Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To 551 mg methyl 6-[(tert-butoxycarbonyl)amino]-1H-indole-2-carboxylate dissolved in 15 mL dichloromethane was added 5 mL trifluoroacetic anhydride, and the mixture stirred at room temperature for 1.5 h. P The mixture was partitioned between dichloromethane and 1 N sodium hydroxide until neutral, dried over magnesium sulfate and concentrated. Obtained 360 mg of the crude methyl 6-amino-1H-indole-2-carboxylate. To 200 mg (1.05 mmol) of crude product dissolved in 5 mL dichloromethane and 340 □L pyridine at 0° C. was added 81 □L methanesulfonyl chloride. The mixture was stirred at 0° C. for 1 h, was partitioned between dichloromethane and 1 N hydrochloric acid until neutral, was dried over magnesium sulfate and concentrated to obtain 333 mg of methyl 6-[(methylsulfonyl)amino]-1H-indole-2-carboxylate as crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>C(O)(C)C>[NH2:9][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:17]2[CH2:16][CH2:15][C:14]3([CH2:10][N:11]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]3)[CH2:19][CH2:18]2)[N:5]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4,6-dichloro-1,3,5-triazin-2-amine (1.6 g) in isopropanol (14 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.28 g, 3.7 mmol) and Et3N (7 mL). The solution was heated to reflux for 72 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH=50/1) afforded 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][C:39]([NH2:43])=[N:40]2)=[CH:35][CH:34]=1>>[NH2:43][C:39]1[CH:38]=[C:37]([N:44]2[CH2:49][CH2:48][N:47]([C:11]([NH:1][C:2]3[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=3)=[O:12])[CH2:46][CH2:45]2)[C:36]2[C:41](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cccc(N)c1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cccc(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)c1=O

Procedure:
As described for example 78, 3-amino-1-methyl-2-pyridone, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 413 (M++1). 1H NMR (CDCl3) δ 8.15 (dd, 1H), 8.02 (s, 1H), 7.74 (d, 1H), 7.65 (s, 1H), 7.20 (dd, 1H), 6.95 (dd, 1H), 6.25 (m, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.80 (m, 4H), 3.62 (s, 3H), 3.20 (m, 4H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light yellow foam (20%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46]
Reactant: CN(C)CCCO
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 3-dimethylamino propanol (31.6 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 133 as an off-white solid in 25.4% yield. LCMS m/z (%)=464 (M+H 35Cl, 100), 466 (M+H 37Cl, 39). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.47 (s, 1H), 8.07-8.01 (m, 1H), 7.62 (s, 1H), 7.51 (d, J=8.90 Hz, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, J=9.02 Hz, 1H), 7.03-6.97 (m, 1H), 4.11-3.94 (m, 2H), 3.63 (s, 3H), 2.28-2.18 (m, 2H), 2.11 (s, 6H), 1.78-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Br:9][C:10]1[N:11](C)[C:12]([C:16](=[O:19])[CH2:17]Br)=[CH:13][C:14]=1[Br:15].[CH2:21](N(CC)CC)C>C(O)C>[Br:15][C:14]1[CH:13]=[C:12]([C:16]([CH:17]([N:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]2=[O:8])[CH3:21])=[O:19])[NH:11][C:10]=1[Br:9]
Reactant: Cn1c(C(=O)CBr)cc(Br)c1Br
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(C(=O)c1cc(Br)c(Br)[nH]1)n1cc(Cl)cnc1=O
Temperature: 25 °C

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2,3-dibromo-5-bromoacetyl-1-methylpyrrole (1.24 g) in triethylamine (0.84 ml) and ethanol (35 ml) was stirred at room temperature. After 1.25 h the reaction mixture was cooled in ice and the white precipitate collected and washed with cold ethanol. The dried solid was crystallised twice from ethanol and then from ethyl acetate to give the title pyrimidinone (510 mg) m.p. 229°-232° C., λmax (EtOH) 227 nm (ε9,750), 249 nm (ε9.540), 301.5 nm (ε16,910).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)(=[O:7])[CH3:6].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(OCC)(=O)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:1]([N:12]1[C:11]([CH3:18])([CH3:17])[CH2:10][CH:9]([O:8][C:5](=[O:7])[CH3:6])[CH2:14][C:13]1([CH3:16])[CH3:15])=[O:2])[CH3:20]
Reactant: CCNCC
Reactant: CC(=O)OC1CC(C)(C)NC(C)(C)C1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)N1C(C)(C)CC(OC(C)=O)CC1(C)C

Procedure:
A solution of 24.7 g (0.25 mol) of phosgene in about 150 ml of ethyl acetate is added dropwise to a solution of 99.7 g (0.5 mol) of 4-acetoxy-2,2,6,6-tetramethylpiperidine in 400 ml of ethyl acetate at 20°-22° in the course of 6 hours, with stirring. After the reaction mixture has been stirred for another 2 hours at room temperature, 63 ml (0.6 mol) of diethylamine are added dropwise in the course of about 30 minutes. The reaction mixture is stirred at room temperature for another 14 hours and is filtered and the salt residue is washed thoroughly with hexane. The combined filtrates are washed twice with water, three times with ice-cold N hydrochloric acid and again with water and dried over sodium sulfate and the solvent is distilled off in a vacuum rotary evaporator. The crude product is recrystallised from diisopropyl ether to give pure 1-diethylcarbamoyl-4-acetoxy-2,2,6,6-tetramethylpiperidine (Compound No. 1) of melting point 58° -60°.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][CH2:27][O:26][CH3:25])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: COCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 71 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 32 mg, 0.23 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium bicarbonate solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-80% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (42 mg, 43%) as an off white solid: HR-ES(+) m/e calcd for C23H27N4O3F3 [M+H]+ 465.2108, observed 465.2107; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-2.18 (m, 10H), 3.20 (s, 3H), 3.51-4.28 (m, 4H), 4.60-5.34 (m, 3H), 6.40 (d, J=1.81 Hz, 1H), 7.41-8.28 (m, 5H), 10.93 (s, 1H).
Reaction SMILES: C1([NH:7][NH:8][C:9]2[S:10][CH2:11][CH2:12][N:13]=2)C=CC=CC=1.N1C=CC=CC=1.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:26]1([CH2:32][C:33]([NH:7][N:8]([C:9]2[S:10][CH2:11][CH2:12][N:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(NNC2=NCCS2)cc1
Reactant: c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)NN(C1=NCCS1)c1ccccc1

Procedure:
To a solution of 2.0 g. of 2-(phenylhydrazino)-2-thiazoline in 10 ml. of dry pyridine and 20 ml. of dry benzene is added dropwise 2 ml. of phenyl acetyl chloride. The resulting mixture is heated at 60°-70° C. for 30 minutes and poured into 200 ml. of water. The benzene layer is separated and the aqueous solution washed once with 20 ml. of benzene. The combined benzene solutions are washed with water and 5% sodium carbonate solution and dried with anhydrous magnesium sulfate. The benzene is evaporated to dryness and hexane is added to the residue and the resulting suspension is filtered. The solid material is washed with hexane and recrystallized from a mixture of ethyl acetate and hexane affording 2-(2-phenylacetyl-1-phenylhydrazino)-2-thiazoline, m.p. 121°-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14]3[N:13]=[CH:12][CH:11]=[C:10](OC)C=3C(=O)[N:7]([CH:19]3[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:35][NH2:36].[CH2:37]([OH:39])[CH3:38]>>[Cl:1][C:2]1[C:15]2[C:14]3[N:13]=[CH:12][CH:11]=[C:10]([NH:36][CH3:35])[C:38]=3[C:37](=[O:39])[N:7]([CH:19]3[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccnc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(Cl)c21
Reactant: CN
Reactant: CCO
Product: CNc1ccnc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(Cl)c21

Procedure:
To 0.005 g (0.01 mmols) of a compound from Example 696 was combined with 1.0 ml of aqueous methylamine 40% (excess) in ethanol (5 ml). The reaction was refluxed for 30 minutes. MS(ES+)m/z475.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.[NH2:12][NH2:13]>>[NH:12]([C:1](=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Solvent: O
Product: CCOC(=O)C(=O)NN
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of diethyl oxalate (9-1) (6.0 g, 41.04 mmol) in alcohol (30 mL) was added hydrazine hydrate (2.4 mL, 49.26 mmol) dropwise at −20° C. After the addition was over, the solution was stirred for 30 min. The solution was filtered and the filtrate was evaporated to give the product as a white solid (3.0 g, 55%). The compound was used for the next step directly without further purification. LRMS (ESI) calculated M+H for C4H9N2O3: 133.1. Found: 133.3.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].O=P(Cl)(Cl)Cl>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Temperature: 80 °C

Procedure:
The crude 5-nitro-2-trifluoromethyl-pyridin-4-ol (3.4 g, 16.3 mmol) was treated with PCl5 (5.2 g, 24.97 mmol) and POCl3 (7 mL, 24.49 mmol). The resulting mixture is heated at 80° C. for 18 h, cooled and poured into ice-cold water, and extracted with CH2Cl2. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 4-Chloro-5-nitro-2-trifluoromethyl-pyridine as an yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1H), 7.9 (s, 1H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1>>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:34]=[CH:35][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc2ccccc2n1
Reactant: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Product: NC(=O)c1cnc(-c2cnc3c(Nc4cnc5ccccc5n4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(8-chloropyrido[2,3-b]pyrazin-3-yl)-5-(trifluoromethyl)nicotinamide (70.6 mg, 0.2 mmol) and 2-aminoquinoxaline (85.8 mg, 0.6 mmol) in a screw cap vial at 140° C. for 20 hours under N2 atmosphere. Purify the reaction mixture by column chromatography using 1-2% MeOH/EtOAc as eluent to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.017 (s, 1H), 9.461 (s, 2H), 9.335 (d, 1H, J=1.1 Hz), 9.307 (s, 1H), 9.129 (d, 1H, J=1.3 Hz), 8.836 (s, 1H), 8.557(s, 1H), 7.975 (m, 3H), 7.789 (t, 1H), 7.647(t, 1H). MS=463.12 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: COC(=O)c1c(C)sc(C)c1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: Cc1sc(C)c2c(=O)n3cc(C(N)=O)ccc3nc12
Temperature: 180 °C
Yield: 3.2 %

Procedure:
A mixture of 5 g (0.0226 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 3.5 g (0.0226 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot pyridine, cooled, the precipitate collected and dissolved in hot methanol, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.2 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with methanol (1:0.125); mp 272°-275° C. after recrystallization from methanol.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18].C>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: CCN
Solvent: O
Product: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Temperature: 150 °C

Procedure:
8-cyclopropyl-3-ethyl-2,6-dithioxanthine (20.19 g) prepared according to the method of example 2(i), and 70% ethylamine in water (320 ml 4.0M) were placed in a 450 ml pressure reactor and heated to 150° C. for 6 hours. The reaction solution was cooled to room temperature, treated with 2 portions of charcoal (0.2 g) filtered, and evaporated to dryness. The residue was triturated in methanol (300 ml), concentrated to about 200 ml, and the solid collected (16.48 g), mp 265° with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][OH:32])[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[N:13]=[C:14]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:15]=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][O:32][C:46](=[O:47])[NH:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCOC(=O)Nc1ccccc1
Reaction time: 16 h

Procedure:
A suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 3), 10 mg of DMAP and 25 μl of phenylisocyanate in 5 ml of chloroform was refluxed for 15 minutes under argon. 1.5 ml of DMF was added and stirring and heating was continued for 16 h. The clear solution was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2×50 ml of water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting first with hexane:ethyl acetate 1:1, then with DCM containing 4% of methanol to give 47 mg of phenylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a slightly yellow solid. LC-MS: tR=4.80 min, [M+1]+=653.37, [M−1]−=651.33.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]([C:14]1[C:18]([CH3:19])=[CH:17][S:16][C:15]=1[C:20](OC)=[O:21])=[C:12]=[S:13]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:20](=[O:21])[C:15]4[S:16][CH:17]=[C:18]([CH3:19])[C:14]=4[NH:11][C:12]3=[S:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1scc(C)c1N=C=S
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: Cc1csc2c(=O)n(-c3ccc4[nH]cnc4c3)c(=S)[nH]c12

Procedure:
1H-benzo[d]imidazol-5-amine (0.13 g, 0.98 mmol) and methyl 3-isothiocyanato-4-methylthiophene-2-carboxylate (0.21 g, 0.98 mmol) were dissolved in 10 mL of THF. The mixture was stirred by heating under reflux over night. The solvent was removed and the product was purified by means of semi-preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[O:13][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of methyl 4-methoxysalicylate (176 mg, 0.97 mmol), the title C compound, 4-[2-(4-bromomethyl-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole (300 mg, 0.81 mmol) and potassium carbonate (334 mg, 2.42 mmol) in DMF (10 mL) is stirred at RT overnight. The mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel using 15% EtOAc in hexane as the eluent to give 4-methoxy-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid methyl ester.