Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 46.7 %

Procedure:
A solution of 6.80 g (0.0181 mol) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 700 ml of hot benzene was treated with 2.86 g (0.0199 mol) of copperl bromide and 5.1 ml (0.0272 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 20 min., cooled and treated with 300 ml of water. The mixture was filtered, extracted with dichloromethane and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 3.15 g (47%) of methyl 2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-oxazole-4-carboxylate as white crystals; m.p. 266°-268°.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: CCOC(=O)C(C)c1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2cn3cccnc3n2)cc1
Yield: 70.3 %

Procedure:
A mixture of 4.4 g of ethyl 2-[4-(imidazo[1,2-a]pyrimidin-2-yl)-phenyl]propionate, 50 ml of ethanol, 0.72 g of sodium hydroxide and 5 ml of water is heated under reflux for 2 hours. The ethanol is distilled off, and acetone is added to the residue. The crystalline precipitate is dissolved in water, and the solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 2.8 g of 2-[4-(imidazo[1,2-a]pyrimidin-2yl)phenyl]propionic acid as colorless crystals melting at 248°C with decomposition.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH-:6].[Na+].Cl.Cl.Cl.[C:11]1([CH2:17][O:18][CH2:19][CH:20]([N:24]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:21]([NH2:23])=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[OH:6][CH2:11][CH2:17][O:18][CH2:19][CH2:20][NH:23][C:21](=[O:22])[CH:20]([N:24]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]([OH:5])=[O:4])[CH2:32][CH2:31][N:30]([CH2:2][C:3]([OH:5])=[O:4])[CH2:29][CH2:28][N:27]([CH2:2][C:3]([OH:5])=[O:4])[CH2:26][CH2:25]1)[CH2:19][O:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)C(COCc1ccccc1)N1CCNCCNCCNCC1
Reactant: O=C(O)CBr
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(C(COCc2ccccc2)C(=O)NCCOCCO)CCN(CC(=O)O)CC1
Temperature: 0 °C
Yield: 150 %

Procedure:
To a solution of 45.5 g of bromoacetic acid (0.327 mol) in 140 mL of H2O, kept under stirring at 0° C., 31.5 mL of 10N NaOH (0.315 mol) are added in 1 h to pH 6. The resulting solution is added drop by drop to a solution of 46 g of N-[2-(2-hydroxyethoxy)ethyl)]-α-[(phenylmethoxy)methyl]-1,4,7,10-tetraazacyclododecan-1-acetamide trihydrochloride (0.084 mol) in H2O (100 mL) and, at a constant reaction temperature of 0° C., 10N NaOH is slowly added to pH 10. The reaction mixture is heated to 50° C. for 48 h and 50 mL of 10N NaOH (0.5 mol) are added to keep a constant pH of 10. After cooling at room temperature, the mixture is filtered on a MilliporeR filter, neutralized with 37%HCl (w/w), diluted to 1.5 L with H2O and electrodialyzed. When the electrodialysis is over, the solution is concentrated under vacuum to give an oily residue which is placed into a drier to give a glassy solid. The solid is triturated and dissolved with AcOEt (200 mL), filtered and dried again. The crude product is dissolved in H2O (150 mL) and percolated on Amberlite® XAD 16 resin (1000 mL) performing a gradient elution with H2O-MeOH. The fractions containing the pure product are collected and concentrated under vacuum to give 38.83 g of the desired product (0.063 mol).
Reaction SMILES: COC(=O)C(Br)[CH2:5][CH:6]([CH3:8])[CH3:7].NCC(N)(C)C.[CH3:17][C:18]1([CH3:29])[NH:23][C:22](=[O:24])[CH:21](CC(C)C)[NH:20][CH2:19]1>>[CH3:7][C:6]1([CH3:8])[CH2:5][NH:23][C:22](=[O:24])[CH2:21][NH:20]1.[CH3:17][C:18]1([CH3:29])[NH:23][C:22](=[O:24])[CH2:21][NH:20][CH2:19]1
Reactant: CC(C)CC1NCC(C)(C)NC1=O
Reactant: COC(=O)C(Br)CC(C)C
Agent: CC(C)(N)CN
Product: CC1(C)CNC(=O)CN1
Product: CC1(C)CNCC(=O)N1

Procedure:
Following the general procedure of Example 4 and making non-critical variations, but substituting ethyl chloroacetate (VI) for methyl 2-bromo-4-methylpentanoate (V) and 1,2-diamino-2-methylpropane (VI) for ethylenediamine (VII) there are obtained 5,5-dimethylpiperazinone and 6,6-dimethylpiperazinone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[C:22](=[O:25])([O-])[O-].[K+].[K+].ClC[C:30]#[N:31]>C(OC)=O.CN(C)C=O.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:25][CH2:22][C:30]#[N:31])[C:15]([O:17][CH3:18])=[O:16]
Reactant: N#CCCl
Reactant: C=C(C(=O)OC)c1ccccc1OC1CCCCO1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC=O
Product: COC(=O)C(=COCC#N)c1ccccc1OC1CCCCO1
Temperature: 20 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
At 20° C., a solution of 15 g (60 mmol) of methyl 2-[2-(tetrahydropyran-2-yloxy)phenyl]-acrylate in 36 ml of methyl formate is added dropwise to a suspension of 1.96 g (66 mmol) of sodium hydride (80% strength) in 50 ml of dimethylformamide. After 4 hours, 15 g of potassium carbonate and 9 g of chloroacetonitrile are added to this mixture, which is stirred at 20° C. for a further 14 hours and then poured into water. The reaction mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 15.9 g (83.55% of theory) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-cyanomethoxy-acrylate are obtained.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.BrCCBr.[Mg].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH3:10][C:6]1([CH3:11])[C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CC1(C)CCOc2cc(Br)ccc21
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1(C)CCOc2cc(C(=O)O)ccc21
Temperature: 0 °C

Procedure:
A solution of 14.2 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran and 1.1 g or 1,2-dibromoethane in 80 ml of tetrahydrofuran was added dropwise using a heatable ultrasonics bath, to a suspension, boiling under reflux, of 1.6 g of magnesium shavings in 20 ml of tetrahydrofuran. After heating under reflux for an additional 2 hours, the reaction mixture wss cooled to 0° C. and a strong stream of carbon dioxide gas was conducted in (about 1 hour). Thereafter, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried and evaporated. After recrystallization from ethyl acetate/hexane, there were obtained 5.3 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxylic acid, melting point 173°-174° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH2:4][S:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7].[OH:23]O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[CH2:4][S:5]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7])=[O:23]
Reactant: OO
Reactant: CC(SCC(=O)N(C)C)c1ccc(-c2ccccc2F)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)N(C)C
Yield: 57 %

Procedure:
The difficultly soluble isomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid dimethylamide was prepared analogous to Example 51 from [1-(2'-fluoro-4 -biphenylyl)-ethylthio]-acetic acid dimethylamide by oxidation with hydrogen peroxide in glacial acetic acid. Yield: 57% of theory; m.p. 131°-133° C (from toluene)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:24])=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Nc2nc(Cl)nc3nc[nH]c23)cc(OC)c1OC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Nc2nc(Cl)nc3c2ncn3C)cc(OC)c1OC

Procedure:
168 mg (0.5 mmol) of 2-chloro-6-(3,4,5-trimethoxy-phenyl-amino)-purine, 103 mg (0.75 mmol) of potassium carbonate and 0.156 ml (2.5 mmol) of methyl iodide are stirred in 3 ml of dimethylformamide at room temperature for 5 h. 30 ml of ethyl acetate are added to the slightly cloudy reaction solution and the mixture is extracted with water. The organic phase is dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate and diethyl ether. 2-Chloro-6-(3,4,5-trimethoxy-phenyl-amino)-9-methyl-9H-purine is obtained; FAB-MS: (M+H)+=350; Rf=0.6 (CH2Cl2:methanol=9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C:38]([Cu])#[N:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7]([C:38]#[N:39])[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: N#C[Cu]
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCSc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(C#N)c1OCCSc1ccc(Cl)cc1

Procedure:
trans-2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (2.35 g, 3.58 mmole) and CuCN (0.358 g, 4.30 mmole) in DMF (20 mL) were heated at 140° C. for 16 hours. The reaction mixture was cooled and quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (1.79 g, 90.0%). 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H); 3.32 (t, 2H); 3.85 (s, 6H), 3.89 (s, 6H); 4.27 (t, 2H); 5.17 (m, 2H); 6.61 (s, 2H); 7.16 (s, 2H); 7.28 (d, 2H); 7.32 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[C:21]([CH2:33][OH:34])[CH:20]=2)[OH:18])[CH3:14])[CH:7]=1.ClCCl>CO>[NH3:15].[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH:15][CH2:16][C@H:17]([OH:18])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:33][OH:34])[CH:20]=2)[CH3:14])[CH:7]=1
Reactant: COC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Product: N

Procedure:
Prepared according to the procedure used for preparation 37 using methyl-3-{3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]phenyl}propanoate (Preparation 58), substituting dichloromethane:methanol: 880 ammonia (95:5:0.5 changing to 90:10:1 by volume) as column eluent to give the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:41]C)[CH2:38][CH2:39]O)[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[CH:18][CH:17]=1
Reactant: CCN(CC)CCO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 71.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(diethylamino)-1-ethanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 61%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:64]2[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]3[CH:48]=[CH:49][C:50]([O:53][C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[CH:51][CH:52]=3)[CH2:62][CH2:63]2)=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to 4-fluorobenzoic acid (44 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively and, after 10 mins, N-(2-oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-{2-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 49% yield. LC-MS purity: 97%, 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (m, 4H), 7.1 (m, 4H), 4.3 (s, 2H), 3.6 (m, 8H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.C1COCC1.O.[OH-].[Li+]>CO>[CH2:34]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]1[NH:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCCCC4Cc4ccccc4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC1CCCCC1Cc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 1-{4′-[4-(2-benzyl-cyclohexylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.130 g, 0.24 mmol) in 2:1:1 THF:H2O:MeOH was added lithium hydroxide (0.050 g, 1.19 mmol), and the reaction was stirred at 70° C. for 2 hours. After acidic workup, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:28][C:29]1[CH:30]=[C:31]([C:41](=[O:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[C:41]([C:31]1[CH:32]=[CH:33][C:34]([N:35]2[CH2:36][CH2:37][N:38]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[Br:1])[C:11]#[N:12])=[O:6])[CH2:39][CH2:40]2)=[C:29]([F:28])[CH:30]=1)(=[O:43])[CH3:42]
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 2-bromo-5-cyano-benzoic acid (200 mg, 0.885 mmol) in DMF (3 ml) was added dropwise 1,1′-Carbonyldiimidazole (148 mg, 0.885 mmol). When the CO2 evolution ceased, the mixture was heated to 50° C. for 15 minutes. The mixture was cooled to room temperature. 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (198 mg, 0.885 mmol) was added portionwise. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on SiO2 (Heptane/AcOEt 0%-30% (10 minutes)) to provide 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo benzonitrile (185 mg, 49%) as white solid (M+ 430.3).
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH2:16]([N:18]([CH2:21][CH2:22][CH2:23][O:24][NH2:25])[CH2:19][CH3:20])[CH3:17].C(O)(=O)/C=C/C([O-])=O>>[CH2:16]([N:18]([CH2:21][CH2:22][CH2:23][O:24][N:25]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCN(CC)CCCON
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: CCN(CC)CCCON=C1CCCCCCCCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 24.1 g. (0.1 moles) of diethylaminopropoxyamine dihydrochloride, the title compound is prepared as in Example 13. Yield: 25.7 g. (82.77%). Hydrogen fumarate, m.p.: 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:7]=1.[C:16](O)(=O)[C@H:17]([CH3:19])[OH:18].N>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][C:11]([F:12])([F:14])[F:13])[C:16]([C@@H:17]([OH:18])[CH3:19])=[N:15][C:4]=2[CH:3]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Nc1cc(Cl)ccc1NCCC(F)(F)F
Agent: Cl
Agent: N
Product: C[C@H](O)c1nc2cc(Cl)ccc2n1CCC(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
A mixture of 4-chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (478 mg, 2.0 mmol) and L-lactic acid (180 mg, 2.0 mmol) in 6 N aqueous HCl (4 mL) was heated with stirring at 100° C. in a sealed tube for 18 hours. After the reaction was complete, the mixture was poured into aqueous ammonia (10 mL) and then extracted by EtOAc (25 mL×3). The organic layers were combined and then concentrated in vacuo. The residue was purified by flash column chromatography to afford (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol as yellow oil (320 mg, yield 63.0%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:29]=[O:30])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:29]([OH:30])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.24 mL, 0.72 mmol) was added to a stirred solution of 9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (240 mg, 0.649 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with tetrahydrofuran/ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (207 mg, 0.518 mmol, 80%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4]N1.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].[CH3:18]N(C=O)C>C(#N)C.C(OCC)(=O)C>[F:15][CH:11]([F:16])[O:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][CH:18]=1)[CH:8]=[O:9]
Reactant: O=Cc1cc[nH]c(=O)c1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cccc(OC(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 2-oxo-1,2-dihydropyridine-4-carbaldehyde (1.72 g, 11.3 mmol) in 25 mL of acetonitrile was added sodium chlorodifluoroacetate (0.925 g, 7.51 mmol). The reaction was heated to reflux under an atmosphere of nitrogen for 15 h, and then DMF (3 mL) was added. The mixture was heated to 100° C. for 3 d, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 3-(difluoromethoxy)benzaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[CH2:35]([SH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: SCc1ccccc1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(SCc4ccccc4)ccnc32)CC1
Yield: 8 %

Procedure:
A mixture of the title compound from Example 250 (0.25 grams), sodium hydride (0.11 grams, 60% in mineral oil), benzyl mercaptan (0.13 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with 200 W lamp for 10 days. Isolation and purification as in Example 257 provided the title compound (0.02 grams, 8%, MH+ 552).