hydride (33 mg of a 60% suspension in mineral oil, 0.83 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial offgassing ended. 3-Fluorobenzyl bromide (0.08 ml, 0.65 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting residue was purified by flash chromatography to give 156 mg of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one as a yellow solid (81%). MS: 349.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH2:25])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5c(N)cccc45)[nH]c3c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5c(NS(C)(=O)=O)cccc45)[nH]c3c2)CC1

Procedure:
3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: C(O)(=O)C=C.C(Cl)(=O)C(Cl)=O.N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([NH2:23])(=[O:22])[CH:20]=[CH2:21]>[Pd]>[CH:16]1[CH:17]=[CH:18][C:13](/[CH:21]=[CH:20]/[C:19]([NH2:23])=[O:22])=[CH:14][CH:15]=1
Reactant: C=CC(N)=O
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: C=CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)/C=C/c1ccccc1

Procedure:
Acrylic acid vii is converted to the acid chloride with oxalyl chloride, and the resulting acid chloride is reacted with an aniline in the presence of base. The resulting acrylamide viii is then reacted with an appropriately substituted aryl iodide ix in the presence of a palladium catalyst and a base to give the cinnamide vi.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C1COCC1.C(N(CC)CC)C.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A 250 ml round bottom flask was charged with 5-chloro-3-iodo-pyridin-2-ylamine (1) (42 g, 165 mmol), THF (100 ml), copper iodide (315 mg, 1.65 mmol) and PdCl2(PPh3)2 (1.15 g, 1.65 mmol) under nitrogen. Triethylamine (70 ml, 0.5 mol), and trimethylsilyl acetylene (30 ml, 0.21 mol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then cooled to 0° C. and diethyl ether was added. The suspension was filtered through a celite and thoroughly washed with diethyl ether. The filtrate was concentrated and pre-absorbed onto silica gel and purified by column chromatography using as eluent, pentane/DCM 10% to 100%, to afford an off white solid (36 g, 100%). 1H NMR (CDCl3): 0.3 (9H, s), 5.0-5.1 (2H, brs), 7.6 (1H, s), 7.9 (1H, s). MS (ES+): 225, 227.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: Cc1c(OC2CCCCO2)cc(C=O)c(O)c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(C=O)cc(OC2CCCCO2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde (150 mg) from Step 1, methyl bromoacetate (180 mg) and potassium-carbonate (200 mg) in DMF (10 mL) was stirred at room temperature for 2 hours. Then the solution was poured into water and extracted with ethylacetate. The ethyl acetate was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with hexane and ethyl acetate (9:1) to give 100 mg of [6-formyl-2,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-phenoxy]-acetic acid methyl ester, which was then dissolved in DMF (15 mL). To this solution was added cesium carbonate (200 mg) and the mixture was stirred at room temperature overnight. Then the solution was poured into water and extracted with ethylacetate. The organic layer was washed with water and brine, dried over MgSO4 and concentrated to give 6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxylic acid methyl ester. The tetrahydropyranyl ether was dissolved in methanol, p-toluenesulfonic acid monohydrate (20 mg) was added, and the solution was stirred at room temperature for an additional 30 min. After the addition of a small amount of NaHCO3, the methanol was evaporated. The residue was purified by silica gel column chromatography, eluting with hexane and ethyl acetate (7:3) to give 30 mg of 5-hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δ: 7.39 (s, 1H), 6.87 (s, 1H), 4.75 (s, 1H), 3.95 (s, 3H), 2.50, 2.26 (2s, 6H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2CN[C:15](=O)[NH:14][CH2:13]2)=[CH:8][CH:7]=1.CI.[CH3:22][N:23]([CH:25]=[O:26])[CH3:24]>C1COCC1>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][N:14]([CH3:15])[C:25](=[O:26])[N:23]([CH3:24])[CH2:22]2)=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(C2CNC(=O)NC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C2CN(C)C(=O)N(C)C2)cc1
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride dispersion (60% in mineral oil (88 mg, 2.2 mmol) in THF (3 mL) is added a solution comprising of 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid methyl ester (236 mg, 1 mmol, reference example 95) and methyl iodide (300 μL, 5 mmol) in DMF (4 mL). The resulting mixture is stirred for 16 h. then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound (255 mg) as a tan solid. 1H NMR (CDCl3) δ 2.98 (s, 6H), 3.37-3.53 (m, 5H), 3.93 (s, 3H), 7.32 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H). MS (ion spray) m/z 263 (M+H)+.
Reaction SMILES: NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1.CC(C)(C)C([NH:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[C:36]([F:38])([F:37])[CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1)=O>>[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[C:36]([F:38])([F:37])[CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1C2C1(F)F
Agent: COC(=O)c1c(N)ccc2c1OCC1CC21
Product: COC(=O)c1c(N)ccc2c1OCC1C2C1(F)F

Procedure:
Prepared by proceeding in a similar manner to Intermediate 42, starting from methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 62) as an off white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH:16]=[N:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1.CN(C=O)C.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1
Reactant: O=C1CSc2cc(N=Cc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CSc2cc(NCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Yield: 79.8 %

Procedure:
7-[3-(2-Quinolinylmethoxy)benzylidenamino]-3,4-dihydro-2H-1,4-benzothiazin-3-one (6.383 g, 15 mmol) obtained in Example 91 was dissolved in a mixed solvent consisting of 200 ml of DMF and 50 ml of MeOH, followed by the addition of 2.26 g (60 mmol) of NaBH4 in small portions. After the resultant mixture was stirred for 30 minutes at room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with CHCl3. The extract was washed with water, dried over MgsO4 and then concentrated. The concentrate was recrystallized from MeOH-AcOEt, whereby 5.117 g of the title compound were obtained as white powder (yield: 79.8%).
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[C:29]([O:33][C:34]([CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[S:46][CH2:47][CH2:48][NH3+:49])=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][C:34](=[O:35])[CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[S:46][CH2:47][CH2:48][NH:49][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)Cn1c(SCC[NH3+])nc2ccccc21
Reactant: CCCCOC(=O)Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)NCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
tert-butyl[2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor V-02b) is dissolved in 3M HCl in AcOEt and stirred for 1 h at rt. Evaporation of the solvent in vacuo yields 2-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride as a colourless solid. To a solution of n-butylchloroformate (14.9 mg, 14 μl, 0.11 mmol) in dry THF (0.5 ml) cooled to 0° C. is added a solution of HOBt (17.3 mg, 0.11 mmol) and DIPEA (18 mg, 23.8 μl, 0.14 mmol) in dry THF (0.5 ml). The resulting mixture is stirred for 10 min. It is then added dropwise at 0° C. onto a solution of 2-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride (30 mg, 0.09 mmol) and DIPEA (11.2 mg, 14.9 μl, 0.09 mmol) in dry THF (0.7 ml). The resulting mixture is stirred for 1 h at rt. Then tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 25.6 mg) is added and the resulting slurry is allowed to stir for 2 h at rt and then filtered. The solvent is removed in vacuo and the residue is diluted with dichloromethane (5 ml). This organic phase is washed once with a saturated aqueous NaHCO3 solution and a saturated aqueous KH2PO4 solution. Evaporation of the solvent in vacuo yields the title compound (17.1 mg) in 48% as a colourless oil: tR=2.35 min (LC-2), ESI-MS (pos.): m/z 408.29 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[S:7][CH:8]=[C:9]([C:10]3[N:11]=[C:12]([C@@H:15]4[CH2:19][CH2:18][CH2:17][NH:16]4)[NH:13][CH:14]=3)[C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:79])[NH:23][C@H:24]([C:28](N1CCC[C@H]1C1NC(C2C=CC(C3SC4=NC(NC([C@@H]5CCCN5C(=O)[C@H](NC(OC(C)(C)C)=O)C5C=CC=CC=5)=O)=CN4C=3)=CC=2)=CN=1)=[O:29])[CH:25]([CH3:27])[CH3:26].C(OC(=O)N[C@@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(=O)NC1N=C2N(C=1)C=C(Br)S2)=O)(C)(C)C>>[CH3:20][O:21][C:22](=[O:79])[NH:23][C@H:24]([C:28]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:12]1[NH:13][CH:14]=[C:10]([C:9]2[C:5]3[S:4][CH:3]=[C:2]([Br:1])[C:6]=3[S:7][CH:8]=2)[N:11]=1)=[O:29])[CH:25]([CH3:27])[CH3:26]
Reactant: Brc1csc2c(-c3c[nH]c([C@@H]4CCCN4)n3)csc12
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)[C@@H]5CCCN5C(=O)[C@H](NC(=O)OC(C)(C)C)c5ccccc5)nc4s3)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)c[nH]1)C(C)C

Procedure:
Compound 78 was synthesized from compound 77 (1.56 mmol) and compound 1 (1.64 mmol), following the procedure as described for compound 23 to give compound 78 in 82% yield. MS (ESI, EI+) m/z=513.2/515 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25](OCC)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12)N1CCOCC1
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
Morpholine (268 μL, 3.06 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (365 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (0.760 mL). The resulting solution was stirred for 4 hours at room temperature and then quenched with aqueous hydrochloric acid (1.88 mL, 1N) and water (50 mL). The aqueous layer was extracted with chloroforrn (7×50 mL) and ethyl acetate (3×50 mL). The combined organic layers were concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-80:20) to give the title compound (89.9 mg, 80% yield, m.p. 347° C.).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH:8]([CH:10]=[CH2:11])=[O:9]>C1(C=CC(O)=CC=1)O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[CH:2]2[O:9][CH:8]=[CH:10][CH2:11]1
Reactant: C1=CC2CCC1C2
Reactant: C=CC=O
Agent: Oc1ccc(O)cc1
Product: C1=COC2C3CCC(C3)C2C1
Yield: 50 %

Procedure:
56.4 g of norbornene, 16.8 g of acrolein and 0.5 g of hydroquinone were heated 15 hours at 190° in a stainless steel autoclave (pressure about 15 atm.). After evaporation a fractional distillation of the residue gave 22.5 g (yield 49%) of 3-oxa-tricyclo[6.2.1.02,7 ]undec-4-ene; b.p. 35°-7°/0.5 Torr.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]2[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: ClCc1ccccc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CCl
Temperature: 50 °C

Procedure:
A mixture of α,α'-dichloroxylene (8.75 g, 50 mmol) and potassium phthalimide (5.6 g, 30 mmol) was heated to 50° C. for 24 h. Then the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate and, after usual work-up, the desired compound was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (6 g, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:27]2[CH:28]=[N:24][NH:25][CH:26]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: OB(O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(c2ccc(-c3cn[nH]c3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.225 mmol), 4-pyrazoleboronic acid (87 mg, 0.45 mmol), resin-bound PPh3Pd (346 mg, loading 0.13 mmol/g) and aqueous Na2CO3 (0.45 mL of a 2M solution) in DME (3 mL) is heated in a microwave apparatus at 110° C. for 30 min. The mixture is filtered and the solvent removed under reduced pressure. The residue is purified by reverse phase MPLC to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Cl:6][CH:7]([O:9][C:10](Cl)=[O:11])[CH3:8]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10](=[O:11])[O:9][CH:7]([Cl:6])[CH3:8]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCO
Solvent: ClCCl
Product: COCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 11.9 ml 2-Methoxy-ethanol and 17.98 ml 1-chloroethyl-chloroformate in 200 ml absolute CH2Cl2 13.3 ml pyridine were added at 5–10 ° C. in an argon atmosphere. The mixture was stirred at RT for 5 h and washed successively with 1 N HCl, with an aqueous solution of KHSO4/K2SO4 and water. The organic phase was dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue purified by destillation. Kp.=88° C. (5.5 mbar). Yield: 22.4 g.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32](OS(C)(=O)=O)[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-:42])(=[S:41])[CH3:40].[K+]>CN(C)C=O>[C:39]([S:41][CH:32]1[CH2:33][N:30]([C:27]2[O:28][CH:29]=[C:25]([C:23]([N:21]3[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:22]3)=[O:24])[N:26]=2)[CH2:31]1)(=[O:42])[CH3:40]
Reactant: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1)(c1ccccc1)c1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)co2)C1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 57.3 %

Procedure:
To a solution of 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-methanesulfonyloxyazetidine (1.56 g, 2.81 mmol) (obtained as described in Reference Example 74(2)) in dimethylformamide (80 ml) was added potassium thioacetate (1.92 g, 16.8 mmol) at room temperature and the mixture was stirred in an oil bath (80° C.) for 7.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford 3-acetylthio-1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (863 mg, yield 57%) as a pale brown solid.