Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Reaction time: 27 h
Yield: 82 %

Procedure:
tert-Butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate described in Production Example 13-2 (2.11 g, 6.53 mmol) was dissolved in methanol (60 mL), then potassium hydroxide (1.46 g, 26.1 mmol) dissolved in water (16 mL) was added, and then the mixture was stirred for 27 hours. The reaction mixture was concentrated under vacuum and diethyl ether was added for partition. Ethyl acetate was added to the aqueous layer for dilution, then a 5% aqueous potassium hydrogensulfate solution was added for acidification, and the mixture was extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated to obtain the title compound (1.58 g, 82%).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl>CN(C)C=O>[ClH:17].[CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Temperature: 140 °C

Procedure:
A mixture of 28 g of 3-allylsulfamoyl-4-chlorobenzoic acid, 30 g of N-methylpiperazine and 20 ml of dimethylformamide was heated for 4 hours at 140° C. When the reaction solution was subsequently introduced into 0.3 l of 2N HCl, the monohydrochloride crystallized immediately. The product was then purified by recrystallization from water.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:17]([C:30](O)=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1.[NH2:50][C@H:51]([C:73]([NH:75][C@H:76]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][C:78](=[O:80])[NH2:79])=[O:74])[CH2:52][S:53][C:54]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:17]([C:30]([NH:50][C@H:51]([C:73]([NH:75][C@H:76]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][C:78](=[O:80])[NH2:79])=[O:74])[CH2:52][S:53][C:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:31])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.63 g of DCC are added to a stirred solution of 3.4 g of Fmoc-Tyr(tBu)-OH, 3.95 g (7.4 mmol) of H-Cys(Trt)-Asn-OtBu (Liebigs Ann. Chem. 1979, 242) and 1 g of HOBT in 50 ml of dimethylformamide at 0° C., and the mixture is left to stir at 0° C. for 1 h and to stand at room temperature overnight. The next day, the precipitate is filtered off with suction and the filtrate is concentrated. The residue is triturated with ethyl acetate. Yield 2.83 g. A further 3.63 g can be isolated from the mother liquor. Total yield: 6.46 g (89%).
Reaction SMILES: Cl[C:2]1([CH3:17])[CH2:4][C:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].II.[Br-].[Li+].Cl[P:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([CH3:28])([CH3:27])[CH3:26]>CCCCCC.[Cu](I)I.C1COCC1>[C:5]1([C:3]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][C:2]2([P:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC1(Cl)CC1(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: I[Cu]I
Agent: II
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 25.2 %

Procedure:
Under a nitrogen atmosphere, 1-chloro-1-methyl-2,2-diphenylcyclopropane (2.43 g, 10.0 mmol), magnesium (0.279 g, 11.5 mmol) and THF (10 ml) were placed in a reaction flask, followed by addition of a trace amount of iodine and stirring at 60° C. for 5 hours. After cooling, copper iodide (1.92 g, 10.0 mmol), lithium bromide (0.879 g, 10.1 mmol) and chlorodi-tert-butylphosphine (2.1 ml, 11.0 mmol) were added and the resulting mixture was stirred at 60° C. for 3 hours, followed by cooling to room temperature. The resulting mixture was diluted with hexane (20 ml) and crystal separated was collected by filtration. The crystal was dissolved in toluene, and the toluene solution was washed with a 28% (w/w) aqueous ammonia and a brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.89 g, 25%) as white crystal.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]
Yield: 95.3 %

Procedure:
A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (30.0 g, 0.14 mol), N-chlorosuccinimide and acetonitrile (1.3 L) was refluxed for 4 hours. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 ml). The organic layer was washed with water (2×250 ml) and brine (250 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexanes gave 33.5 g (95.3%) of product as an orange solid: mp 109-110° C.; MS (EI) 250/252/254 m/e (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].C(Cl)(Cl)Cl.CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:28](=[O:31])[CH:29]=[CH2:30])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=2)=[N:12][CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: -30 °C
Reaction time: 0.67 h

Procedure:
In a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.40 g) in dry DCM (10 mL) and was cooled to −30° C. An acryloyl chloride solution in DCM (0.107 g in 5.0 mL DCM) was added slowly and the reaction mixture was stirred at −30° C. for approx. 40 minutes. The reaction was monitored on TLC using chloroform:methanol (9.6:0.4) as mobile phase. The reaction mixture was poured into water (100 mL) and basified using sodium bicarbonate. The reaction mixture was extracted with MDC (2×25 mL) and the combined organic layer was washed with 50 mL brine solution. The organic layer was dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Obtained solid was purified by triturating with diethyl ether (2×10 mL) and dried under vacuum to give 0.28 g N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=S)[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1>CO>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=[N:2][NH2:3])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.5 h

Procedure:
Hydrazine monohydrate (2.23 mL, 46.0 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (546 mg, 1.53 mmol) in methanol (25 mL). After 30 min, the mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=355 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]2[NH:12][CH2:13][CH2:14][CH:4]2[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[C:36](O)=[O:37])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C@@H:5]2[N:12]([C:36]([C@H:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]3[NH:29][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:37])[CH2:13][CH2:14][C@@H:4]2[C@@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1c2ccccc2C2NCCC2C1c1ccccc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1c2ccccc2[C@H]2[C@H](CCN2C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.4 %

Procedure:
A mixture of 5-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (130 mg, 0.48 mmol), (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (131 mg, 0.53 mmol), WSC (116 mg, 0.61 mmol), HOBt (97 mg, 0.63 mmol), acetonitrile (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 12 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous Na2SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (150 g) and eluted with hexane-ethyl acetate (4:1-1:1, v/v) to give the title compound (200 mg, 84%) as an amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][NH2:18])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:22](N(CC)CC)C.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][NH:18][CH3:22])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: NCc1cccc(-c2cnc(-c3ccc(Cl)c(Cl)c3)[nH]2)c1
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCc1cccc(-c2cnc(-c3ccc(Cl)c(Cl)c3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A solution of 3-[2-(3,4-dichloro-phenyl)-3H-imidazol-4-yl]-benzylamine (1.59 g, 5.0 mmol) and triethylamine (1.01 g, 10.0 mmol) in THF (32 ml) was cooled in an ice bath and treated with a solution of ethyl chloroformate (1.08 g, 10 mmol) in THF (10 ml). The resulting mixture was stirred at r.t. for 1 hr., filtered, treated with 1.14 g (30 mmol) lithium aluminum hydride and refluxed for 2 hrs. Then saturated Seignette-salt solution (6 ml) was added slowly and stirring was continued for 30 min. The precipitate was filtered and the organic phase evaporated and chromatographed over SiO2 with CH2Cl2—CH3OH—NH4OH (200:10:1) to obtain {3-[2-(3,4-dichloro-phenyl)-3H-imidazol-4-yl]-benzyl}-methyl-amine (0.91 g, 55%) as an oil which after HCl/MeOH addition was crystallized as a light yellow hydrochloride salt. Mp. 145° C. (dec.) (MeOH/Ipr2O), MS: m/e=332 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:13].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH:22]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:13])=[O:23]
Reactant: CC(=O)Nc1cc(C)c(Br)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)c(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-bromo-3,5-dimethyl-phenyl)-acetamide (150 mg) in THF (5 mL) was added n-BuLi (1.36 mL, 1.0 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 30 min, then warmed up to −40° C. for 5 min, then cooled down to at −78° C. again. After 20 min, DMF (0.24 mL) was added. The mixture was stirred at −78° C. for 30 min and then allowed to warm up to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(4-formyl-3,5-dimethyl-phenyl)-acetamide: MS (m/z) 192 (M+1).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1CCC(C1C=CC=CC=1)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32]/[C:33](/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32]/[C:33](/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH:34]\[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)/C=C(/CCc1ccc2ccccc2c1)c1ccccc1
Agent: O=C(CCc1ccc2ccccc2c1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc2ccccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(2-naphthalenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(2-naphthalenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(2-naphthalenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13].[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:21]/[NH:20][C:17](=[NH:18])[NH2:19])/[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: O=C(CCC(F)(F)F)c1cc(Cl)ccc1Br
Reactant: N=C(N)NN
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: N=C(N)N/N=C(\CCC(F)(F)F)c1cc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a screw cap pressure vessel was added the intermediate from Step A (3.22 g, 10.2 mmol), aminoguanidine hydrochloride (1.69 g, 15.3 mmol), methanol (25 mL) and boron trifluoride diethyl etherate (2.6 mL, 20.4 mmol). The reaction solution was heated at 100° C. for 70 minutes. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed twice with aqueous 1N NaOH and brine (1×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the indicated compound as a mixture of E, Z hydrazone isomers. 1H NMR (400 MHz, CD3CN): δ 7.54 (d, J=8.4 Hz, 1H); 7.24-7.17 (m, 1H); 7.10 (d, J=2.6 Hz, 1H); 2.68-2.51 (m, 4H). m/z 371 (M+H).
Reaction SMILES: [CH:1]([O:4][P:5]([C:11]([NH:13][CH2:14][C@H:15]([NH:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:16][OH:17])=[O:12])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].Cl[C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>C(Cl)(Cl)Cl.CO.CCOC(C)=O>[CH2:54]([O:53][C:51]([NH:18][C@@H:15]([CH2:14][NH:13][C:11]([P:5]([O:7][CH:8]([CH3:10])[CH3:9])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[O:12])[CH2:16][OH:17])=[O:52])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OP(=O)(OC(C)C)C(=O)NC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
(S)-3-diisopropylphosphonoformamido-2-(tritylamino)propanol (10.49 g, 20 mmol) was dissolved in a mixture of chloroform-methanol (1:1, 40 mL) and cooled to 0° C. in an ice bath. The reaction mixture was stirred at RT for 7 h, after dropwise addition of trifluoroacetic acid (20.0 mmol, 1.5 mL) at 0° C. The solvents were removed and the resulting residue was azeotroped 5 times with diethyl ether (5×40 mL) and partitioned between diethyl ether (150 mL) and water (50 mL). The ether layer was washed with water (20 mL) and the combined aqueous fractions were basified with NaHCO3 (80 mmol, 6.72 g). Aqueous fraction was diluted with EtOAc (150 mL) and the mixture was cooled to 0° C. in an ice bath. Benzyl chloroformate (2.9 mL, 20 mmol) was then added to the reaction mixture at 0° C. and stirred vigorously at RT for 1.5 h. The layers were separated and the aqueous layer was washed with EtOAc (2×30 mL). The combined organic fractions were washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 5% MeOH in EtOAc) to afford (S)-2-benzyloxycarbonylamino 3-(diisopropy-lphosphonoformamido)propanol as gummy solid in 50% (4.16 g) yield.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18](=[O:24])[C:19](OCC)=[O:20])[N:17]=2)=[CH:6][CH:5]=1.CO.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([CH:18]([OH:24])[CH2:19][OH:20])[N:17]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)Nc1nc(C(O)CO)cs1

Procedure:
2.4 g of sodium borohydride were added to a suspension of 5 g of ethyl 2-(3-p-bromophenylureido)thiazol-4-ylglyoxylate in 60 ml of tetrahydrofuran, then 20 ml of methanol were added dropwise over a period of 1 hour while heating the reaction mixture under reflux, and the reaction mixture was thereafter heated under reflux for a further 1 hour. The reaction mixture was poured into water and neutralized with 3N hydrochloric acid. The crystals which precipitated out were collected by filtration, washed with water and dried, giving crude 1-[2-(3-p-bromophenyl- ureido)thiazol-4-yl]ethane-1,2-diol.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:17]2[NH:16][C:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[N:19][C:18]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1
Yield: 25.8 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.36 mmol,0.15 g) in ethyl acetate (5 mL) for 0.5 h. The solvent was then evaporated under reduced pressure and the residue diluted with saturated sodium bicarbonate (50 mL). The resulting suspension was extracted with methylene chloride (5×20 mL), the organic layers combined, washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting material was crystallized from diethyl ether to give 30 mg of the title compound as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[N:4]([CH3:3])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[C:11]=1[NH2:12])=[O:16])[CH3:19]
Reactant: CNc1ccncc1C#N
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2cnccc2n1C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
Sodium hydride (9.0 g, 60% dispersion, 225 mmol) was suspended in DMF (150 mL) and cooled to 0-5° C. A solution of 4-methylamino-nicotinonitrile (20.0 g, 150 mmol) in DMF (100 mL) was added dropwise over ca. 20 minutes and the resulting mixture stirred cold for 30 minutes and then treated with a solution of ethyl bromoacetate (34.0 g, 225 mmol) in DMF (50 mL). The solution was allowed to warm to room temperature over 1 hour. The mixture was partitioned between ethyl acetate and water and the aqueous further extracted with ethyl acetate. The combined organic layers were washed with water (×2), brine, dried (MgSO4) and evaporated. Trituration of the resultant residue with ethyl acetate gave the title compound (12.2 g, 37%) as a yellow solid. 1H NMR (CDCl3) 1.44 (3H, t, J=7.1 Hz), 3.88 (3H, s), 4.43 (2H, q, J=7.1 Hz), 5.09 (2H, br s), 7.10 (1H, dd, 1H, J=6.1, 1.0 Hz), 8.35 (1H, d, J=6.1 Hz), 8.88 (1H, d, J=1.0 Hz).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29](OCC)=O)[CH2:22][CH2:21]1>>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:22][CH2:21]1
Reactant: CCOC(=O)CCCN1CCC(c2ccc3ccccc3c2)CC1
Reactant: ON=C1CCCCCC1
Product: c1ccc2cc(C3CCN(CCCc4onc5c4CCCCC5)CC3)ccc2c1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-naphthyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(2-naphthyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](NC)=[O:4].[CH2:7]([NH:10][CH2:11][CH2:12][CH3:13])[CH2:8][CH3:9]>C1(C(C)C)C=CC=CC=1>[CH2:7]([N:10]([CH2:11][CH2:12][CH3:13])[C:3]([NH:2][CH3:1])=[O:4])[CH2:8][CH3:9]
Reactant: CNC(=O)NC
Reactant: CCCNCCC
Solvent: CC(C)c1ccccc1
Product: CCCN(CCC)C(=O)NC
Temperature: 137 °C
Yield: 104.9 %

Procedure:
To a 250 ml, 3-neck flask, with an agitator and condenser were added 22.0 g (0.25 mol) of 1,3-dimethylurea, 25.3 g (0.25 mol) of dipropylamine and 100 ml of cumene. The solution was heated at reflux (about 137° C.) for about 12 hours, cooled to 100° C., and the solvent was removed using vacuum distillation to provide a residue. The residue was dried in a vacuum oven at 60° C. to provide 41.5 g of 1,1-dipropyl-3-methylurea.