Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]C)=O)[CH2:3][CH2:2]1.O.[NH2:13][NH2:14]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:13][NH2:14])=[O:10])[CH2:3][CH2:2]1
Reactant: COC(=O)CN1CCOCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1CCOCC1
Temperature: 95 °C
Yield: 92 %

Procedure:
In a 25 mL, 3-neck round-bottom flask, methyl 2-morpholinoacetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.087 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-morpholinoacetohydrazide (0.23 g) which was used without further purification in the following step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#N.F[B-](F)(F)F.[SiH](CC)(CC)CC.[OH2:26]>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])=[O:26]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: O
Agent: CC[SiH](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C=O)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
A solution of 305 mg (1.74 mmol) of methyl 3-cyano-4-methylbenzoate and excess Et3O+BF4− in 7 mL of CH2Cl2 was stirred at 45° C. After 13 h and about 24 h more Et3O+BF4− was added and after a further 20 min. the temperature was increased to 50° C. After 37 h, the temperature was increased to 55° C. and heating was continued for 1.5 h. After this time, the crude solution was added with 3 mL of CH2Cl2 to 0.16 mL of Et3SiH in 5 mL of CH2Cl2. After the solution was stirred at 55° C. for 2 h, 10 mL of H2O was added, and the mixture was stirred at 120° C. for 15 min. and the temperature was decreased to 115° C. for 1 h, stopped for 2 h, and then resumed for 17 h. EtOAc was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (7.5% EtOAc/hexanes) provided 25 mg of methyl 3-formyl-4-methylbenzoate as colorless oil with some impurity. 5-(methoxycarbonyl)-2-methylbenzoic acid was synthesized from the aldehyde following the general procedure as described above for the methyl substituted benzoic acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:28]=[C:27](F)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([NH:7][C:8]2[N:28]=[C:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(F)nc3NC3CCCCC3)cc21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(N4CCCCC4)nc3NC3CCCCC3)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 2-(cyclohexylamino)-6-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide (150 mg), piperidine (64 mg), potassium carbonate (63 mg) and DMF was stirred at 60° C. for 18 hours. Then, water was added, followed by extraction with ethyl acetate. After drying the organic layer with magnesium sulfate, the solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane:ethyl acetate, 2:1 to 1:1) to obtain 2-(cyclohexylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-6-piperidin-1-ylnicotinamide (138 mg) as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[O:28][N:37]=[C:31]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[N:30]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CS(=O)(=O)CC(N)=NO
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 41.8 mg (0.275 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 20.6 mg (16% of theory).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[CH:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][N:22]=[C:19]2[CH2:18][CH2:17][N:16]([C:2]3[N:3]=[CH:4][C:5]4[CH2:11][N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:21][CH2:20]2)[CH2:25][CH2:26]1)=[O:31])([CH3:35])[CH3:34]
Reactant: CS(=O)(=O)N1CCc2nc(Br)ncc2C1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc4c(n3)CCN(S(C)(=O)=O)C4)CC2)CC1
Temperature: 25 °C

Procedure:
Crude 59a, 2d (51 mg) and diisopropylethylamine (0.07 mL) in 0.4 mL of DMSO was heated at 100° C. for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (5 mL) and washed with brine (3×5 mL). The organic layer was dried, concentrated and purified by preparative HPLC to afford 59b: LC-MS 495.4 (MH+), tR=5.11 (Method 4). EC50: 328 nM.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9][N:8]=2)[CH2:3][CH2:2]1>Cl.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(N2CCOCC2)nc1
Agent: Cl
Solvent: O
Product: O=C(O)c1cnc(N2CCOCC2)nc1
Temperature: -78 °C
Reaction time: 48 h
Yield: 107.3 %

Procedure:
A solution of ester 122 (0.205 g, 0.86 mmol) in 2N HCl in H2O (10 mL) was stirred at 110° C. in a pressure vessel for 6 h, cooled to −78° C. and lyophilized for 2 days. The resulting amorphous solid was further dried using a mixture of dry acetonitrile (10 mL) and dry benzene (10 mL) followed by concentration (this was repeated 3 times) to give compound 123 (0.193 g, 92% yield). LRMS: 209.1 (calc) 210.0 (obs).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:11]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:12][CH3:13]>CCCCCC>[F:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]([CH3:13])[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: CC=CN1CCCCC1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Solvent: CCCCCC
Product: CC1N=NN(c2ccc(F)cc2)C1N1CCCCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 21 %

Procedure:
Prepared in analogy to EP 0 433 842 A2. A mixture of 1-azido-4-fluoro-benzene (2.80 g, 20 mmol) and 1-(1-propenyl)-piperidine (18%, 14.2 g, 20 mmol) was stirred under ice cooling (slowly exothermic in the beginning) and at room temperature for 144 h in the absence of light. Hexane was then added to the brown solutions and a solid formed which was filtered off, washed with hexane and dried in hv to give the title product (1.1 g) as a light pink solid. The filtrate was then evaporated and purification by chromatography (silica, 10 to 50% ethyl acetate in heptane) afforded the title compound (4.34 g) as a light yellow solid. Total yield (5.44 g, 98%). MS: m/e=263.1 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1)[C:12](=[O:27])[CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]([CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1)[C:12](=[O:27])[CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16]
Reactant: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccn2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(CN(CCO)C(=O)CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-Nα-(2-nitrobenzenesulfonyl)glycine amide (3.41 g) was dissolved in THF, and to the solution a THF solution (6.1 mL) of 1.0 M tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=10:1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[OH:13])=[O:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]
Yield: 100.5 %

Procedure:
A solution of 2-methoxycarbonyl-5-methoxyphenol (34.1 g, 0.187 mol), 2-nitrofluorobenzene (19.7 mL, 0.187 mol), and K2CO3 (65 g, 0.467 mol) in DMF (200 mL) was heated at 110° C. for 18 h. The solution was diluted with water (200 mL) and extracted with EtOAc. The EtOAc layer was concentrated to give the crude title compound (57 g)which was used as is for the next step without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C12BC(CCC1)CCC2.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:33]=2)[CH:28]=[C:27]([CH3:45])[N:26]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C12B(CC3CCN(C(OC(C)(C)C)=O)CC3)C(CCC1)CCC2>O1CCCC1.CN(C)C=O.O>[CH3:45][C:27]1[CH:28]=[C:29]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[N:33]=2)[N:30]=[C:25]([CH2:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:26]=1
Reactant: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(Cl)n1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: B1C2CCCC1CCC2
Agent: CC(C)(C)OC(=O)N1CCC(CB2C3CCCC2CCC3)CC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To 116.2 mg of tert-butyl 4-methylenepiperidine-1-carboxylate was added a solution of 71.3 mg of 9-borabicyclo[3.3.1] nonane in 2 ml of tetrahydrofuran at room temperature. The reaction mixture was stirred at 90° C. for 1.5 hours, cooled to room temperature, and added to a suspension of 106.8 mg of 2-chloro-6-methyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-amine, 12.3 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-dichloromethane complex, 4.3 mg of triphenylarsine and 49.8 mg of potassium carbonate in 2 ml of N,N-dimethylformamide and 0.2 ml of water. The reaction mixture was stirred at 60° C. for 8 hours. 12.4 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-dichloromethane complex, 4.8 mg of triphenylarsine and 47.3 mg of potassium carbonate was added to the reaction mixture, followed by stirring the reaction mixture at 60° C. for 13 hours, 90° C. for 1.5 hours and 100° C. for 2.5 hours. 13.7 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-dichloromethane complex, 5.0 mg of triphenylarsine, 47.1 mg of potassium carbonate and a solution of tert-butyl 4-(9-borabicyclo[3.3.1]non-9-ylmethyl)piperidine-1-carboxylate (prepared from 117.6 mg of tert-butyl 4-methylenepiperidine-1-carboxylate and 145.2 mg of 9-borabicyclo[3.3.1]nonane in 2.5 ml of tetrahydrofuran at 100° C. for 3 hours) were added to the reaction mixture, followed by stirring the reaction mixture at 100° C. for 4.5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CN1CCOCC1.O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: COc1ccc(Br)nc1F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: COc1ccc(Br)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 94.8 %

Procedure:
A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.030 mmol; 418.1 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (3.044 mmol; 609.7 mg), and N-Methylmorpholine (6.089 mmol; 622 mg; 0.676 mL) in 1-methyl-2-pyrrolidinone (5 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 40% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-2-pyridyl)-3-piperidyl]carbamate (743.5 mg, 95%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:8][CH:9]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.08 mmol) in DCM (2 mL) was added triethylamine (25 uL) followed by benzoyl chloride (11 uL) and the resulting mixture stirred at room temperature for 2 hours The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-(benzamidomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0128 g, 0.03 mmol, 36%). 1H NMR (DMSO) δ 4.54 (2H, d), 7.40 (2H, t), 7.49 (4H, m), 7.55 (1H, m), 7.74 (3H, m), 7.92 (2H, m), 8.18 (2H, d), 9.15 (1H, t). LCMS (2) Rt: 2.82 min; m/z (ES+) 434.
Reaction SMILES: [CH3:1][CH:2]([C:8]([OH:10])=[O:9])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([NH:4][CH:3]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[C:8]([OH:10])=[O:9])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C(=O)O)C(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)C(NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
Using a similar method to above 3-methyl-D,L-aspartic acid (10.0 g, 67 mmol), benzyl chloroformate (12 ml, 100 mmol) in 50% NaOH (16.7 g, 208 mmol) in water (125 ml) yielded N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid 19.0 g as a low melting solid. 1H NMR (90 MHz, CDCl3 /d6DMSO): δ 1.1 (3,d), 2.9 (1,dt), 4.4 (1,m), 4.95 (2,s) 5.9 (1,bd) 7.2 (5,6) 7.9 (1,bs).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:32][C:33]1[CH:34]=[C:35]([NH2:42])[C:36](=[CH:40][CH:41]=1)[C:37]([OH:39])=[O:38]>ClCCl>[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([NH:42][C:17](=[O:18])[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:34]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: O=C(O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)c(NC(=O)Cc2c(-c3ccccc3)[nH]c3ccccc23)c1
Yield: 20.9 %

Procedure:
2-Phenyl-3-indole acetic acid (0.166 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.127 g) and 4-methylanthranilic acid (0.100 g) in dichloromethane (20 ml) were refluxed for 48 h under nitrogen. The solvent was then removed and the residue purified using mass spectroscopy directed automated HPLC to afford the title compound (0.053 g). LC/MS TR 3.58 min, MH+ 384.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:14][C@H:10]3[C:11]=2[NH:12][N:13]=1)=[O:5])[CH3:2].Br[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[CH:16]([N:12]1[C:11]2[C@@H:10]3[CH2:14][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:13]1)([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1n[nH]c2c1C[C@H]1C[C@@H]21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)C)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
(1aR,5aR)-1a,2,5,5a-Tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid ethyl ester (0.100 g, 0.520 mmol) (from Example 1.4, Step A) was dissolved in anhydrous DMF (5.20 mL). CsCO3 (0.678 g, 2.081 mmol) was added to give a suspension which was stirred at 25° C. for several minutes. 2-Bromopropane (0.098 mL, 1.041 mmol) was added dropwise at 25° C. After stirring for 4 h, the reaction was diluted with EtOAc (50 mL), washed with water (2×10 mL), brine, and dried over MgSO4. The solvent was evaporated under reduced pressure. The oil residue was purified by silica gel column chromatography to give the title compound as an oil (0.073 g). LCMS m/z=235.3 [M+H]+; 1H NMR (400 MHz, CDCl3) ppm 0.29-0.35 (m, 1H), 1.12 (td, J=8.02, 4.93 Hz, 1H), 1.34 (t, J=7.20 Hz, 3H), 1.46 (dd, J=15.16, 6.57 Hz, 6H), 2.04-2.12 (m, 1H), 2.16-2.24 (m, 1H), 2.74-2.82 (m, 1H), 2.90-2.99 (m, 1H), 4.27 (q, J=7.07 Hz, 2H), 5.31-5.43 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 50% yield (yellow solid) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.61 (d, 1H, J=8.2 Hz), 8.18 (s, 1H), 7.96 (d, 1H, J=7.9 Hz), 7.58 (t, 1H, J=7.7 Hz), 7.51 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.26 (m, 1H), 3.53 (s, 2H), 3.30 (m, 4H), 2.53 (bs, 8H), 2.34 (s, 3H), 1.84 (m, 4H); MS (ESI): 542.20 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:29](Br)[CH:30]=[CH2:31]>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:31][CH:30]=[CH2:29])[N:19]=3)=[O:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=C(NCCN1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Product: C=CCn1nc(C(=O)NCCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21

Procedure:
The title compound was synthesized by using N-[2-(4-p-fluorobenzyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 11 and allyl bromide according to the same process as in Example 12.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:8]([Cl:11])(Cl)Cl>C1C=CC=CC=1>[CH:1]([N:4]([P:8]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[Cl:11])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: ClP(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C

Procedure:
The synthesis shown in FIG. 2A can be carried out, for example, by adding anhydrous N,N-diisopropylamine to a solution of phosphorus trichloride in dry benzene to produce bis(N,N-diisopropylamino)chlorophosphine, and reacting it in situ with 2-(N-formyl-N-methyl) aminoethan-1-ol to produce phosphordiamidite 120 in about 73% yield. Phosphordiamidite 120 can then be reacted with a suitably protected nucleophile, such as 5′-O-(4,4′-dimethoxytrityl)-2′-deoxythymidine (Barone et al., Nucl. Acids Res., 12, 4051-4061 (1984)) to produce deoxyribonucleoside phosphoramidite 101 (FIG. 2A).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[CH:62]=[CH:61][C:54]([O:55][C:56]([CH3:60])([CH3:59])[CH2:57][NH2:58])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:58][CH2:57][C:56]([O:55][C:54]2[CH:53]=[CH:52][C:51]([F:50])=[CH:62][CH:61]=2)([CH3:60])[CH3:59])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(CN)Oc1ccc(F)cc1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[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(C)(CNC(=O)c1ccc(N)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (200.0 mg, 1.289 mmol) and HBTU (490 mg, 1.3 mmol) in DMF (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.67 mL, 3.9 mmol) and 2-(4-fluorophenoxy)-2-methylpropan-1-amine (Preparation 91, 280 mg, 1.5 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform).