Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[CH3:18][CH:19]([CH:21]=O)[CH3:20].CC(O)=O>C(COC)OC>[CH2:2]([O:3][C:4](=[O:5])[C:6]([CH3:7])=[CH:18][CH:19]([CH3:21])[CH3:20])[CH3:1]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=CC(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Within a period of 90 min., a solution of triethyl 2-phosphonopropionate (238 g, 1.00 mol) in dimethoxyethane (DME, 150 ml) was added dropwise with stirring under an atmosphere of N2 to a solution of NaH (43.6 g, 1.00 mol) in DME (600 ml). The mixture was then heated to reflux, and after 15 min. at reflux temp., isobutyric aldehyde (72.1 g, 1.00 mol) was added dropwise. After a further 30 min. stirring at reflux, the mixture was poured into ice/water (1:1, 1 L). AcOH (60 ml) was added, and the product was extracted with Et2O (2×200 ml). The combined organic extracts were washed with water (400 ml) and brine (100 ml), dried (Na2SO4), and concentrated in a rotary evaporator. The resulting residue was distilled to provide at 86-75° C./27 mbar 117 g (75%) of 2,4-dimethylpent-2-enoic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][CH:9]=2)[N:4]=1)#[N:2].[H][H]>[Pd].C(O)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[CH:11]=[CH:12][C:3]=1[CH2:1][NH2:2]
Reactant: N#Cc1ccc2ccc3ccccc3c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NCc1ccc2ccc3ccccc3c2n1
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 2-cyanobenzo[h]quinoline (2.04 g, 10.0 mmol) and 10% palladium on carbon (0.40 g) in acetic acid (120 ml) was hydrogenated at ambient temperature, in a Parr reactor, with hydrogen gas at a pressure of 2 atm. After 4 hours, during which time absorbance of two hydrogen equivalents was observed, the reaction mixture was filtered and the solvent evaporated under reduced pressure. The oily residue was taken up with ethyl ether and the mixture washed with a 10% NaOH solution until an alkaline pH was achieved. The organic phase was then separated and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography using MeOH as eluent. 1.87 g (90% yield) of 1-(benzo[h]quinolin-2-yl)methanamine in the form of a red solid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:89]1([CH2:95][CH2:96][OH:97])[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C=O)C>[OH:97][CH2:96][CH2:95][N:89]1[CH2:94][CH2:93][N:92]([C:2]2[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:18]=[C:19]([C:20]5[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=6)[CH2:27][C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)=[N:24][CH:25]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:91][CH2:90]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(Br)c3)cn2)cc1
Reactant: OCCN1CCNCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(N4CCN(CCO)CC4)c3)cn2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a DMF solution (2.0 ml) of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide (70.5 mg) obtained in Step B, tris(dibenzylideneacetone) dipalladium (4.3 mg), S-Phos (3.8 mg) and potassium phosphate (39.8 mg), 2-piperazin-1-yl-ethanol (23 μl) was added, and degassed under ultrasonic irradiation. After this was stirred at 100° C. for 4 hours, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography, to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-methyl-amide. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-153) as a colorless solid (7.2 mg, 14%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=2)[CH2:8]1.[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:21][C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])[CH2:8]2)[CH:17]=[CH:16][C:15]=1[NH2:18]
Reactant: [H][H]
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 2-(2R)-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl (2 g, 6.9 mmol) in MeOH (15 mL) was de-aerated and nitrogen was introduced. To this solution was added Pd—C (10%, 0.20 g). The nitrogen was replaced with hydrogen and the mixture was stirred under H2 atmosphere at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS showed the reaction was complete. The mixture was passed through a celite pad, rinsed with methanol. The filtrate was concentrated to dryness, and further dried under high vacuum to yield the title compound as a reddish brown liquid after drying under high vacuum, 2.02 g (100% yield).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6]CC)=O)[CH2:2]1.[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.O>C1COCC1.C1(C)C=CC=CC=1>[OH:6][CH2:4][C:3]1([CH3:12])[CH2:9][CH2:10][CH2:11][NH:1][CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CI
Product: CC1(CO)CCCNC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To ethyl nipecotate (1.3 g) in THF (20 mL) at r.t was added potassium bis(trimethylsilyl)amide (18 mL of a 0.5 M solution in toluene). After 1 h, methyl iodide (0.5 mL) was added and the mixture was stirred for 15 h. Water was added and the mixture extracted with ether. The organics were washed with brine, dried and concentrated. The residual material (1.3 g) was dissolved in THF (20 mL) and treated with lithium aluminum hydride (8.7 mL of a 1 M solution in THF) at r.t. After 15 h, the mixture was cooled to -5° C. and aqueous sodium potassium tartrate was added followed by concentrated NH4OH, 10 N NaOH and the resulting mixture was stirred for 30 min. The mixture was filtered through anhydrous sodium sulfate and the filtrate was concentrated from toluene twice. The residual oil (1 g), containing the title compound, was used without further purification in Step 2.
Reaction SMILES: [CH3:1][C@@:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.CN(C=O)C.N1C=NCC=1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.CCOCC>[C:19]([Si:23]([CH3:26])([CH3:25])[O:8][C@:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@]1(O)C=CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C1=NC=NC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@]1(C)C=CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-methylcyclohex-2-enol, 50a, (1.00 g, 8.91 mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.82 g, 26.74 mmol), tert-butyldimethylchlorosilane (2.02 g, 13.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.11 g, 0.89 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed consecutively with water, citric acid and water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil 1.98 g was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:34]=[CH:33][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[CH2:31]([O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=1)=[O:23])[CH3:32]
Reactant: CCOc1cccc(C(=O)c2ccc(Br)cc2)c1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Product: CCOc1cccc(C(=O)c2ccc(Nc3nccc(-c4cnc5ccccn45)n3)cc2)c1
Yield: 48 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo-3′-ethoxybenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent affording 0.11 g (48% yield) of the title compound as a yellow solid: mp 197.3-197.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1 H), 10.17 (d, J=6.8 Hz, 1 H), 8.68 (s, 1 H), 8.53 (d, J=5.4 Hz, 1 H), 8.00 (d, J=8.5 Hz, 2 H), 7.82-7.79 (m, 3 H), 7.55-7.51 (m, 2 H), 7.47 (t, J=8.2 Hz, 1 H), 7.28 (d, J=7.5 Hz, 1 H), 7.23-7.17 (m, 3 H), 4.10 (q, J=6.8 Hz, 2 H), 1.36 (t, J=6.9 Hz, 3 H); 13C NMR (400 MHz, DMSO-d6) δ 194.4, 159.4, 158.7, 157.6, 157.4, 148.4, 145.4, 139.7, 139.4, 131.6, 129.9, 129.8, 129.8, 127.5, 22.0, 121.3, 118.6, 118.2, 117.8, 114.8, 114.2, 108.6, 63.6, 15.0; MS (ESP) m/z 436 (M+1).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[O:25][CH3:26].[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.OS([O-])(=O)=O.[Na+]>CCCCCCC.C1COCC1>[Cl:16][C:17]1[C:22]([F:23])=[C:21]([B:27]([OH:32])[OH:28])[C:20]([F:24])=[CH:19][C:18]=1[O:25][CH3:26]
Reactant: COc1cc(F)cc(F)c1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1cc(F)c(B(O)O)c(F)c1Cl
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
5.1 g of 2,2,6,6-tetramethylpiperidine were dissolved using 200 ml of anhydrous THF. 12.4 ml of a 2.7M solution of n-butyllithium in heptane were added at −10° C. and the mixture was stirred for 10 minutes at −10° C. The mixture was then cooled to −70° C. and a solution of 5.0 g 2-chloro-3,5-difluoroanisole in 40 ml of anhydrous THF added dropwise at −70° C. Stirring was continued for 1 h at −75° C. Then, 7.9 g of triisopropyl borat were added and the mixture was allowed to warm to room temperature. Stirring was continued for 1 h at room temperature. Then, the reaction mixture was poured into 200 ml of a saturated aqueous NaHSO4-solution and extracted twice using 100 ml EA each. The organic layer was washed using 100 ml of a saturated aqueous NaHSO4-solution, dried using MgSO4 and evaporated to yield 5.6 g of the title compound that was used without further purification.
Reaction SMILES: N1C=CC=CC=1.C(Cl)Cl.[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][OH:16]>CC(C)=O>[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[O:16]
Reactant: CNc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of dry pyridine (15 ml) and dry methylene chloride (225 ml), chromic anhydride (9.0 g) is added in one portion, and the mixture is stirred for 15 minutes. A solution of 3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol (4.6 g; prepared as described in Example 5) in acetone (25 ml) is then added in one portion and the mixture is stirred for a further 15 minutes. The resulting inorganic precipitate is removed by filtration and the filtrate is evaporated in vacuo. The residue is extracted with diethyl ether (300 ml) and filtered to remove a small amount of insoluble material. The diethyl ether is removed in vacuo to yield crude 3-methylamino-4-phenoxy-5-sulfamylbenzaldehyde. After recrystallization from ethanol it is obtained with a melting point of 166°-167° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)[CH3:2].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNCc1cncc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 36 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.3 mg of the title compound (36%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.C[N:34]1C(=O)CCC1>[OH-].[NH4+]>[NH2:34][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN1CCCC1=O
Reactant: CCC(O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (85 mg, 0.18 mmol) in NMP (1 mL) and ammonium hydroxide (15 M, 1 mL) was stirred at 175° C. in a microwave for 10 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with ethanol/dichloromethane, 1:9) gave the title compound. MS (+ESI): 445 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[F:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][C:15]1[CH:16]=[CH:17][C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:48]3[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(-c5cnn(C)c5)ccn34)c2)CC1
Temperature: 25 °C

Procedure:
A mixture comprising 7-bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (Ex 1.1, step 1) (100 mg, 0.177 mmol) and cesium carbonate (230 mg, 0.707 mmol) in DME (2.5 ml) and water (1 ml) under nitrogen was treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followed by PdCl2(dppf).CH2Cl2 adduct (7.22 mg, 8.84 μmol) and heated using microwave radiation at 100° C. for 1 hr. After cooling to RT, the reaction mixture was partitioned between water (4 ml) and EtOAc (10 ml)/MeOH (1 ml). The organic portion was separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-20% MeOH in DCM followed by trituration of the resulting solid with EtOAc afforded the title compound;
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30]>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[N:10][P:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1cccc(C)c1NC(=N)c1ccc(C(C)(C)C)cc1
Agent: [Li]CCCC
Product: Cc1cccc(C)c1NC(=NP(C(C)C)C(C)C)c1ccc(C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.40 g of 4-t-butyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine IV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a slightly cloudy yellow oil was isolated (2.04 g, 100%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])=[CH:17][CH:18]=1)=[O:11]
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(CO)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of DMSO (0.190 mL, 2.68 mmol) in 4 mL DCM at −78° C. was added oxalyl chloride (0.146 mL, 1.67 mmol) dropwise. After 15 min a solution of N-(4-(hydoxymethyl)phenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (0.241 g, 0.669 mmol) was added via cannula. The reaction was stirred for 30 min and triethylamine (0.932 mL, 6.69 mmol) was added and warmed to 0° C. over 1 h. The mixture was poured into saturated NaHCO3 solution and diluted with ether. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel with 5:1 DCM/EtOAc to give 173 mg of a clear oil (72%). 1H NMR: 9.97 (s,1H), 8.50 (dd,J=4.9, 1.5 Hz, 1H), 8.35 (d,J=2.0 Hz, 1H), 7.87 (m,2H), 7.66 (dt,J=7.8, 2.0 Hz, 1H), 7.44 (m,2H), 7.24 (ddd,J=7.8, 4.9, 1.0 Hz, 1H), 4.97 (s,2H), 3.84 (q,J=9.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]2[CH2:14][CH2:13]2)[C:9](O)=[O:10])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH:12]2[CH2:14][CH2:13]2)[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: OC[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
To a stirred solution of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (7.25 g, 34.4 mmol) in tetrahydrofuran (200 ml) at 0° C. under nitrogen is added dropwise over one hour borane-tetrahydrofuran complex (58 ml of a 1.0 solution in tetrahydrofuran, 58 mmol). The solution is warmed to room temperature and stirred for an additional 4 h. The reaction mixture is cooled to 0° C. and carefully quenched by the dropwise addition of water: THF(1:1, 50 ml). The mixture is diluted with ethyl acetate (250 ml) and washed with water (250 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with ether:hexane (25:75 to 40:60) to afford the title compound as a colorless syrup (5.70 g, 84%) which is characterized by 1HNMR, 13CNMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:4]([O:25][CH3:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:32]3[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=3[Cl:34])[C:2]([Cl:1])=[CH:3][C:4]=2[O:25][CH3:26])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cc(Cl)c(I)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate (180 mg, 0.36 mmol), (2,5-dichlorophenyl)boronic acid (138.9 mg, 0.72 mmol), Na2CO3 (114.5 mg, 1.08 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at 90° C. under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (135 mg, 73% yield) as a solid. ESI-MS m/z: 514.3[M+H]+.