Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@H:15]3[CH2:17][C@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[NH2:21][CH2:22][C:23]1([N:29]([CH3:31])[CH3:30])[CH2:28][S:26](=[O:27])[CH2:25][CH2:24]1>>[CH3:30][N:29]([CH3:31])[C:23]1([CH2:22][NH:21][C:18]([C:11]2[C:12]3[CH2:13][C@@H:14]4[CH2:17][C@@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH2:24][CH2:25][S:26](=[O:27])[CH2:28]1
Reactant: CN(C)C1(CN)CCS(=O)C1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@@H]1C[C@H]21
Product: CN(C)C1(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@@H]2C[C@H]32)CCS(=O)C1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 3 (see Example 1.3) and 3-(aminomethyl)-3-(N,N-dimethylamino)tetramethylene sulfoxide LCMS m/z=435.4 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 0.48-0.51 (m, 1H), 1.21-1.28 (m, 1H), 2.20-2.28 (m, 1H), 2.35-2.40 (m, 1H), 2.41 (s, 3H), 2.47 (s, 3H), 2.50-2.58 (m, 1H), 2.71-2.80 (m, 1H), 2.90-3.10 (m, 3H), 3.15-3.20 (m, 1H), 3.30-3.38 (m, 2H, buried), 3.56-3.85 (m, 2H), 7.19-7.26 (m, 1H), 7.29-7.37 (m, 1H), 7.75-7.83 (m, 1H).
Reaction SMILES: [H-].[Na+].[O-]CC.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([CH2:23][C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (15 mmol) is added to anhydrous ethanol (50 mL) and to the resulting sodium ethoxide solution is added 2-acetylaminomalonic acid diethyl ester (15 mmol) in one portion. The resulting mixture is stirred at room temperature for 30 minutes. A solution of 2-bromoacetophenone (10 mmol) in ethanol (10 mL) is then added and the resulting mixture is stirred at room temperature for 12 hours. After concentrating under reduced pressure, the residue is dissolved in EtOAc and water. The organic phase is washed with brine and dried over Na2SO4. After removal of the solvent, the crude material is purified by column chromatography using EtOAc/hexane (1/3) giving 2-acetylamino-2-(2-oxo-2-phenyl-ethyl)-malonic acid diethyl ester as white solid; MS: (ES+): 336.1 (M+1)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:4].[CH3:18]I>C1COCC1>[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:18])[CH3:4]
Reactant: CC(=O)SCCCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of NaH (0.57 g, 60%, 14.25 mmol) in 20 ml of THF at 0° C. was added S-3-(tert-butoxycarbonylamino)propyl ethanethioate (1.25 g, 5.36 mmol) under Ar. After stirring at 0° C. for 30 min, MeI (1.0 ml, 16.06 mmol) was added to the mixture. Stirring was continued at 0° C. for 2 h then RT overnight. The mixture was concentrated, redisolved in 120 ml of EtAc/Hexane (1:2), washed with 1 M NaH2PO4 NaCl (conc.), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1:7) to afford 1.121 g (85%) of the title compound. 1H NMR (CDCl3) 3.69 (t, 2H, J=7.3 Hz), 2.41 (t, 2H, J=7.3 Hz), 2.39 (s, 3H), 2.03 (s, 3H), 1.76 (m, 2H),1.47 (s, 9H); 13C NMR 173.21, 153.39, 83.28, 43.67, 31.84, 28.26, 28.19, 27.11, 15.65; MS m/z+ 270.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([SH:17])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1.[CH2:19](N(CC)CC)C.CI>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([S:17][CH3:19])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1
Reactant: Sc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CCO
Product: CSc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidine-7-thiol (1.29 g, 4.1 mmol) and triethylamine (1.66 g, 16.4 mmol) in ethanol (20 mL) was added methyl iodide (2.32 g, 16.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-20% EtOAc/hexane gradient to give the desired compound as a white solid (0.59 g, 44% yield). 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 7.49-7.47 (M, 2H), 7.45-7.40 (m, 1H), 2.81 (s, 3H). LCMS (ESI) m/z: 328.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4](Cl)[N:3]=1.[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(O)C.CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:14]2[CH3:13])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Solvent: CCO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2,6-dichloro-9-methyl-9H-purine (1.41 g, 6.96 mmol) and (S)-3-methylmorpholine (817 mg, 8.08 mmol, 1.16 eq.) in anhydrous ethanol (60 mL) and anhydrous DMF (5.0 mL) was added N,N-diisopropylethylamine (1.8 mL, 10.43 mmol, 1.5 eq.), and the reaction mixture was stirred at RT under N2 for 3 days. The reaction mixture was diluted with 1:1 v/v diethyl ether:ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 80% ethyl acetate in hexane) to give the desired compound (a-4) as a solid (1.59 g, 85.2%). 1H NMR (CDCl3, 500 MHz) δ ppm 7.65 (s, 1H), 5.34 (broad d, 2H), 3.99 (m, 1), 3.76 (m, 5H), 3.61 (ddd, 1H), 3.36 (broad s), 1H), 1.39 (d, 3H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[N:21]=[C:20]([N:22]4[CH2:27][C@H:26]5[CH2:28][CH:23]4[CH2:24][N:25]5C(OC(C)(C)C)=O)[N:19]4[CH:36]=[N:37][N:38]=[C:18]4[C:17]=3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[CH:23]12[CH2:28][CH:26]([NH:25][CH2:24]1)[CH2:27][N:22]2[C:20]1[N:19]2[CH:36]=[N:37][N:38]=[C:18]2[C:17]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:47])([F:48])[F:46])[CH:40]=2)=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[CH:15]=2)[N:21]=1
Reactant: C[C@H](Nc1cc(-c2nc(N3C[C@H]4CC3CN4C(=O)OC(C)(C)C)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(-c2nc(N3CC4CC3CN4)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-{7-(2-(1(S)-phenylethyl)amino-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl}-2-(tert-butoxycarbonyl)-(1R)-2,5-diaza-bicyclo[2.2.1]heptane (240 mg, 0.4 mmole) in ethyl acetate (5 mL) was treated with HCl-ether solution (1M, 4 mL) at room temperature. The suspension was stirred at room temperature for 5 minutes. The resulting precipitate was filtered, washed with ether and dried under vacuum to give the product as a light yellowish solid; MS m/z (M)+ 557.3; C30H27F3N8 requir. 557.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:10][CH2:11][C:12]4([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:14][CH2:13]4)[CH2:24][CH2:25]3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccnc(Cl)n3)CC2)C1
Reactant: Cn1cc(N)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)C4)n2)cn1
Temperature: 150 °C
Reaction time: 16 h
Yield: 109.4 %

Procedure:
To a solution of tert-butyl 8-((2-chloropyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.4 g, 1.09 mmol) and 1-methyl-1H-pyrazol-4-amine (0.16 g, 1.64 mmol) in n-BuOH (5 mL) was added DIPEA (0.28 g, 2.18 mmol). The mixture was stirred at 150° C. for 16 h then concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a red solid (0.51 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[F:32][C:33]1[CH:38]=[C:37]([S:39][CH3:40])[CH:36]=[CH:35][C:34]=1[NH2:41].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:41][C:34]1[CH:35]=[CH:36][C:37]([S:39][CH3:40])=[CH:38][C:33]=1[F:32])=[O:5])[CH3:2]
Reactant: CSc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1sc2ccncc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc2ccncc2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A degassed solution of 3-(nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.74 g, 1.5 mmol), 2fluoro -4-methylsulfanyl-phenylamine (0.12 g, 0.76 mmol), Pd2 dba3 (0.035 g, 0.038 mmol), Xantphos (0.044 g, 0.076 mmol) and K3PO4 (0.32 g, 1.5 mmol) in toluene (10 ml) was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a pad of Hyflo washing with ethyl acetate. The filtrate was concentrated in vacuo and the resultant residue subjected to flash chromatography (Si-SPE, gradient 0-10% ethyl acetate in dichloromethane) to provide the title compound as a yellow solid (0.16 g, 57%). LCMS (method B): RT=3.84 min, M+H+ 363.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CCN(CC)CC.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH3:20][N:21]([CH3:25])[C:22]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C=Nc1ccncc1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C=Nc1ccncc1OC(=O)N(C)C

Procedure:
4-[[(Dimethylamino)methylene]amino]-3-pyridinol (1.65 g) was refluxed for 1 hour in 20 ml of benzene containing 1.10 g of Et3N and 1.10 g of N,N-dimethylcarbamyl chloride. At the end of this time, the reaction mixture was applied directly to a silica column and eluted with 5% Et3N/ethyl acetate. Concentration of the product-containing fractions gave 2.05 g of chromatographically pure product which was distilled in a bulb to bulb apparatus (oven temperature=175° C.) to give analytically pure material, m.p. 64°-66° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[C:11]=2[O:21][CH3:22])=[O:9])=[C:6]([O:23]C(=O)C(C)(C)C)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[C:11]=2[O:21][CH3:22])=[O:9])=[C:6]([OH:23])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(C(=O)c2c(C)cccc2OC(=O)C(C)(C)C)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(C(=O)c2c(C)cccc2O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3B (1.42 g, 3.6 mmol), potassium carbonate (1.5 g), methanol (30 ml) and water (10 ml) is stirred at room temperature for 16 hours. The reaction mixture is poured into water, acidified and extracted with diisopropylether. The organic phase is separated and concentrated. The pure product is obtained as a yellow solid, 0.75 g (65.8%), mp. 82-84° C.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:2][N:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: c1cc2c(cn1)CNCC2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCc3ccncc3C2)cc1
Yield: 69.1 %

Procedure:
Commercially available 1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (14.5 g; 0.085 moles), 4-fluoronitrobenzene (18.0 g; 0.13 moles) and potassium carbonate (37.5 g, 0.27 moles) in anhydrous DMF (100 mL) were heated at 80° C. for 18 hours, cooled and partitioned between ethyl acetate (500 mL) and water (1 L). The layers were separated and the aqueous layer re-extracted with ethyl acetate (300 mL). The combined organic layers were washed with water (400 mL), brine, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on silica (250 g) eluting with 20% ethyl acetate in DCM then 7.5% methanol in ethyl acetate gave the title compound (15 g) as an orange solid.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[N+:5]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.BrCC(C1C=CC=CC=1)=O.CC1C=C2C([CH:37]=[CH:38][CH:39]=[N:40]2)=CC=1>C(#N)C>[C:14]([C:13]1[N:5]2[C:6]3[C:11]([CH:12]=[C:3]([Br:2])[C:4]2=[C:38]([C:39]#[N:40])[CH:37]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: O=C(C[n+]1cc(Br)cc2ccccc21)c1ccccc1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: N#Cc1cc(C(=O)c2ccccc2)n2c1c(Br)cc1ccccc12

Procedure:
3-Bromo-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (485 mg, 2.44 mmol), 7-methyl-quinoline (430 mg, 2.07 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 303 mg (36%) as a light tan solid: 1H NMR (CD3OD) 9.73 (d, J=2.1 Hz, 1H), 9.65 (d, J=1.8 Hz, 1H), 8.44 (dd, J=1.2, 8.1 Hz, 1H), 8.31–8.18 (m, 4H), 8.08 (m, 1H), 7.81 (m, 1H), 6.67 (m, 2H), 6.91 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:20]#[N:21])=[N:4][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1.[OH:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[N:4]=[C:3]([C:20]#[N:21])[C:2]([O:22][CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1Br
Reactant: OC1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1OC1CCOC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-bromo-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile (0.600 g, 1.71 mmol), 3-hydroxytetrahydrofuran (301 mg, 3.41 mmol), and anhydrous Cs2CO3 (1.67 g, 5.13 mmol) in DMSO (7 mL) was heated by microwave irradiation at 150° C. for 35 min. The mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (Na2CO3) and concentrated. The residue was purified by FCC to give the title compound (280 mg, 46%). MS (ESI): mass calcd. for C19H24N4O3, 356.4; m/z found, 357.5 [M+H]+. 1H NMR (CDCl3): 7.94 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 5.08-5.04 (m, 1H), 4.12-3.93 (m, 4H), 3.77-3.72 (m, 2H), 3.69-3.63 (m, 2H), 2.98-2.92 (m, 2H), 2.87-2.81 (m, 2H), 2.35-2.25 (m, 1H), 2.25-2.18 (m, 1H), 1.97-1.83 (m, 3H), 0.51-0.35 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2].C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[Br:29]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[Br:29][C:13]1[C:14]([OH:16])=[N:15][C:10]([S:9][CH2:8][C:7]2[S:6][CH:5]=[N:4][C:3]=2[CH2:1][CH3:2])=[N:11][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: BrBr
Reactant: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ncsc1CSc1nc(O)c(Br)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (500 mg, 1.56 mmol) in a mixture of 2:1 CCl4-DCM (40 mL) was dropwise added bromine (80 μL, 1.56 mmol) at 0° C. After 1 hour of stirring at room temperature, water and a solution of sodium thiosulfate were added. The mixture was extracted with DCM (3 times). The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford a crude oil. The residue was dissolved in DCM and purified on silica gel using DCM/MeOH (0 to 15%) to provide 5-bromo-2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol as a white solid (72 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6): δ 1.17 (t, J=7.4 Hz, 3H), 2.75 (q, J=7.4 Hz, 2H), 4.64 (s, 2H), 8.87 (s, 1H). LRMS (ES+) m/z 402 (50%, M+2), 400 (50%, M).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]=[O:14]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:13]([NH:12][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzhydrazide in 50 ml of dry THF was introduced at 50° C. and admixed dropwise with a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF. First of all a solution formed, and then a precipitate was produced. After the end of the addition, the mixture was stirred at 50° C. for 2 h more, then left to stand overnight at RT. The crystals were isolated by filtration, washed with a little diethyl ether and dried in an HV. This gave 21.43 g (89% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][N:7]=[CH:6][C:5]=1Br.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][N:7]=[CH:6][C:5]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1c(Br)cncc1Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
3-Bromo-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (250 mg, 0.77 mmol), 2-chlorophenylboronic acid (0.18 g, 1.2 mmol), Pd(OAc)2 (10 mg, 0.025 mmol), S-Phos (20 mg, 0.05 mmol), and K2CO3 (0.32 g, 2.3 mmol) were suspended in dioxane/H2O (1.65 mL, 9/1, v/v) and stirred overnight at 100° C. The reaction solution was diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the desired product (220 mg, 80%) as a yellow oil. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:8]=2[Cl:7])=[CH:17][CH:16]=1)=[O:4]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 80.8 %

Procedure:
13 g (0.14 mole) of dimethylcarbamic acid chloride were added dropwise to 29 g (0.1 mole) of 4-(2-chloro-4-trifluoromethyl-phenoxy)-aniline, dissolved in 50 ml of pyridine, at 0° C. The mixture was warmed to 70°-75° C for half an hour, the bulk of the pyridine was stripped off in vacuo and the residue was poured into water and acidified with dilute hydrochloric acid. The precipitate was filtered off, dried and recrystallized from toluene. 29 g (89% of theory) of N,N-dimethyl-N'-[4-(2-chloro-4-trifluoromethylphenoxy)-phenyl]-urea were obtained as pink crystals of melting point 140° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].[K+].[Br-]>>[CH:26]1([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[C:11]([C:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:32])=[O:2])=[O:10])[O:15][N:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1)C(C)C
Agent: [Br-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1)C(=O)O
Yield: 62 %

Procedure:
The title compound was prepared from (S)-2-({3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carbonyl}-amino)-3-methyl-butyric acid methyl ester as set forth in Example 8 and was obtained in 62% yield. Mass (ES+): 429 (M++1); IR (KBr): 3339, 2933, 1744; 1651 (br), 1594, 1527 (br); 1H NMR (DMSO-d6) δ: 0.92-0.96 (2×d, 6H), 1.09-1.79 (4×m, 10H), 2.18 (m, 1H), 3.45 (br, 1H), 4.25 (dd, 1H), 6.18 (d, 1H), 7.50 (d, 2H), 7.63 (s, 1H), 7.74 (d, 2H), 8.59 (s, 1H), 8.89 (d, 1H), 12.84 (br, 1H).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[N+]([O-])(O)=O.[NH2:16][NH:17][C:18](N)=N.[OH-].[Na+]>C(O)C>[NH2:5][C:4]1[C:3]([C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:1])=[CH:18][NH:17][N:16]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Nc1n[nH]cc1C(=O)c1ccccc1

Procedure:
A reaction mixture comprising 73.36 g of α-(dimethylamino)methylene]-β-oxo-2-benzenepropanenitrile, 63.45 g of aminoguanidine nitrate, 500 ml of ethanol and 36.6 ml of 10N sodium hydroxide was refluxed for 10 hours and then cooled. The resulting precipitate was collected and washed with water, giving 17.1 g of the desired product, mp 177°-179° C.