Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Br)ncc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(C)ncc1F
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O.O.CCOCC>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:9])=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Cl)nc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
5-Amino-2-chloropyridine (3.0 g) was dissolved in DMF (40 mL), N-iodosuccinimide (5.25 g) was added and the reaction mixture was stirred at room temperature for 3 hours. Water and MTB-ether were added to the reaction mixture, the layers were separated and the organic layer was washed 3× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.30) to afford 4.80 g of the title compound of the formula
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([I:16])=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH3:20].C(N(CC)CC)C>C(O)(C)C.O1CCOCC1>[I:16][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH3:20])[N:7]=2)=[CH:12][N:11]([CH:13]([CH3:15])[CH3:14])[N:10]=1
Reactant: COC(=O)N[C@@H](C)CN
Reactant: CC(C)n1cc(-c2ccnc(Cl)n2)c(I)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2I)n1

Procedure:
A solution of Intermediate 2-chloro-4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidine (1.4 g, 4.01 mmol), (S)-methyl 1-aminopropan-2-ylcarbamate (0.8 g, 6 mmol) and triethylamine (2.8 ml, 20 mmol) in isopropanol (30 ml) and dioxane (20 mL) was heated in a sealed vessel at 125° C. for 48 hours. The cooled mixture was concentrated under vacuum, and aqueous sodium bicarbonate was added to the residue. The mixture was extracted with ethyl acetate, and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (1:2 hexanes/ethyl acetate eluant) to provide the title compound as a white solid. MS m/z 445.0 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]([NH:48]C(=O)OC(C)(C)C)[C@@H:9]([OH:47])[CH2:10][C@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:63][O:64][C:65]([NH:67][C@@H:68]([C:72]([CH3:75])([CH3:74])[CH3:73])[C:69]([OH:71])=O)=[O:66].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>ClCCl.C1COCC1>[CH2:1]([C@H:8]([NH:48][C:69]([C@@H:68]([NH:67][C:65](=[O:66])[O:64][CH3:63])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:71])[C@@H:9]([OH:47])[CH2:10][C@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@H](Cc3ccc(-c4ccccn4)cc3)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution containing the product from Example 94A (0.042 g, 0.056 mmol) in dichloromethane (0.3 mL) was treated with trifluoroacetic acid (0.3 mL) and the mixture was stirred at 25° C. for 1 hour. The solvent was concentrated and the residue was dissolved in toluene and concentrated several times. A solution of the residue (0.056 mmol) in THF (0.6 mL) was treated with the product from Example 1F (0.011 g, 0.058 mmol), DEPBT (0.025 g, 0.083 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.281 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.023 g, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77(s, 9H), 0.81(s, 9H), 1.41-1.31(m, 1H), 1.59-1.49(m, 1H), 2.43(s, 3H), 2.70-2.59(m, 3H), 2.88-2.77(m, 1H), 3.25-3.12(m, 2H), 3.53(s, 3H), 3.64-3.44(m, 2H), 3.94-3.84(m, 2H), 4.08(s, 1H), 4.19-4.10(m, 2H), 4.43-4.26(m, 2H), 6.77-6.73(d, J=9.56 Hz, 1H), 7.03-7.01(d, J=7.72 Hz, 1H), 7.18-7.09(m, 5H), 7.28-7.25(d, J=8.46 Hz, 2H), 7.34-7.30(m, 2H), 7.53-7.50(d, J=9.93 Hz, 1H), 7.65-7.60(t, J=7.72 Hz, 1H), 7.92-7.83(m, 2H), 7.97-7.95(d, J=8.09 Hz, 2H), 8.17-8.15(d, J=8.46 Hz, 1H), 8.65-8.64(d, J=4.78 Hz, 1H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl.CCOC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 81.2 %

Procedure:
Methyl anthranilate (110 g, 0.73 mol) was dissolved in dichloromethane (1 liter) at 0° C. and triethylamine (115 ml, 0.8 mol) was added. Tosyl chloride (133 g, 0.745 mol) was added portionwise at 0° C. The reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was reduced in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with 5% KHCO3 (aq) solution, 1N HCl solution and brine, dried, filtered and concentrated in vacuo. The residue was crystallised from EtOAc/hexane to yield the title compound (181 g, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)c1cccnc1
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccnc1
Yield: 50 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-pyridine boronic acid (2 eq) to give 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (60 mg, 50%).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-]C1C=CC=CC=1.[Li+].C([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#N.C1([Mg]Cl)C=CC=CC=1.C1(S[Li])C=CC=CC=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].CP(C)C>[C:1]1([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: N#Cc1ccncc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CP(C)C
Solvent: C1CCOC1
Product: c1ccc(-c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
In a 1 L 3-neck flask, equipped with a mechanical stirrer, were mixed phenyl magnesium chloride (96.1 mL; 192 mmol; 2.00 M in THF) and lithium thiophenoxide (211 mL; 211 mmol; 1.00 M THF) under a blanket of nitrogen. This mixture was heated to 60° C. for 1 h, and then cooled to 0-5° C. with an ice bath. In a separate 150 mL flask, nickel acetylacetonate (“anhydrous”; 0.617 g; 2.40 mmol; 0.025 equiv.) was dissolved under nitrogen in anhydrous THF (100 mL). To this green solution was added trimethylphosphine (4.8 mL; 4.80 mmol; 1.00 M in toluene; 0.05 equiv.) forming a blue solution. After stirring for 10 min, solid 4-cyanopyridine (10.0 g; 96.1 mmol; 1 equiv.) was added to the catalyst mixture forming a green solution. This solution was added via addition funnel to the PhMgCl/PhSLi reaction solution at a rate which maintained the reaction temperature below 15° C. After the addition was complete, the reaction was heated at 60° C. for 2 h. The reaction was then allowed to cool to room temperature, and was poured into 1M aqueous sodium citrate (500 mL). The organic layer was separated and the aqueous layer extracted three times with MTBE (265 mL each). The combined organic phase was extracted three times with 2 N aqueous HCl (250 mL each) and this combined aqueous extract was basified to pH 12 with 1 N aqueous NaOH. This mixture was then extracted three times with MTBE (330 mL each) and the combined organic phase was dried over anhydrous magnesium sulfate. After filtration of the drying agent, solvent was removed in vacuo leaving 14.1 g (91% yield) of 4-phenylpyridine as a light yellow solid. GC analysis of the product showed it to be >95% pure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:19])[CH:17]=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:17](=[O:18])[CH:16]([OH:19])[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A mixture of 21.2 g (0.10 mol) of 2,4-di-tert-butylphenol (97%), 16.3 g (0.11 mol) of 50% aqueous glyoxylic acid and 0.05 g (0.26 mmol) of p-toluenesulfonic acid monohydrate in 30 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. Afterwards the reaction mixture is concentrated on a vacuum rotary evaporator. The residue is taken up in 80 ml of hexane and washed three times with water. The aqueous phases are separated in the separating funnel and further extracted with 30 ml of hexane. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. The residue yields 26.23 g (~100%) of analytically pure 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one in the form of a thick yellowish resin (compound (101 ), Table 1).
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.[NH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:23][CH2:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)COc1ccc(CN)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde, methyl [4-(aminomethyl)phenoxy]acetate, acetate salt and DIEA (1 eq.) (purification by flash chromatography on SiO2, DCM/MeOH 95:5) as a pale yellow oil (63%). M+ (ESI): 422.2. HPLC, Rt: 4.3 min (purity: 96.4%). 1H NMR (CDCl3) δ: 7.37 (d, J=8.3 Hz, 2H), 7.28 (m, 4H), 6.88 (d, J=8.6 Hz, 2H), 4.63 (s, 2H), 3.78 (m, 7H), 2.40 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.30 (brs, 8H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:56][C@H:57]1[CH2:62][CH2:61][CH2:60][C@@H:59]([CH3:63])[NH:58]1>CN(C)C=O>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:58]3[C@H:59]([CH3:63])[CH2:60][CH2:61][CH2:62][C@@H:57]3[CH3:56])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:26]
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(C(=O)O)CC1)c1cccc(Cl)c1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1C(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.7 %

Procedure:
To a solution of 0.040 g (0.11 mmol) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in N,N-dimethylformamide (2 mL) is added 0.048 g (0.15 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate followed by 0.042 mL (0.304 mmol) of triethylamine. The mixture is stirred at room temperature for 1 h then 0.034 g (0.304 mmol) of cis-2,6-dimethylpiperidine is added and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.002 g (4%) of the title compound (273) as a white solid. [M+H]+=489.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][S:52](Cl)(=[O:54])=[O:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:36][C:33]1[CH:34]=[CH:35][N:22]2[C:23]=1[C:24](=[O:32])[N:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]([C@@H:18]([NH:17][C:15]1[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:52]([CH2:51][CH:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)(=[O:54])=[O:53])[CH:7]=4)=[CH:9][N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:11]=3[N:12]=[CH:13][N:14]=1)[CH3:19])=[N:21]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: O=S(=O)(Cl)CC1CCOCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(NS(=O)(=O)CC5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 54.9 %

Procedure:
(S)-2-(1-((5-(2-Aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (26 mg, 0.13 mmol) and triethylamine (36 μl, 0.26 mmol) in pyridine (2 ml) according to the method described in Preparation 15b. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to give 55 mg (53% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:18][CH2:19][CH:20]=[O:21])[CH3:17]>C(O)C.O>[CH2:16]([N:18]([CH2:19][CH:20]=[O:21])[C:8]([NH:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][N:4]=1)=[O:9])[CH3:17]
Reactant: CCNCC=O
Reactant: O=C=Nc1ncc(Cl)s1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chlorothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-ethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-chlorothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Nc1cccnc1
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4cccnc4)c3cc2OC)c1
Yield: 55 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol) with 3-aminopyridine (19 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 55% yield (46 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:28])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:29])[C:6]([C:30]([OH:32])=[O:31])=[CH:5]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][CH2:41][CH2:42]Br.[OH-].[K+].[I-].[K+]>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:28])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([P:20]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:29])[C:6]([C:30]([O:32][CH2:42][CH2:41][O:40][CH3:39])=[O:31])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOP(=O)(OCC)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOP(=O)(OCC)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)OCCOC)cn3C2CC2)CC1
Reaction time: 192 h
Yield: 80.8 %

Procedure:
To a solution of 0.467 g of the product of Example 40 in 5 ml of hexamethylphosphoramide was added 0.163 g of cesium carbonate, 0.304 g of 2-bromoethyl methyl ether, 0.137 g of 45% aqueous potassium hydroxide and 0.017 g of potassium iodide. The suspension was stirred in the dark under argon for 8 days. Ether (40 ml) was added and the mixture was extracted successively with water, brine and water. The ether layer was discarded. The aqueous layers were extracted with chloroform, the chloroform extracts were dried over sodium sulfate and then evaporated, finally at <100° and 0.06 mm. to remove hexamethylphosphoramide. Two recrystallizations of the solid residue from methylene chloride-n-heptane gave 0.424 g of ivory-colored needles, m.p. 138°-141° C. The product was easily soluble in water and in 0.1M phosphate buffer, pH 7.5.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:15])C(O)=O)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1.[OH-].[Na+].Cl>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:15])=[O:1])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: O=C(O)C(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 30% hydrogen peroxide solution (4.95 mL, 0.04 mol) was added dropwise to a solution of 4-bromo-2-nitrophenylpyruvic acid (0.04 mol) and sodium hydroxide (5.3 g 0.1 mol) in water (175 mL) stirring at 0° C. The reaction solution was stirred for 1 h at 5° C. and then acidified with dilute HCl. The yellow precipitate was filtered and the crude product recrystallized from hexane and ethyl acetate to yield 8.4 g (75%) as a light beige solid; 1H-NMR (DMSO-d6): δ12.67 (br s, 1H), 8.28 (d, J=2.0 Hz), 7.97 (dd, 1H, J=9.0 Hz, 2.0 Hz), 7.55 (d, 1H, J=8.0 Hz 4.00 (s, 3H). MS (−ve) m/z: 259 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10](C3CCN(C(OC(C)(C)C)=O)CC3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:26].C(O[CH2:31][CH3:32])(=O)C>>[ClH:26].[ClH:26].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:9]3[CH2:32][CH2:31][CH2:3][CH2:4][CH2:8]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Product: Fc1cccc(-c2csc(N3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (2.89 g, 7.95 mmol) in ethyl acetate (200 ml) was added a 4N solution (50 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 30 hours. The solvent was distilled off under reduced pressure to give 1.86 g (70.0%) of the desired product as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][N:27]=3)[CH:15]=[CH:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc21
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60° C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60° C. for an additional 10 minutes. A solution of 3.195 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 mintues. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.