Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][N:13]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: CCOc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(Br)C(=O)O
Product: CCOc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
134 mg (0.37 mmol) of 4-chloro-2-(5-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 89 mg (purity 86%, 60% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][C:64](O)=[O:65]>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[N:17]=[C:16]([NH:18][C:64](=[O:65])[CH2:63][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][N:57]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: O=C(Cc1ccccn1)Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a dichloromethane (5 ml) solution of 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamine (74 mg, 0.187 mmol) were added N-methylmorpholine (90 μl, 0.818 mmol), 1-hydroxybenzotriazole (11 mg, 0.313 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.312 mmol) and 2-pyridylacetic acid hydrochloride (54 mg, 0.312 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane. The diluted solution was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (48 mg, 0.0934 mmol, 50%) as a white amorphous substance.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[C:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(Br)ccc1OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl bromoacetate (0.88 mL) was added to a mixture of 4-bromo-2-isopropylphenol (1.0 g) and potassium carbonate (0.96 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethylether/n-hexane=1/10) to afford benzyl (4-bromo-2-isopropylphenoxy)acetate (1.70 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:50])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][N:24]4[C:27]([C:30]5[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]6[CH:44]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[O:42][N:41]=6)=[O:38])=[C:32]([F:49])[CH:31]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:51]>C(Cl)Cl>[ClH:51].[C:45]([C:43]1[O:42][N:41]=[C:40]([NH:39][C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[N:24]4[CH:25]=[CH:26][C:21]([C:18]5[CH:19]=[CH:20][C:15]([C:14]([N:11]6[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]6)=[O:50])=[CH:16][CH:17]=5)=[CH:22][C:23]4=[N:29][CH:28]=3)=[CH:31][C:32]=2[F:49])=[O:38])[CH:44]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)N6CCNCC6)cc5)ccn34)cc2F)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 4-[4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-imidazo[1,2-a]pyridin-7-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (1.53 g, 2.24 mmol) in CH2Cl2 (25 mL), to which is added HCl (5.6 mL, 4 M in dioxane). Stir at room temperature for three hours, then concentrate in vacuo to give light brown solid as product (1.60 g, 115%). MS (ES), m/z 582 (M+1, free base).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].COC[O:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[CH:15][C:16](OCC)=O>O1CCCC1>[OH:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[CH:15][C:16]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1
Reactant: CCOC(=O)C=Cc1ccccc1OCOC
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C=Cc2ccccc2O)n1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
Acetamide oxime (7.5 g), molecular sieves (4A) (10 g) and sodium hydride (5 g) were added to tetrahydrofuran (200 ml) and the mixture was refluxed under heating. To this reaction mixture was added dropwise ethyl 2-(methoxymethyloxy)cinnamate (12 g) and the mixture was continuously heated for 2 hr. After cooling, the mixture was poured on ice and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. Thereto were added tetrahydrofuran (10 ml) and 6N hydrochloric acid (20 ml) and the mixture was stirred with heating at 50° C. for 30 min to allow precipitation of crystals. The crystals were collected by filtration and dried to give the title compound (6.0 g) as white crystals, melting point 184–186° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.Cl[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCO
Product: Fc1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 30.8 %

Procedure:
2-Fluoroaniline (4.0 g, 36.0 mmol) and bis-(2-chloroethyl)-amine hydrochloride (6.4 g, 36.0 mmol) were dissolved in n-butanol (40 mL) and potassium carbonate (12.0 g, 86.8 mmol) was added. The reaction mixture was heated to 100° C. for 16 h, cooled to room temperature, and concentrated under reduced pressure. The crude reaction mixture was diluted with 10% MeOH in CHCl3 and filtered. The clear filtrate was concentrated under reduced pressure to get 1-(2-fluorophenyl)piperazine (2.0 g, yield 31%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 9.95 (br s, 1H), 7.12-6.95 (m, 4H), 3.43 (br s, 8H). MS (ESI) m/z: Calculated for C10H13FN2: 180.11. found: 180.9 (M+H)+
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[CH:27]=3)=[CH:19][C:17]=2[N:18]=1)[CH2:2][CH3:3]>[Zn]>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[CH:27]=3)=[CH:19][C:17]=2[N:18]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1
Agent: [Zn]
Product: CCCNc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 47b), from 2-(2-propylamino-5-nitrophenyl)-5-(2-benzofuranyl)benzoxazole (190 mg, 0.46 mmol) and zinc (300 mg, 4.6 mmol) the subtitle compound was obtained (150 mg, 85%). The product was used directly in the next step without purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:6]3[S:7][C:3]([Cl:2])=[CH:4][CH:5]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(c1ccc(Cl)s1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1

Procedure:
From (5-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (585 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 530 mg) by procedure A.2. Yield: 513 mg (51%). Light yellow solid. MS (m/z): 455.2 ([M+H]+).
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[NH:23][C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[N:23]([CH2:2][CH:3]([F:5])[F:4])[C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)n(CC(F)F)c2nccnc12
Temperature: 120 °C

Procedure:
1-Bromo-2,2-difluoroethane (0.113 g) was added to a mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.3) (0.126 g), potassium carbonate (0.044 g) and potassium iodide (0.053 g) in acetonitrile (5 ml). The reaction mixture was heated in a microwave for 25 minutes at 120° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate, 8:2 to 1:1) to give Compound No. A2 of Table A as a yellow solid (0.083 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:13][C:12]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:8]=2)[CH2:9][CH2:10][N:11]=1
Reactant: CC(=O)NCCc1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccc(C(F)(F)F)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:33])[N:7]([CH3:8])[CH:9]([CH3:32])[C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C(=O)Nc1ccc(-c2cncnc2)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate C1a (3.5 g, 6.5 mmol), pyrimidin-5-ylboronic acid (1.0 g, 7.8 mmol), Na2CO3 (1.4 g, 13.2 mmol), Dichlorobis(triphenylphosphine)palladium(II) (450 mg, 0.64 mmol), dioxane (20 ml), MeOH (5 ml) and water (3.5 ml) is stirred under argon atmosphere for 17 h at 80° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 2.33 g (67%). HPLC-MS: M+H=538; tR=2.26 min (*Method—4).
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[C:9]([C:10](OC)=[O:11])[C:8]=1[OH:17])([O-:6])=[O:5].[OH-].[Na+]>O1CCCC1>[OH:17][C:8]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:2][NH2:3])=[O:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cccc([N+](=O)[O-])c1O
Yield: 90 %

Procedure:
40 ml of hydrazine hydrate were added to a solution of 30 g (0.15 mol) of methyl 3-nitrosalicylate in 200 ml of anhydrous tetrahydrofuran (THF). After dilution with THF, the resulting suspension was stirrable; it was refluxed for approximately 18 hours. After cooling, the batch was poured onto ice. The aqueous solution was rendered neutral by adding NaOH solution. The crystals which precipitated were filtered off and washed with water. After drying, 27 g (90%) of the title compound were obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.C(O)=O>CN(C)C=O.[Zn]>[Cl:1][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Yield: 59.7 %

Procedure:
2,2,2-Trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.5 g) was dissolved in dried dimethylformamide (8 ml) and to this solution were added formic acid (1.5 ml) and then zinc powder (1.5 g) under stirring while ice-cooling. After stirring for 2 hours at the same temperature, zinc powder was filtered off and washed with dimethylformamide (5 ml). The filtrate and the washings were added to a mixed cool solution of ethylacetate (30 ml) and 5% hydrochloric acid (15 ml). After extracting with ethyl acetate, the extract was washed with water and dried over magnesium sulfate. The gummy substance (1.16 g) obtained by distilling off the solvent under reduced pressure was crystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylic acid (660 mg) mp. 110° to 112° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:15])([CH3:14])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH:24][CH3:25]>CN(C)C=O>[CH2:22]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:15])([CH3:14])[C:6](=[O:13])[NH:7]2)[CH:23]=[CH:24][CH3:25]
Reactant: Cc1ccc(O)c2c1NC(=O)C(C)(C)C2
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCOc1ccc(C)c2c1CC(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 5-hydroxy-3,3,8-trimethyl-3,4-dihydrocarbostyril (23 g, 11.2 mmol) and potassium carbonate (3.1 g, 22.4 mmol) in dimethylformamide (20 ml), crotyl bromide (1.8 g, 13.4 mmol) was added and stirred at 70° C. for 2 hours. The reaction mixture was poured into ice-water, and precipitated crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with water, and dried. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane. 1.9 g of the title compound was obtained as colorless needles (65.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[CH2:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]1[O:27][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene (1.43 g, 5.08 mmoles) in 20 mL of CH2Cl2 was added 3-chloroperoxybenzoic acid (2.19 g, 60%, 7.62 mmoles) in several portions, and the mixture was stirred at room temperature for 30 hrs. After addition of EtOAc (60 mL), the mixture was washed with saturated NaHCO3 and brine, and the organic layer was dried over Na2SO4. Evaporation of the solvent afforded an oily residue. The crude product was purified by column chromatography on silica gel with elution by 2:8 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane. Part C: Preparation of 2-benzyloxycarbonylamino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 16 h

Procedure:
2-Chloro-5-nitropyridine (25 g) is dissolved in acetonitrile (150 ml) and the mixture is added dropwise over 30 min to a stirred suspension of piperizine (61.3 g) and potassium carbonate (26.2 g) in acetonitrile (550 ml). The reaction mixture is stirred at 20°-25° for 16 hr. The solvent is removed on a rotary evaporator and the residue is diluted with methylene chloride/water. The organic layer is separated and washed with water (twice) and saline, dried over potassium carbonate and concentrated to give 1-(5-nitro-2-pyridinyl)-piperazine, IR 3338, 3102, 3068, 1603, 1570, 1482, 1347, 1340, 1320, 1306 and 1253 cm-1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN([CH:10]=[O:11])C.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=1)#[N:13].C(N(CC)CC)C>C(Cl)Cl.Cl.CO>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:11][CH3:10])=[O:19])=[C:16]([F:23])[CH:15]=1)#[N:13]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C

Procedure:
Oxalyl chloride (9.0 mL, 106.6 mmol) and DMF (0.5 mL) were added into a suspension of 4-cyano-2-fluorobenzoic acid (ABCR, 16 g, 96.9 mmol) in anhydrous DCM (300 mL) The resulting mixture was stirred at RT, and then evaporated under reduced pressure. The residue was taken up with anhydrous THF (150 mL) and added dropwise into a solution of methanol (50 mL) and triethylamine (25.8 mL, 193.8 mmol) at 4° C. The reaction mixture was diluted with a 0.1N aqueous solution of HCl (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with a semi-saturated aqueous solution of NaHCO3 (200 mL) and water (200 mL), dried (MgSO4) and concentrated under vacuum to give the title compound as a pale yellow solid (17.8 g, quantitative). HPLC (Method A) Rt 2.81 min (Purity: 93.9%).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O>C(Cl)Cl>[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([Cl:38])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.5 g, 1.041 mmol) in DCM (10.41 mL) was added thionyl chloride (0.380 mL, 5.20 mmol). The suspension was stirred for 30 minutes at 0° C. The reaction was concentrated, resuspended in ACN (5 mL), and reconcentrated to generate cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride (0.50 g, 96% yield) as a white powder.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH:26](Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:27][CH2:26][Br:25])=[CH:22][CH:23]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Br
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCC(=C(c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1

Procedure:
A mixture containing 31,6 g of (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-1-buten-4-ol, 93,9 g of dibromoethane, 20,7 g of anhydrous potassium carbonate and 250 ml of methyl ethyl ketone is refluxed for 24 h. The inorganic salts are removed by filtration followed by evaporating the solvent and recrystallizing frommethanol. The yield is 17,3 g (41%) and m.p. 133°-7° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[N:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:11]=[C:10]4[CH2:12][CH2:13][O:14][C:9]4=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Reactant: NCCCN1CCOCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCO3
Yield: 93.3 %

Procedure:
A solution of chloride 206 (250 mg, 1.1 mmol) and 3-(4-morpholinyl)propylamine (0.65 mL, 4.5 mmol) in DME (25 mL) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1-oxide 211 (340 mg, 92%) as a yellow solid: mp 152-154° C.; 1H NMR δ 8.10 (t, J=1.6 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 6.09 (br s, 1H, NH), 4.42 (t, J=8.3 Hz, 2H, H-7), 3.75 (t, J=4.7 Hz, 4H, 2×CH2O), 3.55-3.60 (m, 2H, CH2), 3.30 (dt, J=8.3, 1.6 Hz, 2H, H-7), 2.46-2.52 (m, 6H, 2×CH2N, CH2), 1.82 (p, J=6.5 Hz, 2H, CH2); 13C NMR δ 166.5, 159.4, 151.8, 129.2, 126.4, 116.6, 102.1, 72.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 28.6, 25.3. Anal. calcd for C16H21N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 57.8; H, 6.2; N, 21.1%.