Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Yield: 97.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (15.0 g), 1-(2-pyrimidyl)piperazine dihydrochloride (19.8 g) and potassium carbonate (42.0 g) in dimethylformamide (200 ml) was stirred at 80° C. for 8.5 hr. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (24.0 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-brown oil (18.7 g). The obtained pale-brown oil was crystallized from ethyl acetate: hexane (5:1, 100 ml) and the crystals were recrystallized from ethyl acetate:hexane (10:1, 100 ml) to give the title compound (12.8 g) as white crystals,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:31][C:12]3=[N:13][C:14]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:32](C(OC(C)(C)C)=O)[CH2:33][C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:31][C:12]3=[N:13][C:14]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cc(N)cc(Br)c4)sc3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.5 %

Procedure:
To a solution of tert-butyl 4-(2-(3-amino-5-bromophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (30.0 mg, 0.059 mmol) in DMF (2 ml) are added Boc-Gly-OH (20.7 mg, 0.118 mmol), HATU (45.0 mg, 0.118 mmol) and i−Pr2NEt (31 μl, 0.177 mmol). The mixture is stirred at room temperature for 2 h. EtOAc (10 ml) is added and the solution is washed with H2O and brine. The organic layer is dried over Na2SO4. After removing EtOAc, the residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/20 gradient) to give the desired product (33 mg, 84%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:20][CH2:21][C:22]([C:24]([O:26]C)=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:20][CH2:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 90 °C
Yield: 93.7 %

Procedure:
To a solution of methyl 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (720 mg) in THF (25 ml) and methanol (25 ml) was added a 1 N aqueous sodium hydroxide solution (6.4 ml), and the mixture was heated at 90° C. for 3 hours. After cooling to 0° C., water was added thereto, and the mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was washed with hexane to give 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylic acid (654 mg) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[C:16]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CCC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and propionylchloride
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:7]=1[CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH2:2][CH2:3][CH3:4]>Cl.C(O)(=O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:7]=1[CH2:26][N:27]1[C:28](=[O:37])[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]1=[O:36])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)OCC)c(=O)c2cc(Cl)c(Cl)cc12
Agent: Cl
Solvent: CC(=O)O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)O)c(=O)c2cc(Cl)c(Cl)cc12
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of ethyl 3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2 (1H)isoquinolinyl]propionate (1.36 g, 2.5 mmol) in 6N hydrochloric acid (15 ml) and acetic acid (15 ml) was refluxed with stirring for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]propionic acid (1.08 g, 83.7%) as crystals.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][N:16]1[CH2:21]CC[C:18](=O)[CH2:17]1.N>CO>[CH3:15][N:16]1[CH2:17][CH2:18][C:6]2[C:7](=[N:2][CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=2)[CH2:21]1
Reactant: CN1CCCC(=O)C1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CN1CCc2cc([N+](=O)[O-])cnc2C1
Temperature: 60 °C

Procedure:
A mixture of 400 mg (2.0 mmol) 1-methyl-3,5-dinitro-pyridone, 300 mg 1-methyl-piperidin-3-one and 15 ml 2M ammonia in methanol are heated to 60° C. for 20 h. It is concentrated and purified by chromatography (silica gel, CH2Cl2/MeOH 98/2).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23](O)=[O:24])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>ClCCl.CO>[OH:37][CH:35]([CH3:36])[CH2:34][NH:33][C:23]([C:21]1[S:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)(=[O:12])=[O:13])=[CH:32][C:19]=2[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: CC(O)CN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(O)CNC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 17 %

Procedure:
According to Step 1 after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 1-amino-2-propanol (0.027 mL, 0.35 mmol) and subsequent chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)), the desired compound is obtained at 17% yield (2 mg).
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42]>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][C:9]1[N:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Reactant: Oc1ccccc1F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 60 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 2-fluorophenol gave 64 mg (100%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:20])(=[O:3])[CH3:2].[N:21]#[C:22][NH2:23]>>[C:1]([N:4]1[C@H:5]([CH3:20])[CH2:6][N:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:22]([NH2:23])=[NH:21])=[CH:13][CH:12]=2)[C@@H:8]([CH3:10])[CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](C)N(c2ccc([N+](=O)[O-])cc2)C[C@H]1C
Reactant: N#CN
Product: CC(=O)N1C[C@H](C)N(c2ccc(NC(=N)N)cc2)C[C@H]1C
Temperature: 95 °C

Procedure:
The title compound was prepared from (2R,5S)-1-acetyl-2,5-dimethyl-4-(4-nitrophenyl)piperazine (Method 30, 6.5 g, 26.29 mmol) and cyanamide (2.43 g, 57.84 mmol) by the procedure of Method 31 and heating for 10 h at 95° C. The bicarbonate salt was dried in vac oven at 60° C. overnight. It was obtained as a solid (10.23 g, >100% contaminated with solvent). M/z 290.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[C:6]([S:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:14])=[O:13])[C:5]=1[SH:20].Br[CH2:22][Cl:23]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:3][C:4]1[C:5]([S:20][CH2:22][Cl:23])=[C:6]([S:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:13])=[O:14])[CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: CCN(CC)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1S
Reactant: ClCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: CCN(CC)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1SCCl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a slurry of 1.63 grams (0.025 mole) of finely powdered potassium hydroxide (85 percent) in 150 milliliters of bromochloromethane were added 8.72 grams (0.025 mole) of 2,3,4-trichloro-6-((diethylamino)sulfonyl)benzenethiol. To this mixture, 0.40 gram of benzyltriethyl ammonium bromide, was added and the temperature rose from 26° to 30° C. over 20 minutes. The reaction mixture was cooled to room temperature and stirred at this temperature for 2 hours. The reaction mixture was thereafter heated at the reflux temperature of the mixture for 0.5 hour and then cooled to room temperature. The mixture was filtered to remove the potassium bromide by-product produced and then the bromochloromethane was removed from the filtrate, under reduced pressure, leaving a light orange solid as a residue. The residue was recrystallized from diethylether to give 4.2 grams of 3,4,5-trichloro-N,N-diethyl-2-((chloromethyl)thio)benzenesulfonamide as a cream colored solid which melted at 82°-83° C. Hexane was added to the ether filtrate, and the resulting solution concentrated to give an additional 4.1 grams of the desired product. The additional product melted at 81°-82° C. and the combined total yield of the product was 83 percent of theoretical. Upon analysis, the product was found to have carbon, hydrogen, chlorine, nitrogen and sulfur contents of 32.60, 3.17, 35.20, 3.85 and 17.38 percent, respectively, as compared with the theoretical contents of 33.26, 3.30, 35.71, 3.52 and 16.15 percent, respectively, calculated for the above named structure.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:20]([O-])=O)=[CH:4][CH:3]=1.N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])[C:7]=1[NH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(Cl)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(p-chloroanilino)-3-nitro-5-sulphamyl-benzoic acid (7.43 g), water (50 ml), and concentrated aqueous ammonia (15 ml) was stirred at 25°C, and a solution of sodium dithionite (13.5 g) in water (50 ml) was added dropwise. After 1 hour, the pH of the reaction mixture was adjusted to 2.5, and the precipitated reaction product was filtered off. After repeated recrystallizations from aqueous ethanol, and after drying for 4 hours in vacuo, 3-amino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid was obtained with a melting point of 273°-274°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([F:27])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.C(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)CCC.O>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:22]1[C:23]([F:27])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Nc2nc(Cl)ncc2F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In a pressure tube 2-(benzyloxy)-5-nitroaniline (0.65 g), 2,4-dichloro-5-fluoropyrimidine (0.66 g) and DIPEA (0.69 g) were taken in n-butanol (10 mL). The reaction mixture was heated at 120° C. for 24 hr. The reaction was monitored on TLC using DCM: hexane:ethyl acetate (3:5:2) as mobile phase. The reaction was complete after 24 h. After completion, reaction mixture was allowed to cool at room temperature. The reaction was poured into water and extracted with ethyl acetate (3×25 mL). The ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure at 40° C. Crude material was purified by triturating with diethyl ether to give 0.25 g of N-(2-(benzyloxy)-5-nitrophenyl)-2-chloro-5-fluoropyrimidin-4-amine. M+1=374.8.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]#[N:40]>>[OH:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[NH:19][S:20]1(=[O:21])=[O:22])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]#[N:40]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: N#CCc1ccccc1CI
Product: N#CCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (2-iodomethylphenyl)-acetonitrile analogous to Example 310, steps C, D and E. (M−1)−=356. HPLC retention time=0.93 min (Method A).
Reaction SMILES: [CH2:1]([O-:4])[CH2:2][CH3:3].[Na+].[Na].C(O)CC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[N:13]=1>CCOC(C)=O>[Br:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:4][CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: CCC[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCOc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a sodium propan-1-olate solution, prepared by addition of sodium (36 mg, 1.58 mmol) to propanol (1 mL), was added 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 189 mg of Intermediate 161.1 as a colorless oil. LCMS (2 min gradient) RT=1.82 min, 216.1 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>[Cl-].[Zn+2].[Cl-]>[C:18]([O:21][CH:4]1[C:5]2=[N:12][C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:1]2[CH2:2][CH2:3]1)(=[O:20])[CH3:19]
Reactant: O=[N+]([O-])c1cnc(N2CCCC2)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OC1CCn2c1nc1cc([N+](=O)[O-])cnc12
Temperature: 0 °C

Procedure:
A mixture of 1 g (4.2 mmol) of 2-(pyrrolidin-1-yl)-3,5-dinitropyridine (Org. & Biomol. Chem. 2003, 1(6), 1004-1011) and 0.584 g (4.2 mmol) of zinc chloride in 10 ml of acetic anhydride is heated at reflux for six hours. After this time a further 0.584 g (4.2 mmol) of zinc chloride are added and the stirring at reflux is maintained for eighteen hours. After this time the mixture is poured onto 100 g of ice and then extracted with three times 50 ml of ethyl acetate. The organic phases are combined and then washed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water and then once with 50 ml of saturated sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on a silica column, eluting with a mixture of ethyl acetate and n-heptane. The resulting product is recrystallized from a mixture of diisopropyl ether and isopropanol. This gives 0.29 g of the expected compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>>[C:11]1([CH2:15][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[S:10][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccs1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NCc2cccs2)cc1
Yield: 37.8 %

Procedure:
The procedure of Example 40 was repeated, except that 1.43 g of 4-aminobenzonitrile was used in place of aniline, and 1.57 g of 2-thiophenecarbaldehyde was used in place of 4-formyl-phenyl sulfamate. The resulting crude product was purified by silica gel column chromatography (using a 2:1 mixture of hexane and ethyl acetate as the eluent) to obtain 0.98 g of 4-[N-(2-thenyl)amino]-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37])#[N:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH:17][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([C:31]#[N:32])[CH:34]=3)[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](N)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)c1cccc(C#N)c1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (20 mg, 0.059 mmol) in CH2Cl2 (0.60 mL) was treated with Et3N (0.011 mL, 0.077 mmol), m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (0.75 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL) and dried by filtration through a PTFE membrane. Concentration afforded the 1-(4-chlorobenzyl)-4-[{N-(3-cyanobenzoyl)valyl}aminomethyl]piperidine (compound No. 619) (24.2 mg, 88%) which required no further purification: The purity was determined by RPLC/MS (85%); ESI/MS m/e 467 (M++H, C26H30ClN4O2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[C:24]([NH:27][CH2:28][CH2:29][NH2:30])(=[O:26])[CH3:25]>>[C:24]([NH:27][CH2:28][CH2:29][NH:30][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CC(=O)NCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 67 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using N-acetylethylendiamine instead of 2-aminoethyl isopropylether, to the title compound (170 mg, 67%) which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](O)=O)=[N:12]1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=2)=[N:12]1
Reactant: CCOC(=O)C(N)=NO
Reactant: Cc1cc(C(=O)O)nn1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2cc(C)n(C)n2)n1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (95%, 3.78 mmol, 0.530 g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were suspended in DCM (70 ml) under nitrogen atmosphere. The mixture was stirred at RT for a day. The solvent was evaporated and pyridine was added to the residue. The resulting mixture was refluxed for 6 h and stirred at RT overnight. Pyridine was evaporated and the residue diluted with DCM and water. The phases were separated and the water phase was extracted four times with DCM. The combined organics were washed with aqueous HCl solution, saturated NaHCO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.285 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.43 (t, 3H), 2.30 (s, 3H), 4.23 (s, 3H), 4.49 (q, 2H), 6.96 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:19][NH:20][CH3:21]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9]([N:20]([CH3:21])[CH3:19])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1OCC
Solvent: CC#N
Product: CCOC(=O)c1cnc(N(C)C)nc1OCC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Ethoxy-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (60 mg, 0.22 mmol) was dissolved in acetonitrile. Dimethylamine (0.6 mL, 2.0 M in methanol) was added and reaction mixture was stirred in seal tube at 80° C. for 3 h. The reaction progress was checked by LC-MS. After the reaction was completed, it was concentrated to give 2-dimethylamino-4-ethoxy-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50 mg). LR-MS: 239 [(M+H)+]