Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.COC(CCC/C=C1/C(=O)C2C(C/1)CCC2)=O.O.C(O)(=O)C>[Cl-].[Na+].O1CCCC1>[OH:8][CH:9]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)COc3ccccc3)CCC2C1=O
Yield: 28.2 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (4.1 mg), prepared as described in Reference Example 54, and in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (1.0 ml; 7:13:2 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The extract was washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue (3.0 mg) was subjected to preparative thin layer chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (3:2 v/v), to give 6-[(E)-3-hydroxy-4-phenoxybut-1-enyl] -3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (0.9 mg), in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 77.9 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.3 ml.), tetrahydrofuran (10 ml.) and methanol (30 ml.) was treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([CH2:11][OH:12])[O:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([C:19](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([O:12][CH2:11][C@H:7]2[O:6][CH2:5][C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:9][C@@H:8]2[OH:10])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18]2[CH:35]=[CH:36][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](CO)[C@@H](O)C1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@@H](N=[N+]=[N-])C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 75.5 %

Procedure:
7.6 g (44 mmole) of 1,5-anhydro-2-azido-2,3-dideoxy-D-mannitol (4) were coevaporated with 3×40 ml of pyridine and then dissolved in 120 ml of pyridine. Thereafter, 19.6 g (53.3 mmole) of 4,4′-dimethoxytritylchloride in 120 ml of pyridine are added at r.t. within 1 h under stirring. The reaction mixture was stirred for another 2 h at r.t. Then pyridine was evaporated and the residue was dissolved in 800 ml of ethyl acetate und washed twice with 400 ml of 5% sodium hydrogencarbonate solution. Organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 30 ml of ethyl acetate and purified by flash-chromatography over silica gel (n-hexane/ethyl acetate/1% triethylamine gradient). Product fractions were combined, evaporated and dried at high vacuum to yield 15.8 g (77%) of a yellowish foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[N:3]=[CH:2][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Yield: 94.9 %

Procedure:
To a solution (60 ml) of 4,6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs. The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give tert-butyl 4-(6-chloropyrimidin-2-yl)piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])[CH2:3]1.N1C=CN=C1.[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[Si:28]([O:18][CH2:17][C:10]1[C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[C:14]([F:15])[C:13]([F:16])=[CH:12][CH:11]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@H]1CN(c2c(CO)ccc(F)c2F)C[C@H](C)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To an ice cooled and stirred solution of [2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-phenyl]-methanol (Intermediate 2, 27.0 g, 105 mmol) in CH2Cl2 was added imidazole (8.5 g, 126 mmol) followed by t-butyl chlorodiphenylsilane (30 mL, 115 mmol) over a period of 15 min. The mixture was brought to room temperature and stirred for 12 h during which tlc showed the disappearance of starting material. The reaction mixture diluted with CH2Cl2 and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer dried (Na2SO4), filtered and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as a white solid. Yield: 45 g (94%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[ClH:27].[ClH:27].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:36]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C=Nc1ccccc1Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Nc5ccccc5Cl)c4)CC3)cccc2n1
Product: Cl
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield according to the general procedure for the preparation of ureas (Method E) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1-chloro-2-isocyanatobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH2:15][NH2:16])[OH:14].[CH2:17]1COCC1>>[OH:14][CH:13]([CH3:17])[CH2:15][NH:16][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:12]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: C1CCOC1
Reactant: NCCO
Product: CC(O)CNC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
4-Nitrophenyl isocyanate (45 grams, 0.27 mol) was added dropwise to a solution of ethanolamine (16.7 grams, 0.27 mol) in THF (200 mL) with stirring. After the addition was complete, stirring was continued for three hours. The precipitate was filtered off and washed repeatedly with THF. N-(2-hydroxypropyl)-N'-(4-nitrophenyl) urea was prepared similarly using amino-2-propanol. This product was used in cases where a secondary alcohol was required at the acceptor end of the dye.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][S:12][CH3:13])[C:3]=1[NH2:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>COC1C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]1[N:9]([CH2:10][CH2:11][S:12][CH3:13])[C:4]2[C:3]([N:14]=1)=[C:2]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)[N:7]=[C:6]([CH3:8])[N:5]=2
Reactant: CSCCNc1nc(C)nc(Cl)c1N
Reactant: CN1CCNCC1
Reactant: O=Cc1ccccc1Cl
Solvent: COc1ccccc1
Product: CSCCn1c(-c2ccccc2Cl)nc2c(N3CCN(C)CC3)nc(C)nc21
Yield: 85.4 %

Procedure:
Dissolve 6-chloro-2-methyl-N4-(2-(methylthio)ethyl)pyrimidine-4,5-diamine (28.1 g, 120.7 mmol), and N-methyl piperazine (14.76 ml, 132.81 mmol) in methoxybenzene in a 2 L round bottom flask. Add 2-chlorobenzaldehyde (20.38 mL, 181.1 mmol) in one portion and raise the temperature to 140° C. and maintain at this temperature for 4 days. Cool the reaction mixture and concentrate under reduced pressure. Dilute the resulting oil with 2 N aqueous hydrogen chloride (200 mL) and wash with dichloromethane (500 mL). Discard the organic layer. Treat the aqueous layer with a sodium hydroxide solution until pH=14 is attained. Extract into dichloromethane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate to give the title compound as a brown oil (43 g). ES/MS m/z 417 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:18][CH:17]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:20][CH:21]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 77.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].C.[CH2:14]([OH:16])[CH3:15]>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:16][CH2:14][CH3:15])=[O:6])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=O)C1=COCC1
Agent: C
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (10 g) was dissolved in Ethanol (50 ml) and Methane sulphoic acid (0.1 ml) was added to it. The reaction mass was stirred at 40-50° C. for 12 hrs. Reaction mass was concentrated to residue under vacuum. Residue was dissolved in dichloromethane (50 ml) and washed with water (50 ml). Reaction mass was concentrated to residue to get ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 9.2 g).
Reaction SMILES: [NH2:1][C@H:2]([C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9](=[O:11])[CH3:10].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[O:70]=[C:71]1[C@H:75]([C:76](O)=[O:77])[C@@H:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:73][NH:72]1>C(Cl)Cl.CN(C=O)C>[O:70]=[C:71]1[CH:75]([C:76]([NH:1][C@H:2]([C:12](=[O:20])[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9](=[O:11])[CH3:10])=[O:77])[CH:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:73][NH:72]1
Reactant: CC(=O)SCCCCC[C@H](N)C(=O)Nc1ccccc1
Reactant: O=C(O)[C@H]1C(=O)NC[C@@H]1c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)SCCCCC[C@H](NC(=O)C1C(=O)NCC1c1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thioacetic acid S—((S)-6-amino-6-phenylcarbamoyl-hexyl) ester-trifluoroacetate (1.03 mmol), DIPEA (3.08 mmol) and PyBOP (1.03 mmol) were added to a solution of (3R*,4S*)-2-oxo-4-phenyl-pyrrolidine-3-carboxylic acid in DCM/DMF: 5/9. The resulting reaction mixture was stirred at RT overnight. After removal of the solvent under reduced pressure, the resulting solid was poured into water and extracted twice with AcOEt. The organic layer was then washed with NaHCO3, water and brine before being dried over Na2SO4 and concentrated under reduced pressure to yield an oil. The latter was partially purified by silica gel chromatography and then subjected to HPLC purification.
Reaction SMILES: F[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:43]([O:50][C:51](=[O:57])[NH:52][CH2:53][C:54](=[NH:56])[NH2:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.ClCCl>[CH2:43]([O:50][C:51](=[O:57])[NH:52][CH2:53][C:54]1[NH:56][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[N:10][C:2]=2[N:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc(F)cnc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nc2ncc(F)cc2c(=O)[nH]1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 30 h
Yield: 22 %

Procedure:
2,5-Difluoronicotinic acid (547 mg, 3.44 mmol), TBTU (1.33 g, 4.14 mmol) and DIPEA (3.40 ml, 19.85 mmol) were added to a solution of carbamimidoylmethyl-carbamic acid benzyl ester [77390-81-9] (725 mg, 3.51 mmol) in DMF (20 ml). The solution was stirred for 5 hours at ambient temperature and 30 hours at 90° C. The brown suspension was poured onto ice cold aqueous buffer solution pH5/dichloromethane 1/1. The layers were separated, the aqueous layer was extracted twice with dichloromethane, the combined extracts were washed with brine and dried over magnesium sulfate. Removal of the solvent under reduced pressure and crystallization (EtOAc/TBME) yielded (6-fluoro-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester (250 mg, 0.757 mmol; 22%) as white solid. MS: m/e=327.1 [M−H−].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:12][CH2:11][CH2:10][CH:7]1[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1COc2ccc(F)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)C(CCCCl)CO2
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared as described in EXAMPLE 11, (51 g) was dissolved in 300 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. During 20 min 50 ml of thionyl chloride was added dropwise followed by stirring for 3 h. Ice cold water was added, the organic phase separated, dried over magnesium sulfate and concentrated in vacuo giving 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil. Sodium cyanide (12 g) was suspended in dimethyl sulfoxide (180 ml) and heated to 80° C. A solution of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran (42 g) in 40 ml of dimethyl sulfoxide was added dropwise followed by heating to 140° C. for 15 min. After cooling ether and water were added, the ether phase separated, washed with water and dried over magnesium sulfate. Removal of solvent in vacuo left a viscous oil which was applied to a silica gel column giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyronitrile as an oil (20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH3:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[N:10]=[C:9]3[CH2:12][CH2:13][CH3:14])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2c(OC)cccc2[nH]1
Product: CCCc1nc2c(OC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 53.8 %

Procedure:
Using 4-methoxy-2-propyl-1H-benzo[d]imidazole (Journal of Pharmacy and Pharmacology; 1956, vol. 8, p 661, 338 mg, 1.78 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (700 mg, 1.95 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (448 mg, 54%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[OH-:25].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:25])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (0.83 g, 2.0 mmol) in THF (10 mL) and water (2.5 mL) was added 1.6 mL of 6N sodium hydroxide solution. Reaction mixture was stirred at 45° C. overnight. Reaction mixture was concentrated down to s small volume, and diluted with 10 mL of icy water. The pH of reaction solution was adjusted to ˜7, and extracted with ethyl acetate (35 mL×2). Combined organic layers were dried over anhydrous sodium sulfate, and concentrated to dryness. The crude material was purified with column chromatography. Product was obtained and used without further purification in the next step. (0.273 g, 34%); LC/MS: MS (ES+) m/e 396 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1>C1C=CC=CC=1.O.[Fe]>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Agent: [Fe]
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2ccc(N)cc2)OCCO1
Yield: 69.7 %

Procedure:
To a solution of 2-methyl-2-(4-nitro-phenyl)-[1,3]dioxolane (100 mg, 0.48 mmol) in benzene (6 ml) was added iron powder (700 mg, 12.5 mmol) and 3 drops of water and then heated to reflux for 30 min. The reaction mixture was cooled, filtered and the filtrate was evaporated to give 4-(2-methyl-[1,3]-dioxolan-2-yl)-phenylamine (60 mg, 70%).
Reaction SMILES: O.N.Cl.C[N:5](C)CCCN=C=NCC.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2>CN(C)C1C=CN=CC=1.ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40]([NH2:5])=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: O=C(O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.8 %

Procedure:
Ammonia water (28%, 0.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.36 g, 1.9 mmol) and 4-dimethylaminopyridine (DMAP) (0.05 g, 0.4 mmol) were added to a dichloromethane solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-cyclohexanecarboxylic acid (0.5 g, 1.2 mmol) and the mixture was stirred at room temperature for 19 hours. To the reaction solution, dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-cyclohexanecarboxylic acid amide (0.1 g, 22% yield), as white powder.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Yield: 43 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with methyl 3-(bromomethyl)benzoate to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 43% yield: mp 49-51° C. (dichlorometyhane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.01-7.94 (m, 2H), 7.53-7.31 (m, 7H), 5.91 (br s, 1H), 4.58 (d, J=6.0 Hz, 2H), 4.53 (s, 2H), 4.12-4.06 (m, 2H), 3.92 (s, 3H), 3.50-3.44 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.2 (M+1).