Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:4]([O:5]2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][N:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:4]([OH:5])[CH2:3]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN1CC[C@H](c2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-methyl-6-phenyl-7-oxa-3-azabicyclo[4.1.0]-heptane (1.00 g; 5.30 mmoles, described in Example 6) in anhydrous ether (10 ml) is added dropwise, with stirring to a slurry of lithium aluminum hydride (0.50 g, 13.2 mmoles) in anhydrous ether (50 ml). The mixture is stirred for 4 hours at room temperature. Excess lithium aluminum hydride is decomposed by slow addition of water (10 ml). The white precipitate is filtered and washed with ether. The combined ether layers are dried over potassium chloride and evaporated. The white solid residue is dried to give the title compound, mp 95°-97° C. (R. E. Lyle and W. E. Krueger, supra, reported mp 95°-97° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](C2C=C(C)C=CC=2C2C=NN(C)C=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.NC[C@@H]1[C@H](C)CCCN1C([C:46]1[C:51]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:50][CH:49]=[C:48]([CH3:59])[N:47]=1)=O>>[F:58][C:55]1[CH:54]=[CH:53][C:52]([C:51]2[C:46]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]3[CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][N:26]=3)=[O:9])=[N:47][C:48]([CH3:59])=[CH:49][CH:50]=2)=[CH:57][CH:56]=1
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-(4-fluorophenyl)-6-methylpyridin-2-yl)methanone. ESI-MS (m/z): 487 [M+1]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(C)cc2)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CN2CCC(C(=O)O)CC2S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6 g (61%); off white solid, mp 204° C.; MS: 514.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1O)=[O:5])[CH3:2].S(Cl)([Cl:21])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1[Cl:21])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccccc2)CCC=CC1Cl

Procedure:
15 g of 1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester and 15 cc. of thionyl chloride and 1 cc. of dimethylformamide are heated under reflux for 10 minutes. Then direct distillation is done. 12.2 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester of the boiling point 0.1/122°-5° C are obtained. By reacting with 12 g of β-phenylethyl amine in 100 cc. of DMSO for 2 hrs. at 100° C, processing as described above, 6.0 g of hydrochloride m.p. 179°-82° C are obtained.
Reaction SMILES: [F:1][C:2]1([C:9]([OH:11])=[O:10])[CH:7]2[CH:3]1[CH2:4][CH2:5][C:6]2=[O:8].C(=O)([O-])O.[Na+].[CH2:17](I)[CH3:18].Cl>CN(C)C=O>[F:1][C:2]1([C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:7]2[CH:3]1[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: CCI
Reactant: O=C1CCC2C1C2(F)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)C2CCC(=O)C21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(1RS,5RS,6RS)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid in an amount of 1.0 g was dissolved in 5.0 mL of N,N-dimethylformamide, and 0.58 g of sodium hydrogencarbonate and 1.5 mL of ethyl iodide were added thereto. The mixture was stirred overnight at 50° C. The reaction mixture was poured into 1M hydrochloric acid, followed by extractions with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1), thereby yielding 1.1 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate.
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:25]1([C:16]2[C:17]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])=[CH:18][C:13]([C:11]([NH:10][C:4]([CH:1]3[CH2:3][CH2:2]3)([CH2:5][C:6]([NH:30][CH3:29])=[O:8])[CH3:9])=[O:12])=[N:14][CH:15]=2)[CH2:27][CH2:26]1
Reactant: CN
Reactant: CC(CC(=O)O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1
Agent: Cl
Product: CNC(=O)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]butanoic acid (Example 229d) and methanamine hydrochloride as starting materials and isolated (90 mg, 58%); MS (ESI, m/z): 400.5 (M+H+).
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(CC(O)c2cccnc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C(C)=Cc1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
Ethyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]-α-methylcinnamate (1.84 g) was dissolved in 60 ml of acetone, followed by dropwise addition of 2.27 g of 2.67M Jones Reagent, and stirred for 30 minutes. After addition of 2 ml of isopropanol, the resulting mixture was concentrated under reduced pressure, followed by addition of water for extraction with ethyl acetate. The organic phase was washed in saturated aqueous sodium and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with chloroform-methanol(98:2 v/v) was obtained 0.77 g of ethyl 4-[2-oxo-2-(3-pyridyl)ethyl]-α-methylcinnamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[O:9]1[CH2:13][CH2:12]OC1=O.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:12][CH2:13][OH:9])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel, eluants EtOAc and DCM 10%, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34%. 1H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[CH2:17][C:16]2[CH:18]=[N:19][C:20]([N:22](OC)[CH3:23])=[CH:21][C:15]=2[N:14]([CH2:26][CH3:27])[C:13]1=[O:28].[H][H]>[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH2:17][C:16]3[CH:18]=[N:19][C:20]([NH:22][CH3:23])=[CH:21][C:15]=3[N:14]([CH2:26][CH3:27])[C:13]2=[O:28])[CH:4]=1
Reactant: [H][H]
Reactant: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2Cl)Cc2cnc(N(C)OC)cc21
Agent: [Pd]
Product: CCN1C(=O)N(c2cc(N)c(F)cc2Cl)Cc2cnc(NC)cc21
Yield: 86.6 %

Procedure:
3-(2-Chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.7 g, 6.6 mmol), Pd/C (1.4 g) and hydrogen (30 psi) were combined at 45° C. by the procedure of Example A4 to provide 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2 g, 87.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1 H), 7.24 (d, J=10.8 Hz, 1 H), 6.81 (d, J=9.2 Hz, 1 H), 6.44 (bs, 1 H), 6.02 (s, 1 H), 5.42 (s, 2 H), 4.50 (d, J=13.2 Hz, 1 H), 4.38 (d, J=13.2 Hz, 1 H), 3.77 (m, 2 H), 2.76 (d, J=4.8 Hz, 3 H), 1.15 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 350.2[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: ClCC1CC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
5.0 g (28.9 mmol) 4-bromophenol, 3.93 g (43.4 mmol) (chloromethyl)cyclopropane and 7.99 g (57.8 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(#N)CCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)=[O:26]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: NC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CCCC#N
Product: NC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Temperature: 20 °C
Reaction time: 22 h

Procedure:
Pyridine (1.6 mL, 1.1 equivalents) is added to a mixture of 4-aminobenzamide (2.5 g, 18 mmol) and n-butyronitrile (65 mL) at 20° C. under an atmosphere of nitrogen. The mixture is stirred for 15 minutes before a solution of 8-bromooctanoyl chloride (3.7M in toluene, 5.5 mL, 20 mmol, 1.1 equivalents) in n-butyronitrile (10 mL) is added over 20 minutes. The mixture is then stirred at 20° C. for 22 hours. Upon complete reaction the mixture is filtered. The resulting product is washed with methanol (10 mL), water (2×25 mL), methanol (10 mL) and tert-butyl methyl ether (TBME, 10 mL) before being dried in vacuo to yield the title compound, generally as a solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:25][C:26]([C:28]1[NH:29]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)[CH:32]=1)=O.N[C@H](CO)C>>[OH:25][CH2:26][C@@H:28]([NH:29][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[NH:7][N:6]=1)=[O:4])[CH3:32]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n[nH]1
Agent: C[C@H](N)CO
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)n[nH]1
Yield: 50 %

Procedure:
As described for example 6, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.22 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using L-alaninol instead of ethanolamine, to the title compound (40 mg, 50%) which was obtained as a colorless oil. MS: m/e=358.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:28][CH3:29])[C:4]1[CH:5]=[C:6]([C:13](N2CCOCC2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C#N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].CC(O)=[O:32]>>[CH3:1][O:2][CH:3]([O:28][CH3:29])[C:4]1[CH:5]=[C:6]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:32])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)O
Reactant: COC(OC)c1cc(C(C#N)(c2ccccc2)N2CCOCC2)ccc1[N+](=O)[O-]
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
(3-Dimethoxymethyl-4-nitro-phenyl)-morpholin-4-yl-phenyl-acetonitrile (0.7 mol) in CH3CO2H (1500 ml) was stirred and refluxed for 30 min. The mixture was poured on ice/water and extracted with diisopropyl ether. The organic layer was washed with alkalic water and water. The organic layer was dried (MgSO4) and evaporated to yield a residue. The aqueous layers which contained product were extracted with CH2Cl2. The organic layer was dried (MgSO4) and evaporated to yield a residue. The combined residues were purified on a glass filter over silica gel (eluent: CH2Cl2). The pure fractions were collected and evaporated to yield the title compound as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:31]2[CH2:32][CH2:33][CH:28]([CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:26][CH2:25]3)[CH2:29][CH2:30]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of 4-bromophenylsulphonyl chloride (411 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine trihydrochloride (545 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-bromophenylsulphonyl)-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (410 mg), mp 163-164° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=1.[Li+].[OH-].Cl>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][C:3]([OH:17])=[O:2])=[CH:6]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester (100 mg, 0.43 mmol) in THF (1 mL) at 0° C. was added dropwise 2N aqueous LiOH (0.5 mL). After warming to ambient temperature over 4 hours, the mixture was added dropwise to 0.5N aqueous HCl (10 mL). The resultant light brown solid was collected by filtration, washed with H2O, and dried in vacuo over P2O5 to yield 700 mg (74%) of analytically pure 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid as a solid, mp 100-2° C. 1H NMR: δ 7.34-7.30 (m, 2H), 7.10 (t, 2H, J=8.6 Hz), 6.97-6.95 (m, 2H), 6.29 (t, 1H, J=2.2 Hz), 3.60 (s, 2H). Anal. Calculated for C12H10N2F. 0.15 H2O: C, 64.95; H, 4.68; N, 6.31. Found: C, 65.03; H, 4.71; N, 6.25.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].CO.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>CC(O)=O>[N+:1]([CH2:4][CH2:5][C:6](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(N)=S
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: NC(=S)NN=C(CC[N+](=O)[O-])c1ccccc1
Yield: 60.4 %

Procedure:
Into a round bottom flask containing 3-nitropropiophenone (1.02 g, 5.53 mmol), 30 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes. To the warm ketone solution, thiosemicarbazide (0.485 g, 5.33 mmol) and 1% solution of HOAc (0.4 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 30 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (50% EtOAc/50% hex) to obtain 0.8119 g (3.22 mmol) of the product in a 58% yield.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[C:22]([CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:24])=[O:23]>C1COCC1.O>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:26]/[CH2:25][C:22]([OH:24])=[O:23]
Reactant: Cc1cccc(C=O)c1C
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(/C=C/CC(=O)O)c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of 2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40 mL) was added NaHMDS (41.1 mL, 82.1 mmol) at −20° C., and the reaction was stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide (5.0 g, 37.3 mmol) was added to the reaction at −78° C., and reaction was stirred while warming to rt overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (50×3 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated to give 7.00 g (99%) of the crude title compound as a yellow solid. [M+H] calc'd for C12H14O2, 191; found 191.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:14](Cl)=[O:15]>ClCCl>[C:1]([O:5][C:14](=[O:15])[CH:13]([Cl:12])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C(Cl)c1ccc(Cl)cc1Cl
Yield: 82.6 %

Procedure:
While stirring and with ice cooling, a solution of 17.6 g of t-butanol and 19.2 ml of pyridine in 60 ml of dichloromethane is dripped into a solution, cooled at 5° C., of 62 g of α-chloro-α-(2,4-dichlorophenyl)-acetyl chloride in 60 ml of dichloromethane in such a manner that the temperature of the reaction mixture stays below 10° C. After all the solution has been dripped in, the mixture is stirred overnight at room temperature, is then diluted with 100 ml of dichloromethane and extracted 5 times, each time with 100 ml of water. The organic phase is dried over magnesium sulfate and distilled after the solvent has been evaporated. There is obtained 58 g of α-chloro-α-(2,4-dichlorophenyl)-acetic acid t-butyl ester as a colorless oil; b.p. 98°-103° C./0.13 mbar.
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][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
516 mg (purity 91%, 1.8 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 464 mg (68% of theory)
Reaction SMILES: [Na].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]#[N:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=3)[N:12]=[C:29]([NH2:30])[CH2:28]2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(NN)cc1
Reactant: N#CC=Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(N2N=C(N)CC2c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium (3.19 g) was added portionwise to ethanol (160 ml) After all sodium was dissolved, 4-methoxyphenylhydrazine hydrochloride (14.5 g) was added in one portion to the solution. The mixture was stirred at room temperature for 10 min. To this mixture was added 3-(4-benzyloxyphenyl)acrylonitrile (16.3 g) in one portion, and the mixture was refluxed for 3 days.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(Br)ccc1Sc1ccccc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 121c (437 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (129 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 6.43 (d, J=6.99 Hz, 1H) 7.20 (d, J=8.46 Hz, 1H) 7.34 (s, 5H) 7.69 (dd, J=8.82, 2.21 Hz, 1H) 7.81 (m, 2H) 8.47 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H); MS (ESI+) m/z 422 (M+H−TFA)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: CC(=O)Nc1cccc(Oc2cncc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(NC(C)=O)c3)n2)cc(OC)c1OC
Yield: 35 %

Procedure:
Using Method EE with 2-chloro-6-(3-acetamidophenyl-oxy)-pyrazine (150 mg, 0.57 mmol) and 3,4,5-trimethoxyaniline (125 mg, 0.68 mmol), and crystallisation (AcOEt), the title compound was obtained (81 mg). Yield: 35%. 1H NMR (250 MHz, DMSO-d6) δ 2.03 (s, 3H, CH3—NH), 3.44 (s, 6H, [CH3O]3+5), 3.56 (s, 3H, [CH3O]4), 6.80 (s, 2H, Harom2′+6′), 6.82-6.87 (m, 1H, Harom 5), 7.31-7.49 (m, 2H, Harom 4+6), 7.50 (s, 1H, Harom 2), 7.76 (s, 1H, HPz 5), 7.97 (s, 1H, HPz 3), 9.55 (s, 1H, NH), 10.04 (s, 1H, NH). m/z: 411.2 [(M+H)+, calcd for C21H22N4O5 410.2].