Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([NH:39][NH2:40])=O)[N:32]=1>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:33]3[N:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Reactant: NNC(=O)c1cccnn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2cccnn2)C1
Temperature: 120 °C
Reaction time: 0.67 h

Procedure:
4-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.23 g, 0.790 mmol) was dissolved in Dichloromethane (DCM) (1.975 ml) and triethyloxonium tetrafluoroborate (0.180 g, 0.948 mmol) was added. The solution was left to stir under an argon atmosphere for 40 minutes. A clear solution was formed. 3-pyridazinecarbohydrazide (I23) (0.131 g, 0.948 mmol) was added and the solution was stirred under an argon atmosphere for a further 40 minutes. The solvent was removed under reduced pressure and then 1-butanol (1.975 ml) was added and the solution was left to reflux under an argon atmosphere at 120° C. for 3 hours. The reaction was followed by LCMS. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography (Biotage SP4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure and the isolated material was purified further using MDAP. The columns were combined and the solvent removed under reduced pressure. The material was triturated with ether to afford the desired material in 27 mg.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.O.[NH2:23][NH2:24]>C1COCC1>[C:8]([C:7]1[C:2]([NH:23][NH2:24])=[N:3][CH:4]=[CH:5][C:6]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)#[N:9]
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1Br
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Temperature: 160 °C
Yield: 88.7 %

Procedure:
To a solution of compound D6 (0.5 mg, 1.461 mmol) in THF (4 ml), was added hydrazine monohydrate (0.366 g, 7.305 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 15 min. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (0.380 g, 89%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:38]#[N:39].[Na+]>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19]([C:38]#[N:39])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(S(C)(=O)=O)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above product, 4-[2-(5-benzylcarbamoyl-6-chloro-2-methanesulfonylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2/H2O (20 mL/2 mL) is added NaCN (3.3 mmol) and tetra-n-butylammonium bromide (0.14 mmol) at 0° C. After warmed up to room temperature, the reaction mixture is vigorously stirred for 1.5 h at room temperature. The mixture is diluted with CH2Cl2, washed with aq. NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyano-pyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H-NMR (CDCl3), δ 1.09-1.19 (2H, m), 1.46 (9H, s), 1.63-1.74 (5H, m), 2.66 (2H, br t), 4.07 (2H, m), 4.51 (2H, t), 4.66 (2H, d), 6.11 (1H, t), 7.31-7.37 (5H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])=O.[NH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH2:11]([C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH2:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)[S:25][CH:2]=1)[CH3:12]
Reactant: CCc1ccncc1C(=O)CBr
Reactant: NC(=S)c1ccc(S(N)(=O)=O)cc1
Product: CCc1ccncc1-c1csc(-c2ccc(S(N)(=O)=O)cc2)n1
Yield: 51.7 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-ethylpyridin-3-yl)ethanone hydrobromate (161 mg) and 4-(aminosulfonyl)benzenecarbothioamide (109 mg), the title compound (90 mg) was obtained as colorless powder crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11]>>[CH3:22][C:19]([C:17]1[CH:16]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:33])[CH:14]=[C:13]([C:10]([CH3:9])([CH3:11])[CH3:12])[CH:18]=1)([CH3:20])[CH3:21]
Reactant: NCc1cccnc1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCc2cccnc2)cc(C(C)(C)C)c1

Procedure:
Substituting 3-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(3-pyridinylmethyl)-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:7]=[N:6]1
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCO
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Reaction time: 8 h
Yield: 94 %

Procedure:
2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25° C. under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Si:27]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:10][CH2:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(N2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)n1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol obtained in Step A (1.00 g) and imidazole (0.636 g) in N,N-dimethylformamide (13 mL) was added tert-butyl(chloro)dimethylsilane (0.793 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.42 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:14]=[CH2:13])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1OC
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-methoxyphenol (27.0 g) in DMF (50 ml) was added dropwise to a mixture of 60% NaH (7.0 g) in DMF (250 ml). After stirring the reaction for 1 hour, allylbromide (21.0 ml) was added and stirring was continued for 1 hour at room temperature. The reaction was poured onto ice/water and extracted with ethyl acetate. The organic layer was separated, dried and evaporated to afford the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:24][CH:23]=2)=O)=[C:6]([N:8](C)[C:9](=O)OC(C)(C)C)[CH:7]=1.[ClH:36].O1CCOCC1>>[ClH:36].[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH:29]4[S:33][C:32](=[O:34])[NH:31][C:30]4=[O:35])=[CH:26][CH:27]=3)[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(O)cc21
Reaction time: 19 h

Procedure:
A suspension of this carbamate (0.75 g) in 4N hydrogen chloride/dioxane (10 ml) was allowed to stand at room temperature for 19 hours. The solvent of the reaction mixture was evaporated under reduced pressure. Ethyl acetate was added to the residue and the mixture was treated with ultrasonic waves, filtered and then dried to afford the title compound (0.52 g, mp 217-220° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][CH2:13][C:14]([N:16]([CH2:39][C:40]([OH:42])=[O:41])[C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[NH:26][C:27]([C:29]1[NH:33][C:32]2[C:34]([Cl:38])=[C:35]([Cl:37])[S:36][C:31]=2[CH:30]=1)=[O:28])=[O:15])(=O)C>C1COCC1>[C:40]([CH2:39][N:16]([C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[NH:26][C:27]([C:29]1[NH:33][C:32]2[C:34]([Cl:38])=[C:35]([Cl:37])[S:36][C:31]=2[CH:30]=1)=[O:28])[C:14](=[O:15])[CH2:13][OH:12])([OH:42])=[O:41]
Reactant: CC(=O)OCC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(C(=O)CO)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
Potassium carbonate (20 mg) and MeOH (1 mL) were added to a solution of [[(acetyloxy)acetyl]((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetic acid (Method 19, 120 mg, 0.23 mmol) in THF (5 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in water and acidified to pH 2.0 and then extracted into EtOAc (3×10 mL). The volatiles were removed by evaporation under reduced pressure to afford the title compound (110 mg, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CN(C)C=O.C(Cl)(=O)C(Cl)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:16]2[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=2)=[O:9])=[C:5]([CH3:12])[CH:4]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: Cc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2ccc(C)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
Oxalyl chloride (3.43 mL, 0.0400 mmol) and N,N-dimethylformamide (2 drops) were added to chloroform (60 mL) solution of 4-methoxy-2-methylbenzoic acid (5.0 g, 0.0300 mol). After the reaction mixture was stirred at room temperature for one hour, the reaction solvent was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (60 mL). Toluene (3.52 mL, 0.0330 mol) and aluminum chloride (8.02 g, 0.0601 mol) were added to this solution while cooled on ice, and the reaction mixture was stirred for three and a half hours while keeping the reaction mixture cooled ice. After 5% hydrochloric acid was added to the reaction mixture and extracted with chloroform, the organic phase was washed with 10% hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain yellow oily (4-methoxy-2-methylphenyl) (4-methylphenyl)methanone (4.26 g, 58.9%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([OH:14])=[C:4]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[N:3]=1.[CH3:22][N:23](C)C(=O)C>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[C:22]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([OH:14])=[C:4]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[N:3]=1)#[N:23]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc2c(O)c(C(=O)NCC(=O)O)nc(Cl)c2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c2c1
Temperature: 25 °C

Procedure:
[(1-Cyano-4-hydroxy-7-methoxy-isoquinoline-3-carbonyl)-amino]-acetic acid was prepared by adding 159 mg (0.511 mmol) of [(1-chloro-4-hydroxy-7-methoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (prepared according to U.S. Pat. No. 6,093,730), 24 mg (0.025 mmol) tris(dibenzylideneacetone)dipalladium(0), 28 mg (0.051 mmol) 1,1′-bis(diphenylphosphino) ferrocene, 4 mg (0.06 mmol) zinc dust, and 36 mg (0.306 mmol) zinc cyanide to 1.0 mL of N,N-dimethylacetamide. The resultant mixture was heated at 115° C. for 3 hours under a nitrogen atmosphere, and then cooled to room temperature. The mixture was diluted with ethyl acetate and half-saturated aqueous sodium bicarbonate solution and filtered through a celite pad. The biphasic mixture was separated, and the basic aqueous extract was acidified with concentrated HCl and extracted three times with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated to give 107 mg of the title compound as a white solid; MS (ESI+): m/z 302.3 (M+1)
Reaction SMILES: [CH3:1][C:2]1([C:26]([O-:28])=[O:27])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6]([CH2:20][CH2:21][CH2:22]Br)([C:17]([O-:19])=[O:18])[CH:5]([CH3:24])[NH:4][CH:3]1[CH3:25].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:29].[CH3:1][C:2]1([C:26]([OH:28])=[O:27])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6]([CH2:20][CH2:21][CH2:22][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)([C:17]([OH:19])=[O:18])[CH:5]([CH3:24])[NH:4][CH:3]1[CH3:25]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CC1NC(C)C(CCCBr)(C(=O)[O-])C(c2cccc([N+](=O)[O-])c2)C1(C)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1NC(C)C(CCCN2CCC(c3ccccc3)(c3ccccc3)CC2)(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C1(C)C(=O)O
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of 86.6 g of (-)-3-methyl-5-(3-bromopropyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely powdered potassium carbonate is heated for 5 h in 300 ml of dimethyl formamide to 100° C. under a nitrogen atmosphere and with vigorous sti rring. After cooling, 500 ml of ethyl acetate and 1 l of water are added with vigorous stirring. The phases are separated; the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 1 l of dioxane; then 15.2 ml of concentrated hydrochloric acid solution (12.5 M, d =1.19) are added, and about 200 ml of the solvent mixture are removed by distillation in vacuo. The product crystallizes spontaneously on standing at room temperature or after inoculation or trituration, and is filtered off by suction after 16 h, washed with dioxane and diisopropyl ether, and dried at 80 to 100° C. in vacuo. For further purification the crude product is dissolved in dichloromethane. After addition of 800 ml of dioxane the dichlormethane is distilled off. The product which crystallizes after inoculation on standing at room temperature for 16 h is filtered off by suction, washed with dioxane and diisopropyl ether, and dried at 100° C. in vacuo. 97 g of the title compound {m.p. 158° C. to 160° C. and [α]43622 =-39° (c=1, methanol) or [α]=-14,4 (c =1, methanol)} are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[S:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Fc1ccccc1-c1csc(N2CCNCC2)n1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To a solution of benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (0.85 g, 2.1 mmol) in CH2Cl2 (2 μL) cooled to −50° C. was added boron tribromide (1 M in CH2Cl2, 8.6 mL, 8.6 mmol). The reaction was stirred at −50° C. for 20 min and then carefully quenched with saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2, and the combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine. LC/MS: m/z 264.1 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[NH4+].[Cl-]>C1COCC1>[C:24]([O:23][C:21]([NH:6][C@@H:7]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:8][CH2:9][C:5]([NH:2][NH2:3])=[O:4])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Hydrazine monohydrate (0.93 mL, 18.6 mmol) was added to a solution of (R)-tert-butyl 2-oxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate (1.6 g, 4.65 mmol) in THF (23 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting off-white solid was purified by recrystallization from EtOAc to provide (R)-4-(tert-butoxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanehydrazide (1.40 g, 80%) as a white solid. LCMS (API-ES) m/z: 399.1 (M+Na+).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:11]([C:13]1[O:17][CH:16]=[N:15][C:14]=1[CH3:18])=[O:12].C(O)C.[Cl-].[Na+]>O1CCCC1>[C:1]1([C:11]([C:13]2[O:17][CH:16]=[N:15][C:14]=2[CH3:18])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)c1ocnc1C
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ncoc1C(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Phenyllithium (1.8M solution in cyclohexane-diethylether, 11.7ml) in dry tetrahydrofuran was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (3.0g) in dry tetrahydrofuran was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 84-86° C. 1H Nmr (CDCl3) 2.59 (3H, s), 7.5-7.68 (3H, m) and 7.96-8.06) (3H, m) ppm.
Reaction SMILES: C(O[C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])(C)(C)C.C(OC(=O)[CH2:16][N:17]=[C:18]=[O:19])C.[ClH:21].C(O)C>C(Cl)Cl>[ClH:21].[NH2:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[CH2:16][NH:17][C:18]1=[O:19]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: NCCN1C(=O)CNC1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(2-Aminoethyl)-carbamic acid tert-butyl ester (14.4 g, 90 mmol) was dissolved in DCM (100 mL) and was treated with a solution of isocyanatoacetic acid ethyl ester (11.6 g. 90 mmol) in DCM (100 mL) added dropwise over 30 min. The resulting solution was stirred for 1 h and concentrated to give a pale gum. Aqueous 5N HCl (250 mL) was added and the mixture stirred until dissolved. The resulting solution was heated at 100° C. for 16 h, concentrated, water (250 mL) was added and the solution again concentrated to give a solid. Ethanol (100 mL) was added and the mixture was again concentrated. Ethanol (150 mL) was added and the mixture stirred for 16 h to give the product as a fine white powder which was collected by filtration. Yield=14.7 g, 91%. MS (M+H)+ 144.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccc(I)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(I)c1
Yield: 64.5 %

Procedure:
A solution of 3-iodophenol (3 g, 13.6 mmol), acetyl chloride (2.9 ml, 40.9 mmol) and potassium carbonate (9.42 g, 68.2 mmol) in N,N-dimethylformamide (75 ml) was stirred for 16 h at room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1N NaOH, dried over magnesium sulfate, and evaporated under vacuum. The crude product was chromatographed over silica gel, eluting with 20% ethyl acetate/hexanes to yield 2.3 g (65%) of 3-iodophenyl acetate.