Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:17]([O:19][C:20]1[C:29]([O:30][CH2:31][CH3:32])=[C:28]([O:33][CH2:34][CH3:35])[C:27]([N+:36]([O-:38])=[O:37])=[C:26]2[C:21]=1[CH2:22][O:23][C:24]2=[O:25])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]1[CH:22]1[C:21]2[C:26](=[C:27]([N+:36]([O-:38])=[O:37])[C:28]([O:33][CH2:34][CH3:35])=[C:29]([O:30][CH2:31][CH3:32])[C:20]=2[O:19][CH2:17][CH3:18])[C:24](=[O:25])[O:23]1
Reactant: COc1cc2c(cc1OC)CC[N+](C)=C2
Reactant: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2cc(OC)c(OC)cc2CCN1C

Procedure:
200 g (0.6 mole) of 2-methyl-6,7-dimethoxy-3,4-dihydro-isoquinolinium iodide (prepared in the same manner as the compound of Example A) 186 g of 4,5,6-triethoxy-7-nitrophthalide and 100 g of potassium carbonate are added to 1.5 l of methanol while stirring. The reaction mixture is stirred for 24 hours at a temperature below the boiling point of the solvent, and is then allowed to cool; 900 ml of water is added and the reaction solution is allowed to crystallise. The solution is filtered, rinsed with methanol, and then with water.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 20 °C

Procedure:
To a cooled (−5-0° C.) solution of ethyl 2,4-difluorobenzoate (3.4 g; 18.3 mmol) in conc. sulphuric acid (6 ml) was added potassium nitrate (1.94 g; 19.2 mmol) in small portions over one hour −5° C. Following the addition the temperature was allowed to raise to 20° C. over 4.5 hours. The mixture was poured into ice-water with vigorous stirring. The product was filtered off, washed with water and air-dried. Yield: 3.2 g (76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16].[CH3:17][N:18]=[C:19]=[S:20]>O>[CH3:17][NH:18][C:19]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16])=[S:20]
Reactant: CN=C=S
Reactant: Cc1cc(C)c2ccc(=O)n(CCN)c2n1
Solvent: O
Product: CNC(=S)NCCn1c(=O)ccc2c(C)cc(C)nc21

Procedure:
A mixture of the free base of 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (700 mg., 0.0032 mole) as prepared in Example 12 and methyl isothiocyanate (180 mg., 0.004 mole) in 5 ml. of water is heated at reflux for 30 minutes. On cooling the reaction, the product is collected by filtration. After recrystallization from methanol, 1-{2-[(N-methylthiocarbamoyl)amino]ethyl}-5,7-dimethyl-1,8-naphthyridin-2(1H)-one m.p. 216.5°-218° C. is obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[C:23]([Cl:25])[C:20]([C:21]#[N:22])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[N:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:25][C:23]1[C:20]([C:21]#[N:22])=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=2)[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:15]=2)[CH:24]=1
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1c(Cl)cc(-c2ccc(NC(=O)c3ccccc3)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
Benzoyl chloride (10 μL, 0.086 mmol was added to a mixture of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (13 mg, 0.033 mmol, from Step 3 of Example 199) and Hunig's base (30 μL, 0.172 mmol) in dichloromethane (0.6 mL). After 16 h at room temperature, the reaction was complete as judged by LCMS analysis. Silica gel chromatography, eluting with 0-50% ethyl acetate in hexanes, gave N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)benzamide as yellow solid (17.6 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (2H, δ, J=8.53 Hz), 8.02-8.06 (2H, m), 7.97 (1H, s), 7.91 (2H, δ, J=7.28 Hz), 7.80-7.87 (3H, m), 7.57-7.63 (1H, m), 7.53 (2H, t, J=7.40 Hz), 7.38-7.44 (2H, m), 7.19 (1H, t, J=7.40 Hz), 7.09-7.17 (4H, m); MS (ES+) m/z: 502 (M+H); LC retention time: 4.923 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[C:9]([N:13]1[CH:21]=[C:20]2[C:15]([C:16](=[O:40])[NH:17][C:18]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][C:35](Cl)=[N:36]5)=[CH:31][CH:30]=4)=[O:28])[CH2:23][CH2:22]3)[CH2:19]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[CH:21]=[C:20]2[C:15]([C:16](=[O:40])[NH:17][C:18]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][C:35]([N:2]([CH3:3])[CH3:1])=[N:36]5)=[CH:31][CH:30]=4)=[O:28])[CH2:23][CH2:22]3)[CH2:19]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CNC
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2
Solvent: C1CCOC1
Product: CN(C)c1ccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc2n1
Temperature: 70 °C
Yield: 25 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2.2 mL, 4.4 mmol, 2.0 M) was added to 2′-tert-butyl-1-(2-chloroquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (100 mg, 0.2 mmol). The reaction vessel was sealed and the mixture was heated to 70° C. for 15 hours. The reaction was cooled to room temperature and concentrated. Purification by reversed-phase HPLC gave the title compound (25 mg, 25%). +ESI (M+H) 461.2; HPLC retention time 1.96 minutes (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:12][CH2:22][O:23][CH3:24])=[CH:4][C:5]=1[CH:9]([CH3:10])[CH3:11]
Reactant: COCCl
Reactant: CC(C)c1cc(O)c(Br)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1cc(C(C)C)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol) in chloroform (1.74 L), N,N-diisopropylethylamine (364 mL, 2.09 mol) was added, and cooled on ice. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and a 1M aqueous solution of sodium hydroxide (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with a 1M aqueous solution of sodium hydroxide (1.5 L) and water (1.5 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under reduced pressure (0.93 to 1.5 hpa, 122° C. to 137° C.) to give 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (548 g, 96%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)s1

Procedure:
Following the procedure of Example 32, 2.07 g (10.0 mmoles) of commercially available 5-bromo-2-thiophenecarboxylic acid was reacted with 10 ml of thionyl chloride to give 2.35 g of crude 5-bromo-2-thiophenecarbonyl chloride as a red oil. The total crude acid chloride was coupled to 1.76 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide by the procedure in Example 32 using 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 50 ml of N,N-dimethylformamide. Acidic workup gave a solid which was recrystallized to give 1.77 g (4.43 mmoles, 53% yield) of title compound as reddish-brown crystals, m.p. 228°-229° C (tetrahydrofuran).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(OCC)(=O)C>[N+:24]([C:16]1[CH:17]=[CH:18][C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:14]=2[CH:15]=1)([O-:26])=[O:25]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a cooled (0° C.) solution of trifluoroacetic acid (67.2 ml, =869.38 mmol), 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (18 g, 122.44 mmol) was added drop-wise over a period of 20 min. To this, concentrated sulphuric acid (23.4 ml, 440.78 mmol) was added over a period of 45 min at 0° C., and the mixture was stirred for an additional 30 minutes. To this reaction mixture, concentrated nitric acid (8.1 ml, 192.23 mmol) was added drop-wise at 0° C. over a period of 1 h, followed by stirring at room temperature for 2 h. To the reaction mixture, ethyl acetate (250 ml) was added drop-wise at 0° C. The resulting precipitate was filtered and washed with ethyl acetate (100 ml). The crude solid product was added to chloroform (250 ml), washed with 10% sodium hydroxide solution (150 ml), dried over Na2SO4, and concentrated to give the sub-title compound as a light yellow solid (17.4 g). 1H NMR (300 MHz, DMSO-d6) δ 7.99-7.93 (m, 2H); 7.38 (d, J=8.1 Hz, 1H); 2.98-2.94 (m, 4H); 2.79-2.76 (m, 4H); MS: ESI (positive): 193 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CS(C)=O.[CH2:15]([SH:17])[CH3:16].CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][CH2:15][CH3:16])=[CH:7][CH:6]=1
Reactant: N#Cc1nc(Cl)ccc1Cl
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Cl)nc1C#N
Temperature: 20 °C
Reaction time: 40 h
Yield: 31 %

Procedure:
In a reaction flask with condenser, mechanical stirrer, thermometer and dropping funnel were placed 53.4 g of 3,6-dichloro-2-pyridinecarbonitrile and 300 ml of DMSO. The mixture was chilled to about 10°-15° C. and then 19.8 g of ethanethiol was added. While maintaining the temperature at <20° C., 34.8 g of t-BuOK in 300 ml of THF was added in small portions. After the addition was complete, the reaction mixture was warmed to 20° C. and stirred for about 40 hrs. The reaction mixture was then poured onto about 2 kilograms (kg) of ice, stirred and filtered leaving a solid residue. The residue was washed with water, dissolved in CH2Cl2, dried over MgSO4, concentrated and diluted with hexane to give 19.0 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile. The filtrate was concentrated and separated on a Water's Prep LC 500 instrument using 15% ethyl acetate in hexane to give another 10.1 g of the same isomer. Total yield of 6-chloro-3-ethylthio-2-pyridinecarbonitrile was 29.1 g (46.5%), m.p. 79°-81° C. Further separation on the Prep LC 500 instrument gave a small amount of 3-chloro-6-ethylthio-2-pyridinecarbonitrile (m.p. 46°-48° C.) and 3,6-bis-ethylthio-2-pyridinecarbonitrile (m.p. 63°-64° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].Cl>O1CCCC1>[Cl:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:23]
Reactant: COc1ccc(C)c(N)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 27 h

Procedure:
To a solution of 2-methyl-5-methoxyaniline (4.7 g) in tetrahydrofuran (50 ml), under nitrogen, was added diisopropylethylamine (12.6 ml) followed by dropwise addition of chloroacetyl chloride (2.7 ml) and the mixture stirred under nitrogen for 27 hours. The solution was poured into 2M aqueous hydrochloric acid (150 ml), extracted into diethyl ether (3×150 ml), washed with brine, dried (MgSO4), and concentrated to give the sub-title compound as a brown oil (5.15 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])([O:3]C(C)(C)C)=O.[C:18]([NH:25][C@H:26](C(O)=O)[CH2:27][OH:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(Cl)Cl.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C>[NH:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:26]([C:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:3])[CH2:27][OH:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 6 h

Procedure:
2 g of the Boc-Gln Resin obtained in Step 4 is put in 160 ml of acetic acid and allowed to stand for 6 hours at room temperature. The mixture is filtered with a glass filter. The cake is put in 160 ml of acetic acid, agitated and filtered. This operation is repeated three times. Then, the cake is agitated in 160 ml of 1N aqueous HCl/acetic acid at room temperature for half an hour to remove the Boc group from the resin. The resulting product is filtered off, washed with three portions of each of acetic acid, ethanol and dimethylformamide successively, and agitated in 160 ml of a 10% by weight solution of triethylamine in dimethylformamide to effect neutralization reaction. The resulting product is filtered off and washed with each of dimethylformamide and methylene chloride. The product is immersed in a solution made by adding 2 mmol of Boc-serine (Bzl) to 12 ml of methylene chloride, and agitated. Ten minutes later, a solution made by adding 20 mmol of dicyclohexyl carbodiimide to 60 ml of methylene chloride is added to the mixture and agitated at room temperature for 2 hours to effect coupling reaction. The resulting product is filtered off and washed with each of methylene chloride and ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:26])[CH2:39][CH2:38][CH2:37]1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: C1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCC4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and azetidine hydrochloride (Aldrich, Cat. No. 414336). LCMS (M+H)+: m/z=499.2.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.32 (m, 4H), 7.21-7.15 (m, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (dd, J=10.0, 9.1 Hz 1H), 3.77-3.70 (m, 1H), 3.54 (dd, J=10.1, 6.8 Hz, 1H), 2.45 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (19.3 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.32 g (23.2 mmol) piperazine 1-carboxylic acid tert-butyl ester using 9.86 mL (57.9 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure. The residue is purified via NP-chromatography (DCM/MeOH 75/25 as eluent) yielding 7.2 g (92%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:3][CH:2]=1.CS[C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C.C1(C)C(C)=CC=CC=1>[N+:15]([CH:14]=[C:13]1[NH:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[O:10]1)([O-:17])=[O:16]
Reactant: NCC(O)c1ccccc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Yield: 56.5 %

Procedure:
In a mixture of 60 ml of ethanol and 200 ml of xylene was dissolved 40 g of DL-β-hydroxyphenethylamine, and the resulting solution was added dropwise to a solution of 57.8 g of 1,1-bis(methylthio)-2-nitroethene in 600 ml of xyelene under reflux over a period of 1.5 hours to effect reaction. During the reaction, the low-boiling fractions were gradually removed by distillation and the reaction temperature was maintained at 130° C. to 140° C. After completion of the reaction, crystals were deposited with stirring under ice-cooling. The crystals deposited were collected by filtration, dried, and then mixed with 200 ml of a 5% (by weight) aqueous sodium hydroxide solution. After a slight amount of insolubles were removed by filtration, the filtrate was adjusted to pH 6 with a 10% (by weight) aqueous acetic acid solution, and the crystals deposited were collected by filtration and dried to obtain 34 g of 2-nitromethylene-5-phenyloxazolidine having a melting point of 139°-141° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC(OC)=CC=3)=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(-c3nnc([C@H](Nc4ccc(C#N)c(Cl)c4C)[C@H](C)O[Si](C)(C)C(C)(C)C)o3)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.8 %

Procedure:
A 250 mL round bottomed flask was charged with 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(4-methoxybenzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.76 g, 2.84 mmol), methylene chloride —H2O (20:1, 80 mL) and 2,3-Dichloro-5,6-Dicyanobenzoquinone (3.87 g, 17.05 mmol). The reaction mixture was stirred at room temperature for 36 h and a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added followed by methylene chloride (70 mL). The phases were partitioned and the aqueous phase extracted with methylene chloride (60 mL) (×3). The combined organic extracts were dried (Na2SO4) and concentrated to furnish a white solid (1.33 g, 91%). 1H NMR (500 MHz, acetone d6, δ in ppm) δ 9.17 (br s, 1H), 7.85 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.99 (d, J=9 Hz, 2H), 6.84 (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.52 (d, J=9 Hz), 5.18 (dd, J=2 and 9 Hz, 1H), 4.74-4.68 (m, 1H), 2.41 (s, 3H), 1.46 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.1 (s, 3H) and −0.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9]C)=[O:8].O[Li].O>CO.O>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Methyl 3-chloro-1H-pyrrole-2-carboxylate (18.86 mmol, 1.0 equiv.) was dissolved in MeOH—H2O (2:1, 120 ml); at 0° C., LiOH.H2O (75.4 mmol, 4 equiv.) was added and the mixture was stirred for 16 h at 25° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (60 ml) and extracted with ethyl acetate (2×50 ml). The aqueous phase was adjusted to pH 3-4 with 1 M HCl, and the resulting solid was filtered out. Yield: 90%
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:14][CH2:13][CH2:12][O:11]1>CC(C)=O>[CH2:1]([N:17]1[CH2:18][CH2:19][CH:20]=[C:15]([C:10]2([CH3:9])[O:11][CH2:12][CH2:13][O:14]2)[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccnc2)OCCO1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CC1(C2=CCCN(Cc3ccccc3)C2)OCCO1
Reaction time: 1 h

Procedure:
Benzyl bromide (9.8 ml) was added to a solution of 2-methyl-2-(pyridin-3-yl)-1,3-dioxolane (13.6 g) in acetone (140 ml) and the mixture was refluxed. After confirming the disappearance of the starting material, the acetone was distilled off under reduced pressure. The residue was dissolved in ethanol (140 ml) and while the solution was ice-cooled, sodium borohydride (3.12 g) was gradually added. After the mixture was stirred for 1 hour, water and ethyl acetate were added. The mixture was stirred and, then, allowed to stand. The aqueous layer was separated and extracted with 2 portions of ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (7.86 g).