Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[N:5]1[C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]([C:24]([O:26][CH3:27])=[O:25])=[C:6]1[CH3:28])C.Cl>CC(C)=O>[CH3:28][C:6]1[NH:5][C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1

Procedure:
The resulting (-)-1-ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is then dissolved in acetone (100 mL), and treated with 1N HCl (20 mL) at room temperature for 1 h. The acetone is then removed, the residue taken up in water (20 mL), and the resulting mixture extracted with EtOAc. The ethyl acetate extract is washed with water, dried, and evaporated to yield (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (12-(-), mp=196°-197° C., αD22 =-19.6°). The (+) isomer is similarly prepared (12-(+), mp=194°-195° C., αD22 =+19.1°).
Reaction SMILES: [C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32]O>C(#N)C>[C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH2:32][CH:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:30])[O:8][CH2:32][CH:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CO)Cc1ccccc1
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Solvent: CC#N
Product: NC(COB(c1ccccc1)c1ccccc1Oc1ccccc1B(OCC(N)Cc1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
The entitled compound (73 mg) was obtained by allowing 77 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether and 75 mg of 2-amino-3-phenylpropanol to act in 1 mL of acetonitrile.
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:18]=[C:19]([CH3:23])[C:20](=O)[CH3:21])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([NH2:46])[C:37]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:38][CH:39]=2)[CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[N:8]([N:18]=[C:19]([C:20](=[N:46][N:36]3[C:37]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[CH:38][CH:39]=[C:35]3[C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH3:21])[CH3:23])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nn1c(-c2cccnc2)ccc1-c1cccnc1
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (1.0 g, 3.4 mmol) in toluene (12 ml) is treated with DMF (6 ml), 2,5-di-pyridin-3-yl-pyrrol-1-ylamine (850 mg, 3.6 mmol) and p-toluene sulfonic acid (30 mg). The resulting suspension is fitted with a Dean Stark trap and heated to reflux with azeotropic removal of water in an oil bath until no starting materials remain by TLC. The solution is cooled to rt and concentrated in vacuo. The residue is purified by flash chromatography to afford 2-(2,5-diphenyl-pyrrol-1-ylimino)-3-(2,5-dipyridine-3-yl-pyrrol-1-ylimino)-butane.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9]N=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:25])[N:14]=1.C1C2C(=CC=CC=2)CCN1>CS(C)=O>[CH2:11]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:9]=2)[CH2:6][CH2:7][N:1]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:25])[N:14]=1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1C
Reactant: C1CCC2=NCCCN2CC1
Agent: c1ccc2c(c1)CCNC2
Solvent: CS(C)=O
Product: CCOC(=O)c1c(C)nc(N2CCc3ccccc3C2)nc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (1.086 g, 7.15 mmol) was added to a mixture of 6b (1.02 g, 4.75 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.95 g, 7.13 mmol) in DMSO (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 6c (1.43 g, 4.5 mmol, 95%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nn1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone and 6-chloropyridazine-3-carbonitrile. MS (ESI) 416 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH2:11][O:10][C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]>B(F)(F)F.CCOCC>[N+:1]([C:4]1[C:12]2[CH2:11][O:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1OCc2c1cccc2[N+](=O)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c1COC2
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A suspension of 19.5 g of 1,3-dihydro-4-nitrobenzo[c]furan-1-one in 100 ml of boron trifluoride etherate was cooled to 0°-5° under nitrogen. 125 ml of a 1M solution of borane-tetrahydrofuran complex was added dropwise below 10°. The orange suspension was allowed to warm to ambient temperature (H2 evolution), and the reaction mixture exothermed to 30°. When the exotherm subsided (15-20 minutes), the mixture was refluxed 2.5 hours. The reaction mixture was cooled, decanted from some brown solids, and concentrated in vacuo to a yellow oil. The oil was cooled in an ice bath and acidified with dilute hydrochloric acid (H2 evolution), then diluted with 300 ml water, and the suspension was extracted with ether. The organic solution was washed with brine, dried over magnesium sulfate, filtered, and the solvent evaporated in vacuo. The resulting yellow solid was purified by chromatography, eluting with methylene chloride to give 15.4 g of 1,3-dihydro-4-nitrobenzo[c]furan as a pale yellow solid, m.p. 104°-108°.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:7]([C:8]([O:10]C)=O)=[C:6]([CH:16]=[O:17])[CH:5]=1)[CH:2]=[CH2:3].[BH4-].[Na+]>CO.CCOC(C)=O>[CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:7]2[C:8](=[O:10])[O:17][CH2:16][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)c(C(=O)OC)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCc1cc2c(c(OC)c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask charged with methyl 4-allyl-2-formyl-6-methoxybenzoate (0.77 g, 1 mmol) was added sodium borohydride (0.36 g, 9.33 mmol); the mixture was then dissolved in MeOH (10 mL) and stirred for 18 h at room temp. LC indicated completion of the reaction. The mixture was diluted with EtOAc (150 mL) and washed with brine (2×100 mL). The organic layer was then separated, dried(Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by MPLC (hexanes/EtOAc=1/0.5) to provide 5-allyl-7-methoxy-2-benzofuran-1(3H)-one.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[O:30]1CCC[CH2:31]1>CO.F[B-](F)(F)F.[Ag+]>[CH3:2][C:3]1([O:30][CH3:31])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:15])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:29]1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: C1CCOC1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC1(C)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.55 g) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml). To this solution was added silver fluoroborate (0.24 g) under cooling and then the mixture was stirred for 1 hour. The reaction mixture was concentrated and the obtained residue was dissolved in chloroform. This solution was washed with a saturated sodium bicarbonate aqueous solution and with water and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to chromatography on silica gel using chloroform as developing solvent. The obtained crystals were recrystallized from carbon tetrachloride to give 2,2,2-trichloroethyl 3-methyl-3-methoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.27 g), mp. 132° to 133° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:15](=O)([O:21]C(OC(C)(C)C)=O)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][N:5]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:4]1
Reactant: CN(C)C1CNC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of N,N-dimethylazetidin-3-amine (Intermediate 28, 100 g, 1.0 mol) and triethylamine (487 mL, 3.5 mol) in CH2Cl2 (500 mL) was added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (326 g, 1.5 mol) at 0° C. The mixture was then stirred at r.t. for 5 h. The mixture was then washed with water (4×500 mL) and the organic solution were dried (Na2SO4) and concentrated in vacuo. Purification by FCC gave the title compound (62 g, 31%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:38])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([Cl:35])[C:31]([F:36])=[CH:30][C:29]=5[F:37])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>C(Cl)Cl.CCOCC>[ClH:35].[ClH:39].[ClH:35].[Cl:35][C:32]1[C:31]([F:36])=[CH:30][C:29]([F:37])=[C:28]2[C:33]=1[CH:34]=[C:25]([C:23]1[C:22]([NH2:38])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[N:26]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)c(F)cc(F)c5cn4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)c(F)cc(F)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-{4-[6-Amino-5-(5-chloro-6,8-difluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (0.0311 mmol) was dissolved in DCM (4.4 ml), and 1.0 M of HCl in Et2O (8.8 ml) was added. The mixture was stirred at rt for 16 h. After that time, solvent was removed in vacuo to give the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.30 (m, 4H), 3.03-3.18 (m, 2H), 3.36-3.42 (m, 2H), 4.50-4.60 (m, 1H), 4.97 (brs, 2H), 8.07 (t, J=10.0 Hz, 1H), 8.14 (s, 1H), 8.49 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.63 (d, J=0.8 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.14 (brs, 1H), 9.31 (brs, 1H), 9.66 (s, 1H). MS(ES+): m/z=440.84/442.79 (82/32) [MH+]. HPLC: tR=1.89 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[S:32]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33]>>[CH:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:32]([C:35]2[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=2[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33])[CH:10]=1)=[O:13]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Yield: 60 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (513 mg), sodium hydride (60% in oil, 216 mg), 15-crown-5 (990 mg) and methyl 2-(chlorosulfonyl)benzoate (1.06 g), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 664 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>C(OCC)C>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Yield: 48 %

Procedure:
The title compound was synthesized as described for Example 178 in 48% yield, starting from 2-aminobenzenesulfonamide and 3-bromobenzenesulfonyl chloride. The product solidified after the extractive work up. Diethyl ether (25 mL) was added and the crystals were crushed with a glass stick. The mixture was filtered and the solid was rinsed with diethyl ether and dried in vacuo at ambient temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:10][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CC(Cc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(Cc2ccc(N)cc2)C1
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Ethyl 3-(4-nitrobenzyl)cyclobutanecarboxylate (4.02 mmol) was stirred in EtOAc (20 mL) at room temperature and nitrogen was bubbled through. 10% Palladium on carbon (160 mg) was added and the reaction vessel was put under an atmosphere of hydrogen. The mixture was stirred overnight then filtered through diatomaceous earth and concentrated by evaporation under reduced pressure. The residue was purified by chromatography eluting with 0-55% EtOAc/isohexane to give the title compound (466 mg, 50%) as an oil; 1H NMR δ 1.15-1.20 (3H, m), 1.77-1.94 (2H, m), 2.13-2.20 (2H, m), 2.33-2.37 (2H, m), 2.43-2.46 (1H, m), 2.53-2.56 (1H, m), 2.92-3.07 (1H, m), 4.01-4.08 (2H, m), 4.77 (2H, d), 6.46-6.49 (2H, m), 6.78-6.82 (2H, m); MS m/e M+MeCN 275.
Reaction SMILES: [NH2:1][CH:2]([PH:10](=[O:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O>[C:4]1([CH2:3][CH:2]([PH:10](=[O:11])[OH:12])[NH:1][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(Cc1ccccc1)[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1-Amino-2-phenylethyl)phosphinic acid (1 g., 5.4 mmole) is suspended in water (25 ml.) at 0° and the pH is adjusted to 9.5 with concentrated sodium hydroxide solution. Benzyl chloroformate (0.9 ml., 1.08 g., 6.3 mmole) is added while the pH is maintained at 9.5 by the addition of sodium hydroxide. After the pH stabilizes, the mixture is stirred for 3 hours at room temperature. The basic solution is washed with ether and then acidified. The white solid precipitate is collected on a frit to give [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-phosphinic acid. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.75.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:16])[N:8]=1>C(Cl)(Cl)Cl>[Cl:3][C:7]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:16])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1CC(O)=NN1C
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CC(Cl)=NN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of POCl3 (31.8 ml, 341 mmol) and Net3 (47.6 ml, 341 mmol) in CHCl3 (100 ml) at −5° C. was added a solution of methyl 3-hydroxy-1-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (36 g, 228 mmol) in CHCl3 (100 ml). After 1 h at this temperature, the mixture was stirred for another 20 h under warming to rt. Then, the reaction mixture was poured on ice water and extracted with CHCl3. The combined organics were washed with water, dried over Na2SO4 and evaporated under reduced pressure. This yielded the title compound (21 g, 52%) which was used in the next step without further purification. [LCMS RtJ=0.63 min; [M+H]+=177.0, 179.0]
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[O:21]=[N+:22]=[O:23]>C(Cl)Cl.S1(CCCC1)(=O)=O>[C:11]([C:7]1[CH:8]=[C:9]([N+:22]([O-:23])=[O:21])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: -60 °C

Procedure:
Dissolve 2,6-di-t-butylphenol (721 mg, 3.5 mmol) in methylene chloride (10 mL) and cool to -60° C. Add, by dropwise addition, a solution of nitronium tetrafluoroborate (25 mL of a 0.5M solution in sulfolane, 12.5 mmol) in methylene chloride (15 mL). Warm slowly to 10° C. and partition between methylene chloride (75 mL) and water (75 mL). Separate the aqueous phase and extract with methylene chloride (50 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify and separate by flash silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:22](C)=O.[Na+].CCCCCC.C(OCC)(=O)C>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH3:22])=[CH:16][CH:17]=1
Reactant: COCCOCOCCOc1ccc(N)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(OCCOCOCCOC)cc1
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
To a 25 mL, 3-neck RBF equipped with a magnetic stirrer and calcium chloride guard tube, 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline (1.0 g in 10 mL DMF) and formaldehyde (0.062 g) were added portion wise to the reaction mixture at 0° C. and stirred for an additional 10 minutes. NaBH(OAc)3 (0.88 g) was added and the mixture was stirred for 5 minutes. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion of the reaction, the reaction mixture was poured in water and extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by using column chromatography. Desired product was eluted with 7% ethyl acetate in hexane to give 0.200 g of 4-(2-((2-methoxyethoxy)methoxy)ethoxy)-N-methylaniline. M+1=256.0.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37](Cl)=[O:38])[C:25]=2[CH3:40])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:38])[C:25]=2[CH3:40])=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A mixture of 1.82 g of tert-butyl hydrazinecarboxylate and 2.4 ml of triethylamine in 50 ml of DCM is cooled to 0° C., a solution of 5.24 g of the compound obtained in stage A in 50 ml of DCM is added and the mixture is left stirring while allowing the temperature to rise to AT. The reaction mixture is washed with water, with a buffer solution at pH=2 and with a saturated NaHCO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is taken up in isopropyl ether, pentane is added and the precipitate formed is filtered off. 6.2 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cc(F)ccc12
Yield: 19.1 %

Procedure:
Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-fluoro-2-amino benzothiazole (10.0 g, 59.5 m.mol) and ethyl bromopyruvate (17.4 g, 89.2 mmol), 3.0 g (19% Yield) of ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown semi-solid. (M+H) 265.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[NH2:50][C:51]1[C:56]([C:57]([C:59]2[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:60]=2[O:66][CH3:67])=[O:58])=[CH:55][N:54]=[C:53]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[N:52]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:50][C:51]1[C:56]([C:57](=[O:58])[C:59]2[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:60]=2[O:66][CH3:67])=[CH:55][N:54]=[C:53]([NH:68][CH:69]2[CH2:74][CH2:73][N:72]([C:5](=[O:7])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:71][CH2:70]2)[N:52]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CN(C)C)CC2)nc1N
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
To a solution of N,N-dimethylaminoacetic acid (9.8 mg, 0.095 mmol, Aldrich) in dimethylformamide (2 mL) were added 1-hydroxybenzotriazole hydrate (16.5 mg, 0.108 mmol, Aldrich), O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluorophosphate (40.8 mg, 0.108 mmol, Aldrich). After it was stirred for 20 minutes, a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (47 mg, Example 59) and triethylamine (47 mg, 0.469 mmol, Aldrich) in dimethylformamide (2 mL) were added. The mixture was stirred overnight at room temperature before it was concentrated, taken up in ethyl acetate, washed with brine and evaporated. The crude product was purified on HPLC to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-dimethylamino-ethanone (12.5 mg). MS (M+H)+: 431.