Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: O=C(Cl)CCCCCl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (400 mg, 1.065 mmol) was dissolved in dichloromethane (6 ml) and triethylamine (445 μl, 3.20 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (151 μl, 1.172 mmol). The reaction was stirred under nitrogen at room temperature for 4 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (10 ml) and extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography, eluting with 95:5 dichloromethane/methanol, clean fractions were combined and the solvent was removed under reduced pressure to obtain the title compound (220 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][OH:34])[CH2:27][CH2:28]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[CH:12][CH:13]=1
Reactant: OCCN1CCNCC1
Reactant: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(Cl)nn23)ccn1
Solvent: CCCCCO
Product: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(CCO)CC4)nn23)ccn1
Temperature: 135 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A mixture of 0.25 g (0.70 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(2-methoxypyrid-4-yl)imidazo-[1,2-b]pyridazine and 0.37 g (2.8 mmol) of 2-(piperazin-1-yl)ethanol in 6 mL of pentanol is stirred at 135° C. for 18 hours. The solvent is then evaporated off under reduced pressure and the oily residue is chromatographed on a column of silica gel, eluting with a stepwise gradient of methanol and aqueous ammonia in dichloromethane (0/0/100 to Feb. 1, 1998). 0.136 g of product is isolated after trituration in diisopropyl ether, filtering off and drying under reduced pressure.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:5]1(=[O:23])=[O:22].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.Cl>>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[S:5](=[O:23])(=[O:22])[N:4]([CH2:3][CH2:2][NH:27][CH:24]3[CH2:26][CH2:25]3)[CH2:9][C:8]=2[CH:10]=1
Reactant: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 95 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{2-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]ethyl}cyclopropanamine (0.099 g, 95%) as a white solid:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)O[C@H]3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 10.2 %

Procedure:
After a suspension of 90 mg (0.71 mmol) of (R)-(-)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 15 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.05 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 100 mg (0.49 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1), whereby 15 mg (0.05 mmol) of the title compound were obtained as white crystals (yield: 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 90 %

Procedure:
A solution of 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (126 mg, 0.39 mmol), cesium carbonate (254 mg, 0.78 mmol), and 4-(bromomethyl)benzonitrile (92 mg, 0.47 mmol) was stirred in 2 mL dimethylformamide for 1.5 h. The reaction was partitioned between 25 mL diethyl ether and 25 mL 0.1 M HCl, concentrated and purified by flash chromatography on 40 g silica gel with 0 to 70% ethyl acetate in hexane to yield 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (152 mg, 90%). 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (2H, d, J=8.31 Hz), 7.60-7.65 (2H, m), 7.54 (2H, d, J=8.31 Hz), 7.50 (2H, d, J=8.56 Hz), 4.65 (1H, d, J=16.12 Hz), 4.01 (1H, d, J=16.12 Hz), 3.76-3.88 (1H, m), 3.61-3.72 (1H, m), 3.28-3.41 (1H, m), 2.18 (1H, br. s.), 1.44-1.63 (5H, m), 1.11-1.40 (6H, m). LC/MS R.T.=2.76 min; [M+H]+=433.14. HRMS [M+H]+ calc'd 433.1353, found 433.1352.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.CCN(CC)CC.Cl.[CH:21]12[O:28][CH:25]([O:26][CH2:27]1)[CH2:24][NH:23][CH2:22]2>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]2=[C:2]([N:23]2[CH2:24][CH:25]3[O:28][CH:21]([CH2:27][O:26]3)[CH2:22]2)[N:7]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: C1NCC2OCC1O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc2c(N3CC4COC(C3)O4)nc(Cl)nc21
Yield: 46.2 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.46 mmol), Et3N (1.05 mL, 7.5 mmol) and 6,8-dioxa-3-azabicyclo[3.2.1]octane hydrochloride (373 mg) in CH2Cl2 (5 mL) is stirred for 18 h. Concentration in vacuo followed by silica gel chromatography (hexane/ethyl acetate) gives 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6,8-dioxa-3-azabicyclo[3.2.1]octane as a white powder (320 mg). This material (0.16 g, 0.57 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.186 g, 0.85 mmol), aq. Na2CO3 (0.425 mL, 2M), and tetrakis triphenylphosphine palladium (20 mg) in 1:1 toluene:ethanol. The reaction mixture was heated in a microwave at 120 C for 20 min to give 4-(4-(6,8-dioxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. To this material (190 mg, 0.56 mmol) in CH2Cl2 is added Et3N (0.42 mL) and a solution of triphosgene (83 mg, 0.28 mmol) in CH2Cl2. After 30 min half of the solution is added to 3-aminopyridine (105 mg, 1.12 mmol). After 2 h aq. workup and silica gel chromatography (EtOAc/MeOH) gives the title compound as an off-white solid (104 mg). HRMS m/z=459.1894 (M+H).
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)=O.BrC1C=CC([S:26]([NH2:29])(=[O:28])=[O:27])=CC=1>>[OH:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH:6]=[CH:5][C:10]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:9][CH:8]=2)=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CO)cc2)c1
Product: NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1

Procedure:
This compound was prepared in a manner analogous to the preparation of (3′-methanesulfonyl-biphenyl-4-yl)-methanol (WO 01/70753, Example 27) using 4-bromo-benzenesulfonamide as the starting material. LCMS found for C13H13NO3SNa (M+Na)+: m/z=286.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:26]C(OC(C)(C)C)=O)[C:11]([O:13][CH2:14][C@H:15]([O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(#N)C>O>[NH2:26][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][CH2:14][C@H:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:16])=[O:12]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The solution of (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate 6 from Step 3 was added to a 570 L glass-lined reactor and rinsed with methyl tert-butyl ether (MTBE) (312.4 kg, 13.9 kg). The contents were concentrated under vacuum at a maximum W/G temperature of 40° C. until distillation stopped. Acetonitrile (CH3CN) (116 kg, 3.0 parts) was charged to the reactor and the vacuum distillation repeated until distillation ended. Additional acetonitrile (CH3CN) (112 kg, 2.9 parts) was charged to the reactor and the temperature was adjusted to 40° C. (39-41° C.). Methanesulfonic acid (MeSO3H) (6.97 kg, 0.18 parts) was charged to the reactor while maintaining the temperature at 40° C. (35-45° C.). The pump and lines were rinsed forward with acetonitrile (CH3CN) (3.9 kg, 0.1 part). The reaction was complete after two hrs (2-6 hrs expected) at 40° C. (35-45° C.) as determined by high pressure liquid chromatography (HPLC). The temperature of the mixture was adjusted to 22° C. (19-25° C.) and agitated for 32 hrs. The crude product was collected by centrifugation, the reactor, lines, and filter cake rinsed forward with acetonitrile (CH3CN) (38.7 kg, 1 part) and spun as dry as possible to provide a wet filter cake (10.9 kg). A portion of the wet filter cake (8.0 kg) was transferred to a 570 L glass-lined reactor. Acetonitrile (CH3CN) (278 kg, 10 parts) was charged to the reactor, the contents agitated, and the temperature adjusted to reflux (80-82° C.). Water (2.8 kg, 0.1 parts) was charged to the reactor, maintaining the temperature at 80-82° C. The suspension became a clear solution. The mixture was agitated at 80-82° C. for ca. 30 minutes. The solution was then cooled over 6 hrs to 22° C. (19-25° C.) with a slurry forming at 60° C. The slurry was held at 22° C. (19-25° C.) for an additional 2 hrs. The product, (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1, was collected by centrifugation and the reactor, lines, and filter cake were rinsed with 3 portions of methyl tert-butyl ether (MTBE) (30 kg each) and spun dry. The product was dried at a maximum temperature of 55° C. until LOD was ≦0.5% and acetonitrile is ≦400 ppm as determined by gas chromatography (GC) to provide 5.4 kg of (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32])[NH2:27]>C(O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])[N:27]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: N#Cc1cccc(NN)c1
Solvent: CCO
Product: N#Cc1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1
Yield: 21 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-hydrazino-benzonitrile in ethanol as solvent according to the method described for Example 1 in 21% yield. MS: M=424.1 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.[CH:22]1([CH2:28][CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:34]([O:33][C:31]([C@H:30]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:28][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=O)CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
Reaction of 9.5 g of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 26 and ethyl 4-cyclohexyl-2-oxobutyrate is carried out under reductive conditions in a manner similar to that described in Example 16, and the product is purified by silica gel column chromatography (hexane:ethyl acetate=5:1). From the first fraction, 2.3 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:22]1[N:21]=[C:20]([CH3:19])[NH:24][CH:23]=1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc[nH]1
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccccc1)c1c[nH]c(C)n1

Procedure:
13 g diphenyl-α-chloroacetic acid methyl ester (0.05 mole) are heated to the boil for 20 hours with 12.1 g 2-methyl-imidazole in 100 ml acetonitrile. The acetonitrile is distilled off in a vacuum. 200 ml of water are added to the residue, which is then taken up in 200 ml methylene chloride. The methylene chloride is extracted twice with, in each case, 150 ml of water, dried and distilled off in a vacuum. The residue is recrystallized from a little ethyl acetate. There is so obtained the diphenyl-2-methyl-imidazolyl-acetic acid methyl ester of the melting point 136°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](OC)([O:10]C)[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH2:19][CH3:20].[O:21]=[O+][O-]>>[C:14]([C:4]1[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([OH:21])[C:3]=1[O:18][CH2:19][CH3:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[O+][O-]
Reactant: CCOc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C
Product: CCOc1c(O)cc(C(C)=O)cc1C(C)(C)C

Procedure:
1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-ethoxybenzene (O4.010; 19.68 g) was converted analogously to O3.070. 5.15 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:7]1
Reactant: C1CNCCN1
Reactant: O=S1(=O)CCC(Oc2ccccc2Br)CC1
Product: O=S1(=O)CCC(Oc2ccccc2N2CCNCC2)CC1

Procedure:
Ortho-fluoro bromobenzene was reacted with tetrahydro-thiopyran-3-ol to give 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran in a manner similar to preparation 24A. 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran (1.94 g, 7.10 mmol) is placed in DCM (70 mL) and calcium carbonate (2.84 g, 28.41 mmol) was added. To this mixture cooled to 0° C. in an ice bath was added meta-chloro peroxy-benzoic acid (6.13 g, 17.75 mmol 50%) in portions while monitoring the temperature. The mixture was allowed to warm to r.t and stirred for about 15 minutes. The mixture was filtered over celite, and washed with sodium bisulfite solution (2×250 mL) and sodium bicarbonate (2×250 mL). The mixture was then concentrated to an oil. Chromatography (EtOAc/hexanes) provided 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran 1,1-dioxide (2.2 g, quant.) as a yellow solid. 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran 1,1-dioxide was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+): 311.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (1.0 g) was dissolved in pyridine (25 ml), and cooled to 0° C. Triethylamine (0.46 ml) and methanesulfonyl chloride (0.23 ml) were added, and stirring continued at ambient temperature for 2 hours. Solvent was evaporated and the residue dissolved in ethyl acetate, washed with water, dried (MgSO4), and evaporated to give (5R)-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (1.01 g) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:25][CH:24]([CH3:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CC(C)COc1ccccc1CBr
Product: CC(C)COc1ccccc1Cn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 1-(bromomethyl)-2-(2-methylpropoxyl)benzene according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C20H20N4O, 333. Found, 333.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10](=[O:12])[NH:31][CH2:30][CH2:29][C:19]1[N:18]([CH3:17])[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1)=[O:4]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)O
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Agent: Cl
Product: COC(=O)c1nc(C)n(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
The product was obtained starting from 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (100 mg, 505 μmol; example 8, steps 1-2) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine dihydrochloride (152 mg, 555 μmol; example 7, steps 1-4) according to the method described in example 10, step 5 after stirring at 70° C. for 16 h, aqueous workup and purification as light yellow oil (111 mg, 291 μmol, 57.7%). MS: M=382.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][CH:17]=2)[N:3]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][CH:17]=2)[N:3]=1
Reactant: Cc1nn(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(=O)c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1nn(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c(=O)c2ccccc12
Yield: 79.9 %

Procedure:
##STR41## A solution of 5-[4-[2-[4-methyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl methylene] thiazolidin-2,4-dione (9.0 g, 22.0 mmoles) obtained in example 1, in 1,4-dioxane (500 mL) was reduced with hydrogen in the presence of 10% palladium on charcoal (22.5 g) at 60 psi for 48 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure. The crude compound was recrystallised using CH2Cl2 /pet. ether to afford the title compound (7.2 g, 80%). mp: 170° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCCOc1ccnc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCCOc1ccnc(CCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
5.6 g of crude 2-hydroxymethyl-4(4-methoxybutoxy)pyridine was dissolved in 80 ml of chloroform to obtain a solution. A solution of 3.8 g of thionyl chloride in 10 ml of chloroform was dropwise added to this solution at 0° C. The obtained mixture was stirred at 0° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 200 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The obtained residue was dried in a vacuum to obtain 5.09 g of the title compound as a crude oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]1=[O:26].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[C:27]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][CH:7]=2)[C:15](=[O:26])[CH:16]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccc(OC)cc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 13.9 g of the product of Step C, 8.2 ml of triethylamine and 4.5 ml of benzoyl chloride were reacted to obtain 18 g of the expected product.