Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]([CH3:14])([CH3:13])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:10]([NH:9][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])([CH3:14])[C:11]#[N:12]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(N)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)NS(=O)(=O)CCCCl
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred mixture of 9.90 g (0.05 mole) 3-chloropropane sulfonyl chloride and 4.71 g (0.056 mole) 2-amino-2-methyl-propionitrile in 100 ml methylene chloride at 0° C., 5.66 g (0.056 mole) triethylamine as a 10% solution in methylene chloride was added very slowly. The reaction mixture was allowed to stir overnight in the gradually melting ice bath. The reaction mixture was washed three times with 50 ml water. The organic layer was dried over calcium sulfate and evaporated to give 9.90 g of the above-identified product as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([O:20][CH2:21][CH3:22])([C:9]([OH:15])([CH2:8][CH2:7][NH:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])[CH3:19]
Reactant: CCOC(=O)C(=O)CCNCCN(C)C
Reactant: CCOP([O-])OCC
Product: CCOC(=O)C(O)(CCNCCN(C)C)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 2.15g (0.01 mole) of ethyl 4-(2-(N,N-dimethylamino)ethylamino)-2-oxobutanoate in 6.9 g (0.05 mole) of diethyl phosphite is stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chloroform/ethanol as eluant.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16](=[O:32])[N:17]([C:30]#[CH:31])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12].Cl[C:34]([O:36][CH3:37])=[O:35].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:37][O:36][C:34](=[O:35])[C:31]#[C:30][N:17]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:32])[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:22][CH:23]=1
Reactant: COC(=O)Cl
Reactant: C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: -40 °C
Yield: 61 %

Procedure:
LiHMDS (4.35 ml, 1 M in THF, 4.35 mmol) was added to a solution of ethynyl-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (750 mg, 2.5 mmol, in dry THF (4.3 ml) under nitrogen at −78° C. The mixture was slowly warmed up to −40° C. and maintained at this temperature for 1 hour. The latter was then transferred dropwise via cannula to a solution of ClCO2Me (314 μl, 4.06 mmol) in THF (7.5 ml) at −40° C. The resulting mixture was allowed to return to RT. Saturated aqueous NH4Cl and AcOEt were added and the organic phase was extracted (3×15 ml AcOEt) and dried over Na2SO4. The title compound was obtained after purification by column chromatography (PE/AcOEt:80/20 to 75/25).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:17](=[O:18])[NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:4]=2)=[CH:9][CH:10]=1)(=[O:29])=[O:28]
Reactant: Nc1ncc(-c2ccc(CCO)cc2)nc1C(=O)Nc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a solution of the product of step (iii) (2.5 g, 7.5 mmol, 1.0 eq) and TEA (2.3 g, 22.5 mmol) in dry dichlormethane was added MsCl (1.7 g, 15 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue purified by column to afford the subtitled compounds (1.9 g).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[O:92]1[CH2:97][CH2:96][N:95]([CH2:98][CH2:99][OH:100])[CH2:94][CH2:93]1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:100][CH2:99][CH2:98][N:95]2[CH2:96][CH2:97][O:92][CH2:93][CH2:94]2)=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCCN3CCOCC3)cc2)cc1

Procedure:
Compound 88A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34B and compound 31F with 2-morpholinoethanol and 4-(benzyloxy)phenol, respectively: ESI (+)LC/MS: 314 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH:25][C:37](=[O:39])[CH3:38])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN)O4)CC2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CNC(C)=O)O4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of THF (2.0 mL) containing 1-{5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methaneamine (110 mg, 0.278 mmol) synthesized in Example 108, triethylamine (42 mg, 0.417 mmol) and acetylchloride (26 mg, 0.337 mmol) were serially added under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with water, and THF was removed under reduced pressure, followed by extraction using ethyl acetate. The extract was washed with saturated saline and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 7:3-3:7) and crystallized from ethyl acetate-hexane to obtain 90 mg of the title compound (yield 74%). Melting point was 146 to 152° C.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(N(C(C)C)C(C)C)C.[O-]S([O-])(=O)=O.[Mg+2]>ClCCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[CH2:9][N:8]([C:16]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:23])[CH2:7][CH2:6]2
Reactant: O=C(Cl)c1cccnc1
Reactant: O=Cc1cc2c(cc1O)CCNC2
Agent: Br
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=Cc1cc2c(cc1O)CCN(C(=O)c1cccnc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred suspension of 6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrobromide (129 mg, 0.5 mmol) and nicotinoyl chloride hydrochloride (107 mg, 0.6 mmol) in 1,2-dichloroethane (6 mL), ethyldiisopropylamine (259 μL, 194 mg, 1.5 mmol) was added and the mixture was stirred at room temperature for 3 h. After dilution with 1,2-dichloroethane (30 mL) the mixture was washed with water (3×5 mL). After drying over MgSO4 and concentration the title compound (99 mg, 0.35 mmol, 70%) was obtained.
Reaction SMILES: [F:1][CH:2]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[F:3].C([N-]C(C)C)(C)C.[Li+].[CH3:18][C:19]([CH3:33])=[CH:20][CH2:21][CH2:22]/[C:23](/[CH3:32])=[CH:24]/[CH2:25][CH2:26]/[C:27](/[CH3:31])=[CH:28]/[CH:29]=[O:30].CC(C)=CCC/C(/C)=C/CC/C(/C)=C/CO.Cl>O1CCCC1>[F:1][C:2]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])([F:3])[CH:29]([OH:30])[CH:28]=[C:27]([CH3:31])[CH2:26][CH2:25][CH:24]=[C:23]([CH3:32])[CH2:22][CH2:21][CH:20]=[C:19]([CH3:18])[CH3:33]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: COP(=O)(OC)C(F)F
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)C(F)(F)C(O)C=C(C)CCC=C(C)CCC=C(C)C

Procedure:
In Scheme I, step a, the aldehyde defined by structure (2) is treated with the anion of the phosphonate defined by structure (1) to provide the alcohol defined by structure (3). For example, an equivalent of the appropriately substituted phosphonate (1), such as dimethyl difluoromethylphosphonate dissolved in a suitable organic solvent, such as tetrahydrofuran, is added dropwise to a stirring solution of lithium diisopropylamide at approximately -78° C. The mixture is stirred for 2 minutes to 2 hours. An appropriately substituted aldehyde (2), such as farnesal [prepared by a Swern Oxidation of trans, transfarnesol following the procedure of Biller, S. A. and Forster, C., Tetrahedron 1990, 46(19), 6645] dissolved in a suitable organic solvent, such as tetrahydrofuran, is slowly added to the anion of (1) maintaining the reaction temperature below -72° C. After approximately 2 hours the reaction is poured into a suitable aqueous acid, such as 0.1N hydrochloric acid, and extracted with a suitable organic solvent, such as diethyl ether. The organic phase is dried over a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is then purified by techniques well known in the art. For example, the residue can be purified by flash chromatography using a suitable organic eluent, such as 40% ethyl acetate/hexane to provide dimethyl 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20]([C:21](N)=[CH:22][CH:23]=[CH:24]2)=[CH:19][C:18]=1[CH2:17]3)=[O:15].[BrH:32]>O>[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20](=[CH:19][C:18]=1[CH2:17]3)[C:21]([Br:32])=[CH:22][CH:23]=[CH:24]2)=[O:15]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(Br)cccc3nc2-1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
2.15 g of NaNO2 in 40 mL of H2O were dropped at 5° C. into a solution of 9 g of 9-amino-camptothecin in 850 mL of 16% HBr. After 1 hr at room temperature the solution was dropped in a flask containing 19 g of CuBr in 200 mL of 16% HBr at 70° C. The reaction mixture was kept at 70° C. for 2 hrs, then it was poured into cold water. The precipitate was filtered and the mother liquors were extracted with CH2Cl2; the organic extract, dried and evaporated, was combined with the precipitate and purified by flash chromatography (eluent:CH2Cl2/CH3OH=95/5) to give 8.19 g of the title product (HPLC assay:97.3%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:27]1([CH2:13][C@H:12]([C@@H:11]2[C@:16]3([CH3:24])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:20]([C:19]=4[CH2:18][CH2:17]3)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:25])=[CH:9][CH2:10]2)[CH3:15])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with pyrrolidin and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(pyrrolidin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[C:23](=O)(O)[O-]>CO>[CH3:23][O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: O=C([O-])O
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=O)CC(C)(C)c1ccc(I)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0C and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by-evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]2[S:16][C:15]([NH:17]C(=O)C3C=CC=CC=3)=[N:14][C:13]=2[CH:26]=1)C1C=CC=CC=1.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[NH2:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH3:27])[C:9]([OH:8])=[CH:26][C:13]=2[N:14]=1
Reactant: Cc1cc2sc(NC(=O)c3ccccc3)nc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc2sc(N)nc2cc1O
Temperature: 140 °C
Yield: 69.4 %

Procedure:
To an ice-cooled solution of N-(5-benzyloxy-6-methyl-benzothiazol-2-yl)-benzamide (0.60 g, 1.60 mmol) was added 70% aq. H2SO4 (5-6 mL). The resulting mixture was heated to 140° C. for 1 h. After completion of reaction (TLC monitoring), the reaction mixture was basified with aq. Na2CO3 solution (pH 10) and extracted with EtOAc (2×300 mL). The organic layers were combined and washed with brine solution, dried over Na2SO4, filtered and concentrated to obtain the desired product as a white solid (0.20 g, 70%). MS: 181.16 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[N:23]=[C:22]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=[C:20]2[N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]([C:4]2[NH:5][C:6]([CH3:9])=[C:7]([Cl:8])[C:3]=2[Cl:2])=[O:11])[CH2:14][CH2:15]1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(Cl)c2cc(Cl)ccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cc(Cl)ccc2n1
Yield: 35.5 %

Procedure:
A solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 59 mg, 0.21 mmol), methyl 4,6-dichloroquinoline-2-carboxylate (F R Alexandre, et. al., Tetrahedron 2003, 59: 1413; 57 mg 0.22 mmol) and diisopropylethylamine (0.10 ml) in DMF (2.0 ml) was heated in a microwave reactor to 180° C. for 30 minutes. The reaction was diluted with 50 ml of EtOAc, then extracted with 25 ml of 1 N NaOH, 2×25 ml of water, dried over anhydrous MgSO4 and concentrated in vacuo. The crude solid was flash chromatographed through neutral silica gel using EtOAc as the eluent to give 37 mg of the title compound; crystallization from MeOH gave a white solid.
Reaction SMILES: [CH3:1][CH2:2]N(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:35][CH2:34]3)=[N:29][NH:28][C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(I)C>CC#N>[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:37][CH2:38]3)=[N:29][N:28]([CH2:1][CH3:2])[C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2CC2CCCCC2)CC1
Solvent: CCI
Solvent: CC#N
Product: CCn1nc(CCN2CCN(c3ccccc3OC)CC2)n(CC2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.2 %

Procedure:
To a slurry of PS-BEMP (0.682 g, 1.50 mmol, 2.2 mmol/g) and 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (E17; 300 mg, 0.75 mmol) in MeCN (10 mL), ethyl iodide (0.12 mL, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The resin was filtered, washed with MeOH (10 mL) and the solvent was evaporated in vacuo to afford 280 mg crude foamy solid. Purification by preparative LC-MS afforded 190 mg (59%) of the title compound as a glassy solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:38])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:17]4=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.[O:39]1[CH2:42][C:41](=O)[CH2:40]1>>[Cl:38][C:6]1[C:5]([CH:3]2[CH2:2][N:1]([CH:41]3[CH2:42][O:39][CH2:40]3)[CH2:4]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:32][CH2:31]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C1COC1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CN(C3COC3)C2)c1

Procedure:
The title compound, was prepared from 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 357E) and oxetan-3-one using a method analogous to that used to prepare Example 301.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:24][CH:25]=1)[CH3:40]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc2c1CCN2S(=O)(=O)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 471.15 (M+H+.), was prepared in analogy to example 26, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH2:1]([S:13][C:14]1[O:18][C:17]([C:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:25]([NH:28][CH2:29][CH2:30]O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([NH:28][CH2:29][CH2:30][O:23][C:22](=[O:24])[CH2:21][C:19]([C:17]1[O:18][C:14]([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: CC(=O)NCCO
Reactant: CCCCCCCCCCCCSc1ccc(C(=O)CC(=O)O)o1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSc1ccc(C(=O)CC(=O)OCCNC(C)=O)o1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 20.0 g (0.057 mole) of 2-[5-(dodecylthio)-2-furoyl]acetic acid, 9.2 g (0.057 mole) of N,N'-carbonyldiimidazole and tetrahydrofuran is stirred for 4 hours, after which 5.9 g (0.057 mole) of N-acetylethanolamine is added. The mixture is stirred at room temperature overnight, then is diluted with ice cold 5% aqueous hydrochloric acid and extracted with ether. The ether layer is washed in water and saturated sodium chloride solution, dried with sodium sulfate, and evaporated to dryness to yield 2-[5-(dodecylthio)-2-furoyl]acetic acid 2-acetamidoethyl ester.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[NH2:16][C:4]1[S:3][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N:27]3[CH2:26][CH2:25][O:24][CH2:29][CH2:28]3)[CH:35]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: OB(O)c1cccc(N2CCOCC2)c1
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CCOCC4)c3)sc2N)cn1
Yield: 59 %

Procedure:
Following Example 278, Suzuki coupling of (tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 3-morpholinophenylboronic acid gave 244 as a beige solid (56 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.25-6.95 (m, 4H), 6.07 (s, 2H), 3.92-3.88 (m, 7H), 3.24 (t, J=5 Hz, 4H). LCMS (ES+) m/z 385 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].Cl>O1CCOCC1>[NH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]2[N:7]=[C:2]([Cl:1])[C:3]([C:22]#[N:23])=[N:4][CH:5]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 2.00 g, 5.93 mmol) was treated with 25 mL commercial 4N HCl in dioxane at RT for 2 hours. It was concentrated in vacuo to afford crude (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221) hydrochloride as white solid. It was dissolved in 10 mL DMF and 50 mL dioxane. To it were added DIEA (8.25 mL, 47.4 mmol) and then dropwise dimethylcarbamoyl chloride (1.64 mL, 17.8 mmol). The mixture was stirred at RT for 3 hours. It was concentrated in vacuo, diluted with 200 mL EtOAc, washed with water ×2, dried, concentrated in vacuo, subjected to silica flash column using 0 to 4% MeOH in DCM to isolate (R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222) (1.47 g, 80%) as a white solid.