Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:2].[C:22]([O:26][C:27](N1CCN(C2C=CC(N)=CC=2F)CC1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl>[C:22]([O:26][C:27]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reaction time: 18 h

Procedure:
2-Ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide. To a solution of 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 8.9 mmol) and Et3N (1.4 mL, 10.0 mmol) in DCM (60 mL) was added 1-ethylbutyryl chloride (1.4 mL, 10.0 mol). The mixture was stirred for 18 h, quenched with 1 N NaHCO3 (50 mL), and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; EtOAc/hexanes) gave 4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. A mixture of this intermediate in MeOH (25 mL) and 2 N HCl in Et2O (10 mL) was stirred for 18 h. The solution was concentrated to give 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide hydrochloride. This salt was treated with 1 N NaOH (10 mL) and extracted with EtOAc (40 mL). The organic layer was dried and concentrated to give the title compound as the free base (1.5 g, 58%). MS (ESI): mass calcd. for C16H24FN3O, 293.19. m/z found, 294.4 [M+H]+. 1H NMR (CDCl3): 7.25-7.23 (m, 1H), 7.17 (s, 1H), 6.58-6.55 (m, 1H), 3.08-3.00 (m, 8H), 2.02-1.99 (m, 1H), 1.80-1.50 (m, 4H), 1.00-0.95 (m, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: BrCc1cccc(I)c1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(I)c1)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
A mixture of 3-iodobenzyl bromide 12 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 5.4 g of 13 (91%). 1H NMR (200 MHz, CDCl3): δ 1.15 (t, J=7.05 Hz, 6H), 2.97 (d, J=21.65 Hz, 2H), 3.92 (m, 4H), 6.93 (t, J=7.76 Hz, 1H), 7.17 (m, 1H), 7.52 (m, 2H); 13C NMR (50 MHz, CDCl3): 16.25 (J=5.95 Hz), 33.15 (J=137.60 Hz), 62.19 (J=6.70 Hz), 94.13 (J=3.50 Hz), 128.89 (J=6.35 Hz), 130.07 (J=3.00 Hz), 133.95 (J=9.10 Hz), 135.87 (J=3.55 Hz), 138.51 (J=6.65 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:25]1([C:23]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([S:1][C:2]4[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=4[C:4]([O:6][CH3:7])=[O:5])=[N:18][N:17]3[CH:19]=2)=[O:24])[CH2:26][CH2:27]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 17.5 %

Procedure:
A mixture of methyl 2-mercaptobenzoate (1030 mg, 6.1 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.0 g, 3.1 mmol), potassium carbonate (1050 mg, 7.6 mmol) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 7 hr. The mixture was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give methyl 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoate (200 mg, 18%) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:23]
Reactant: COC(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCSc1cccc2nccn12
Yield: 66.9 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (30 ml) was added methyl chloroformate (0.77 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarborate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.68 g of the desired product (66.9%, colorless crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1
Reactant: COc1cc(Br)cnc1OC
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc(OC)c(OC)c2)cc1
Yield: 44.8 %

Procedure:
According to Scheme 4 Method B: The title compound was prepared from 5-bromo-2,3-dimethoxypyridine (1 eq, 1.83 mmol, 0.40 g) and 4-methoxyphenyl boronic acid (1 eq, 1.83 mmol, 0.28 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography on silica gel using cyclohexane/AcOEt 90/10 as eluent to afford the title compound 2,3-dimethoxy-5-(4-methoxyphenyl)pyridine (0.82 mmol, 0.20 g, 45%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[S:18]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution was prepared containing 0.80 g. of 2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethylamine and 0.29 g. of methylisothiocyanate in 10 ml. of ethanol. The solution was stirred at room temperature for about 17 hours after which time the solvent was removed by evaporation in vacuo. The residual gum, comprising N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethylthiourea formed in the above reaction, was purified by chromatography over silica using a gradient elution technique with ethyl acetate containing increasing quantities of methanol as the eluant. Fractions containing the above compound were combined and the solvent evaporated therefrom in vacuo, leaving as a residue 0.83 g. of a glassy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[C:15]([NH:20][C:21]1[NH:22][CH:23]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C:25]=1[C:26]([NH2:28])=[O:27])(=[O:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[C:15]([NH:20][C:21]1[NH:22][CH:23]=[C:24]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:33][CH:34]=2)[C:25]=1[C:26]([NH2:28])=[O:27])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 44.8 %

Procedure:
0.076 cm3 (0.436 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 25° C. to 0.125 g (0.436 mmol) of 2-isobutyrylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in solution in 15 cm3 of tetrahydrofuran. After stirring for 17 hours at a temperature in the region of 25° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is then diluted in 40 cm3 of ethyl acetate and then washed with 40 cm3 of water. The organic solution is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is crystallized from 8 cm3 of a cyclohexane/ethyl acetate mixture (70/30 by volume). After filtration and drying, 0.096 g of 2-isobutyrylamino-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained in the form of a cream solid melting at 196° C. IR (KBr), 3472; 3384; 1667; 1594; 1546; 1443; 1340; 1313; 1198; 1167; 1120; 1070; 937 & 614 cm−1. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm), 1.17 (d, J=7.0 Hz, 6H); 2.61 (m, 1H); 5.62 (broad m, 1H); 6.40 (d, J=2.5 Hz, 1H); 7.00 (broad m, 1H); 7.30 (d, J=9.0 Hz, 2H); 7.39 (m, 1H); 7.49 (m partially masked, 1H); 7.51 (d, J=9.0 Hz, 2H); 8.62 (dd, J=2.5 and 7.5 Hz, 1H); 8.99 (broad s, 1H); 9.32 (broad s, 1H); 10.95 (broad s, 1H); 11.45 (broad s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:23][N:22]=1)=[O:20])[CH3:17]
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: CCOC(=O)c1ccc(Br)cn1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cn1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-bromo-pyridine-2-carboxylic acid ethyl ester (22) as a gum. MS (ESI) 351.1 (M•)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[N:16]=1.C(OCC)(=O)C>C1COCC1>[Br:17][C:15]1[N:16]=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]([NH2:18])=[N:13][CH:14]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Added sodium hydride (0.348 g, 8.70 mmol) to a solution of phenol (0.819 g, 8.70 mmol) in THF (50 mL) at 0° C. and stirred 30 minutes. Added 3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (10 mL). Removed the ice bath and refluxed overnight. Partitioned between ethyl acetate and water, washed with brine, dried, and concentrated. Purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford the title compound (1.36 g, 64.6% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH2:1]([CH:3]([CH:6]1[CH2:7][C:8](=[O:13])[CH:9]([C:25](=[O:26])[NH:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[C:10](=[O:12])[CH2:11]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)C1CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CCC(CC)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-(1-ethylpropyl)1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ETHYLPROPYL)-2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 121°-122° C. (corr.).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[N:7]([CH3:22])[C:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([O:11][CH3:12])[CH:10]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:8]2[N:7]([CH3:22])[C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:10][C:9]=2[O:11][CH3:12])=[O:21])=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cc(OC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Yield: 88.9 %

Procedure:
Ethyl-5-(p-chlorobenzoyl)-4-methoxy-1-methylpyrrole-2-acetate (145 mg, 0.475 mmole) is dissolved in 1 ml hot ethanol under nitrogen. Subsequently, 2 ml of 2.5 N aqueous sodium hydroxide is added dropwise. The solution is heated at 95° for about 5 min. The reaction solution is then diluted with water, the product precipitated with 2.5 ml of 2.5 N hydrochloric acid. The resulting precipitate is filtered, washed with water and dried in vacuo to yield 130 mg of 5-(p-chlorobenzoyl)-4-methoxy-1-methylpyrrole-2-acetic acid, m.p. 148 (dec).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=[C:32]([F:40])[C:31]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].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>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:31]4[C:32]([F:40])=[CH:33][C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
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
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)(=O)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (15.0 mg, 0.0384 mmol), 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylic acid (15.3 mg, 0.0461 mmol), HATU (36.5 mg, 0.0960 mmol) in DMF (0.09 mL) and DIPEA (14.9 mg, 0.115 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (11.0 mg, 41%). LCMS calc. for C33H37F3N5O7S (M+H)+: m/z=704.2. Found: 704.2.
Reaction SMILES: Br[C:2]#[N:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1>CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[O:13][C:2]([NH2:3])=[N:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: N#CBr
Solvent: CO
Product: Nc1nnc(Cc2ccc(F)cc2)o1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Solid BrCN 13.37 g (130 mmol, 1.1 eq.) was added in one portion into ice-cooled slurry of (4-Fluoro-phenyl)-acetic acid hydrazide (19.85 g, 118 mmol) and KHCO3 14.77 g (147.5 mmol, 1.25 eq.) in MeOH (150 mL) in a 1L flask. (Followed by MeOH 10 mL to wash the funnel). The mixture was stirred on ice bath at 0-5° C. for 2 hours in a loose-capped flask, then the bath allowed to melt gradually and then the mixture was stirred at 5 to 20° C. overnight (17 hrs). The reaction mixture was diluted with water (200 mL), stirred for 1 hour in an open flask, then cooled on ice bath. The precipitate was collected by filtration, washed with water and dried on highvac. [1st fraction]The supernatants were concentrated on rotavap form warm (40° C.) water bath to remove all MeOH and some water. The obtained slurry was cooled to room temperature, the precipitate was collected by filtration, washed with water and dried on highvac. [2nd fraction]. Combined yield: 20.836 g (91.5%) of a white crystalline solid.
Reaction SMILES: NC(N)=O.[C:5]([NH:9][C:10]([C:12]1[S:41][C:15]2[N:16]=[C:17]([S:39][CH3:40])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([O:29]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH:21]=3)[C:14]=2[C:13]=1[NH2:42])=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH3:43][O:44][C:45]1[C:46]([NH2:51])=[CH:47][CH:48]=[CH:49][CH:50]=1>>[C:5]([NH:9][C:10]([C:12]1[S:41][C:15]2[N:16]=[C:17]([S:39][CH3:40])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([NH:51][C:46]4[C:45](=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:44][CH3:43])=[O:29])[CH:21]=3)[C:14]=2[C:13]=1[NH2:42])=[O:11])([CH3:6])([CH3:8])[CH3:7]
Reactant: CSc1nc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: COc1ccccc1N
Agent: NC(N)=O
Product: COc1ccccc1NC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.75 h

Procedure:
The urea coupling of tert-Butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 20, 142 mg) with ortho-anisidine (159 mg) was performed according to the methods described in example 21. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>CO>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1nc(O)cc(O)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a cooled, stirred solution of 25% sodium methoxide (1200 ml, 5.55 mole) was added a slurry of 200 g (1.85 mole) of propionamidine hydrochloride in 300 ml of methanol. Next, 244 g (1.85 mole) of dimethyl malonate was added and the mixture was permitted to warm to about 20° C., after which it was stirred for 16 hours. The mixture was evaporated in vacuo and water (about 2 l) was added. This mixture was neutralized with concentrated hydrochloric acid to provide a white precipitate which was separated by filtration to provide 230 g (96%) of 4,6-dihydroxy-2-ethylpyrimidine, m.p. 312°-215° C. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1([N:52]=[C:53]=[O:54])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:53](=[O:54])[NH:52][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][CH:43]=2)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Product: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazine-2-yl)-ethylamino]-4-(indol-1-yl)pyrimidine (68 mg) and naphthyl isocyanate (24 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 626.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)=[O:2].[H-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[C:10]([N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[CH:4]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cc[nH]c1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccn(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
500 mg of 3-formyl-pyrrole were dissolved in 10 ml of tetrahydrofuran and then, at +20° C., 227 mg of sodium hydride dispersed at 55% in vaseline oil were added all at once. Gas evolved and after stirring for 15 minutes, a solution of 0.58 ml of benzoyl chloride in 2 ml of tetrahydrofuran was introduced dropwise at +5° C. The mixture was stirred for 2 hours at 20° C. and diluted with water. Extracting with ether, concentrating to dryness by distillation under reduced pressure and chromatographing the residue over silica and eluting with a mixture of hexane and ethyl acetate (7-3) yielded 558 mg of 1-benzoyl-3-formyl-pyrrole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH3:30][O:31][C:32](=[O:51])[C:33]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])([CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[CH3:30][O:31][C:32](=[O:51])[C:33]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])([CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:37][CH:36]=1
Reactant: COC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Product: COC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F

Procedure:
The titled compound is prepared, according to the procedure of Example 1, Step A, using toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (0.888 g, 2.12 mmole) and 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methylester (0.645 g, 2.12 mmole) to produce an oil (0.95 g, 81%). Mass [EI+] 551 (M+H)+.
Reaction SMILES: Cl[Si:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[CH2:17]([Mg]Cl)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([Si:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[CH:18]=[CH2:17]
Reactant: COc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CC[Si](c1ccc(OC)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To the crude chloro(4-methoxyphenyl)diisopropylsilane (54.8 g, 214 mmol, 1.0 equiv.) was added THF (335 mL) via cannula under positive argon pressure. The solution was chilled to 0° C. and treated with allylmagnesiumchloride (128 mL, 256 mmol, 2.0 M in THF, 1.2 equiv.). After 3 h at 0° C., the solution was allowed to warm to 23° C. with stirring overnight. The mixture was treated with NH4Clsat'd (50 mL) and the aqueous layer extracted with ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, concentrated in vacuo. The crude material was purified by silica gel chromatography (3-5% EtOAc/hexanes) to yield 52.86 g (94%) of a slightly cloudy, viscous oil. This reagent distills at 130° C. at 500 mtorr as a colorless oil. TLC Rf=0.40 (9:1 Hexanes/EtOAc). IR (film) 2942, 2865, 1630, 1595, 1504, 1463, 1277 cm−1. 1H NMR (500 MHz, CDCl3) δ7.32 (d, 2H, J=6.84, C3-H,C7-H), 6.18 (d, 2H, J=6.84, C4-H, C6-H), 5.82 (q, 1H, J=8.5, 8.5, C15-H), 4.88 (d, 1H, J=17.05, C16-Hb), 4.76 (d, 1H, J=9.77, C16-Ha), 1.82 (d, 2H, J=7.32, C14-H), 1.17 (q, 2H, J=7.3, C8-H, C11-H), 0.94 (d, 6H, J=7.3, C9-H, C10-H), 0.90 (d, 6H, J=7.3, C12-H, C13-H). 13C NMR (125 MHz, CDCl3) δ160.51, 136.48, 135.70, 125.78, 113.78, 113.62, 55.09, 19.34, 18.22, 18.17, 17.68, 11.30. Anal. Calcd for C16H26OSi: C, 73.22; H, 9.98; Si, 10.70.