Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Temperature: 80 °C
Yield: 75.5 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 mL of N,N-dimethylformamide. The mixture was heated to 80° C. for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isoproply-5-methoxycarbonylpyrimidine).
Reaction SMILES: F[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.CS(C)=[O:16].[OH-].[Na+].Cl>O>[F:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:16])[CH:7]=1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-difluoro-2-nitroanisole(4.36 g), dimethylsulphoxide(10 mL) and 10N aqueous sodium hydroxide(6.5 mL) was stirred at ambient temperature for 18 h and then at 60° C. for 3 h. The mixture was diluted with water and acidified with concentrated hydrochloric acid, extracted with ethyl acetate and the extract was washed with water dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (3.0 g),(m/e 186, MH−).
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([O:46]C(=O)C)[CH:38]=2)[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])=[CH:38][C:39]=2[OH:46])=[CH:12][CH:13]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(Cl)nc3)c(O)c2)=C(C)C1=O
Yield: 17.5 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (61 mg, 0.361 mmol), 5-amino-2-chloropyridine (46 mg, 0.361 mmol) and triethylamine (36 mg, 0.361 mmol) were added to a methylene chloride solution (3 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (45 mg, 0.120 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (10 mg, 0.021 mmol, 17%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([CH:24]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([CH:24]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-2-methylbenzoate (2.80 g) in methanol (50 mL) and THF (50 mL) was added a solution of sodium hydroxide (3.30 g) in water (50 mL), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was concentrated. Water (30 mL) was added to the residue, and the mixture was adjusted with 2N hydrochloric acid to pH<2. The precipitated crystals were collected by filtration, and dried to give the title compound (1.70 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: C[Mg]I.[CH2:4](OCC)C.[F:9][C:10]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:11]=1[O:12][C:13]1[C:21]2[N:20]=[CH:19][N:18]([CH3:22])[C:17]=2[C:16]([CH:23]=[O:24])=[CH:15][C:14]=1[C:25]1[C:26]2[CH:35]=[N:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]=2[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>O1CCCC1>[F:9][C:10]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:11]=1[O:12][C:13]1[C:21]2[N:20]=[CH:19][N:18]([CH3:22])[C:17]=2[C:16]([CH:23]([OH:24])[CH3:4])=[CH:15][C:14]=1[C:25]1[C:26]2[CH:35]=[N:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:27]=2[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1
Reactant: Cn1cc(-c2cc(C=O)c3c(ncn3C)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Reactant: CCOCC
Agent: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c2ncn(C)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 3.0 M solution of methylmagnesium iodide in diethyl ether (21.1 μL, 0.0634 mmol) was added to a solution of 4-(2,4-difluorophenoxy)-1-methyl-5-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-1H-benzimidazole-7-carbaldehyde (0.0478 g, 0.0845 mmol) in tetrahydrofuran (0.734 mL) at 0° C. The resultant reaction mixture was stirred at 0° C. for 1 h, after which time an additional amount of 3.0 M solution of methylmagnesium iodide in diethyl ether (42.2 μL, 0.127 mmol) was added to the reaction mixture and stirring was continued at 0° C. for 30 min. The reaction mixture was quenched at 0° C. with methanol, diluted with methanol, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (25.2 mg, 51%). LCMS calculated for C29H34F2N5O4Si (M+H)+: m/z=582.2. found: 582.2.
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CCCCCC/C=C\CO
Yield: 22.8 %

Procedure:
2-Nonyn- 1-ol (20 g, 0.4 mole) in 200 ml methyl alcohol is hydrogenated in a Parr bomb using a Lindlar catalyst (0.5 g Pd/BaSO4) and quinoline (0.5 g). The hydrogenation was monitored by gas liquid partition chromatography on diethylene glycol succinate. Hydrogenation is stopped when the concentration of the acetylenic alcohol equals that of the saturated alcohol. The hydrogenation mixture is filtered, diluted with water and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, concentrated and distilled to yield 13 g of cis-2-nonen-1-ol, b.p. 60°-64°C/0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1.C1C(=O)N([Cl:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:27][C:15]1[N:13]2[CH:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]([C:18]#[N:19])=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2nnc(Cl)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 105.1 %

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (397 mg, 1.37 mmol, prepared according to Example 15, Step 6.4) and NCS (275 mg, 2.06 mmol) in DMF (8 mL) was heated at 50° C. and stirred for 7 h. The reaction mixture was diluted in AcOEt (50 mL) and washed with water (2×25 mL). The organic layer was dried over Na2SO41 filtered, and evaporated to give the crude title compound (466 mg, quant.). MS: 323 [M+1]+; HPLC: AtRet=2.11.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reaction time: 1 h
Yield: 97 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (8.62 g, 19.91 mmol) was diluted with DCM (40 ml) followed by the portion wise addition of TFA (30 ml). After stirring for 1 hour, the reaction was concentrated and placed under vacuum over the weekend. The residue was taken up in DCM and washed with saturated bicarbonate and 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to yield the desired compound (7.278 g, 19.32 mmol, 97.00% yield) as a nice white foam.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:10](O)[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[CH2:12]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)[CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:12]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][C@@H:9]2[CH2:10][C@@:2]3([CH3:1])[C:6]([CH3:8])([CH3:7])[C@@H:5]2[CH2:4][CH2:3]3)=[O:22])[CH2:17][CH2:16]1)[CH2:13][CH3:14]
Reactant: CC1(C)[C@H]2CC[C@]1(C)[C@H](O)C2
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC1CCC(C(=O)O[C@@H]2C[C@]3(C)CC[C@H]2C3(C)C)CC1
Yield: 21.36 %

Procedure:
Example 6 was performed as Example 1 except for substitution of 1.0 g of L-borneol, 1.28 g of 4-n-Propyl-cyclohexanecarboxylic acid, 1.61 g of N,N′-Dicyclohexyl carbodimide (DCC), 0.95 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from a mixed solvent (CH2Cl2:methanol=1:3), giving (1S,2R,4S)-4,7,7-trimethylbicyclo [2.2.1]hept-2-yl 4-propyl-1-cyclohexanecarboxylate, as a white solid in a 21.36% yield. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of −22.82 and a helical pitch P of 11.8 μm, with helical twisting power of 8.45 μm−1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Product: Cc1ccc2c(-c3ccc(Cl)nc3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=368.0 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-chloro-5-pyridineboronic acid and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36]([O-])=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+]>CO.C(Cl)Cl>[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])=[C:3]([C:13]2[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=2)[CH:4]=1)(=[O:11])[NH2:12]
Reactant: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 82 %

Procedure:
The title compound was prepared by the coupling procedure of Example 7, step (e) using 3-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-propionamide (as prepared in the previous step, 75.0 mg, 0.307 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 103 mg, 0.338 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (124 mg, 82%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.3 (M+H). found 522.1.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C[O:14][CH:15]1[CH:19]([CH:20]=O)[CH2:18][CH:17](OC)O1.O>C(OCC)(=O)C>[CH2:1]([N:8]1[CH:17]=[CH:18][C:19]([CH:15]=[O:14])=[CH:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccn(Cc2ccccc2)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Benzylamine (540 mg, 5.00 mmol) and acetic acid (10 mL) were added to 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (1 g, 6.25 mmol), and the solution was stirred for 20 minutes at 90° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with an aqueous solution 2N sodium hydroxide once and with water twice, filtered with a glass filter lined with silica gel, the filtrate was evaporated in vacuo, and title compound (800 mg, 4.3 mmol, 68.8%) was obtained as a brown oil.
Reaction SMILES: C(O)(=O)C.Br.[CH2:6]([O:13][C:14](=[O:40])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](=[O:39])[C@H:21]([CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)[NH:22]C(OCC1C=CC=CC=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:6]([O:13][C:14](=[O:40])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](=[O:39])[C@H:21]([CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)[NH2:22])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 145 %

Procedure:
After ice-cooling 20 ml of an acetic acid solution of 25% hydrobromic acid, 1.91 g of compound (6) was added to the solution followed by reaction for 2 hours at 5°-10° C. The reaction mixture was added to 200 ml of dry ether and after quickly removing the precipitates thus formed by filtration and then the reaction mixture was dried overnight in a desiccator with potassium hydroxide, to provide 1.99 g of L-histidyl-L-proline benzyl ester.2-hydrobromide (7).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH2:17][NH2:18].[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NCc1cccnc1
Reactant: COc1cccc(OC)c1CN
Product: COc1cccc(OC)c1CNc1ccc2c(NCc3cccnc3)cccc2n1

Procedure:
The title compound, MS: m/e=401.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 2,6-dimethoxybenzylamine and 3-(aminomethyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[O:4].C[I:12].[CH2:13](OCC)C>C(#N)C>[I-:12].[CH3:13][N+:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[N:9][CH:8]=1
Reactant: COC(=O)c1cncnc1
Reactant: CCOCC
Reactant: CI
Solvent: CC#N
Product: COC(=O)c1cnc[n+](C)c1
Product: [I-]
Temperature: 25 °C

Procedure:
5-Methoxycarbonylpyrimidine (597 mg, 4.3 mmol) and methyliodide (1.6 ml, 26 mmol) were dissolved in acetonitrile (20 ml) in a stoppered flask and stirred at room temperature. After five days diethyl ether was added to precipitate red crystalline product 314 mg (26%), mp 167°-170° C. with effervescence. Calculated: C 30.02, H 3.24, N 10.00; found: C 29.88, H 3.30, N 10.07.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12]SCCCCCC)[NH:4][N:3]=1.[CH2:20](SCCCl)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:4][N:3]=1
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Reactant: CCCCCCCCSCCCl
Product: CCCCCCCCSCCSc1nc(N)n[nH]1
Yield: 96 %

Procedure:
Compound 7 was prepared by using the procedure used for Compound 12, but with 2-chloroethyl octyl sulfide as the starting material. The yield was 96%. A portion was recrystallized from ligroin/ethyl acetate to obtain a solid, m.p. 85°-86° C. Analysis: Calculated for C12H24N4S2 : C, 49.96; H, 8.39; N, 19.42. Found: C, 49.54; H, 8.12; N, 19.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:34]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[N:10]2[CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35][CH2:34]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 18.5 %

Procedure:
7-Methoxy-3-methylquinazoline-2,4(1H,3H)-dione (Intermediate 112, 523 mg, 2.5 mmol) was deprotonated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 200 mg (18%) of the product as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][CH:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][CH:58]1[CH2:63][CH2:62][N:61]([C:24](=[O:25])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[NH:19][N:18]=2)=[O:21])[CH2:60][CH2:59]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a stirred solution of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol) HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration. Purification by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) afforded 0.19 g (91%) of 5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 544.2 (M+1)+, 96.18%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=O)=[N:6][C:7]=1[Cl:8].[NH2:12][C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH2:16])=[O:15]>>[C:14]([C@@H:13]([NH:12][C:9]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([Cl:8])[N:6]=1)=[O:11])[CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[NH2:16]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Cl)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.0 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[N:10]([CH2:14][CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OCC)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:1]([C:9]1[N:10]2[C:11](=[CH:12][CH:13]=1)[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Agent: [Mn+3]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole (1.00 g, 2.80 mmol) and anhydrous sodium acetate (4.60 mg, 5.6 mmol) in acetic acid (20 mL) is added manganese(III) acetate dihydrate (2.25 g, 8.4 mmol) The mixture was stirred for two hours at 80° C. The reaction mixture was diluted with diethyl ether (100 mL), and filtered. The resulting solution was washed with water (2×25 mL), 10% sodium hydroxide (2×30 mL), and water (2×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude oil was purified by flash chromatography on silica eluting with hexane/ethyl acetate (90:10-80:20) to yield 800 mg (80%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate.