Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)[CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reaction time: 0.5 h

Procedure:
265 mg of sodium hydride was added with stirring under ice cooling to an N,N-dimethylformamide (10 mL) solution of 500 mg of (S)-6-{3-(tert-butoxycarbonylamino)pyrrolidin-1-ylsulfonyl}isoquinoline obtained in Step 1 of Example 10. After stirring in this state for 30 minutes, 0.8 mL of butyl iodide was added dropwise to the reaction solution, and the mixture was further stirred for 30 minutes for reaction. The reaction was terminated by the dropwise addition of water in small portions under ice cooling to the reaction solution. Then, 50 mL of water was added thereto, followed by three extractions with 50 mL of ether. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:1) to obtain 350 mg of the compound of interest as a colorless oil (61%).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>O.CO>[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[C:3]([CH3:19])=[C:4]([NH:11][C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(Cl)nn2ccnc2c1Nc1cccc(O)c1
Solvent: O
Solvent: CO
Product: Cc1c(N[C@H]2CC[C@H](N)CC2)nn2ccnc2c1Nc1cccc(O)c1
Reaction time: 24 h

Procedure:
In a 2 dram reaction vial was added 3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)phenol (0.011 g, 0.028 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 24 hrs. The melt was then cooled, diluted with water and MeOH, and then purified by preparative HPLC to give 0.005 g of the title compound as a TFA salt. 1H NMR (400 MHz, MeOD) δ ppm 8.01 (1H, s), 7.73 (1H, s), 7.11 (1H, t, J=8.14 Hz), 6.48 (1H, d, J=7.63 Hz), 6.28 (1H, s), 3.88-4.10 (1H, m), 3.05-3.27 (1H, m), 2.24-2.37 (2H, m, J=8.65 Hz), 2.11-2.23 (5H, m), 1.45-1.70 (4H, m). LC/MS, m/e 353 (M+1). HPLC Rt, 1.20 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH3:15][CH2:16][O-:17].[Na+]>C(O)C>[CH2:16]([O:17][C:2]1[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1)[CH3:15]
Reactant: CC(C)Nc1nc(Cl)nc2cscc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(NC(C)C)c2cscc2n1
Yield: 67.4 %

Procedure:
A solution of 4.5 g (0.02 mole) of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine and 0.02 mole sodium ethylate in 200 ml absolute ethyl alcohol is heated in an autoclave at 120°C. for 6 hours. It is then evaporated to dryness. The residue is taken up in a mixture of ether and water; the ether phase is washed with water till neutral pH, dried over Na2SO4, filtered and the solvent is driven off in vacuo. The remaining solid (4.4 g) is recrystallized from a mixture of ethyl acetate-hexane containing 30% ethyl acetate. 3.2 g (68% of theory) of 2-ethoxy-4-isopropylamino-thieno[3,4-d]pyrimidine are obtained. M.P. 155°-156°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([NH2:21])=[N:18][C:19]=2[NH2:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:29]([O:31][CH2:32][C:33](Cl)=[O:34])[CH3:30]>C(Cl)(Cl)Cl>[CH2:29]([O:31][CH2:32][C:33]([NH:21][C:17]1[N:18]=[C:19]([NH2:20])[C:14]([CH2:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][N:16]=1)=[O:34])[CH3:30]
Reactant: CCOCC(=O)Cl
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1ncc(Cc2cc(OC)c(OC)c(OC)c2)c(N)n1
Temperature: 50 °C

Procedure:
5.8 g of trimethoprim are suspended in 80 ml of chloroform. After addition of 4 g of triethylamine 2.5 g of ethoxyacetyl chloride are dripped in at room temperature. The mixture is stirred for another hour at 50° C. and then cooled. The triethylammonium chloride is separated by filtration, the filtrate is concentrated and the residue is recrystallized from isopropanol. 4 g of 2-ethoxyacetamido-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 175° to 176° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13]O)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][N:38]2[C:37](=[O:39])[C:36]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]3[C:34]2=[O:44])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
To a solution of 3,5-dintrobenzylic alcohol 6 (1.38 g, 6.94 mmol), triphenylphosphine (2.19 g, 8.33 mmol) and phthalimide (1.23 g, 8.33 mmol) in dry THF (40 mL) was added DIAD (1.64 mL, 8.33 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 48 hours after which solvents were evaporated under reduced pressure. The crude product mixture was triturated in EtOAc and filtered under reduced pressure to give the title compound 7 as a beige solid (1.33 g, 4.05 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 8.98 (t, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 2H), 7.93-7.89 (m, 2H), 7.81-7.77 (m, 2H), 5.05 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.5, 168.4, 149.6, 141.3, 135.5, 132.5, 129.6, 124.7, 119.3, 41.2; HRMS (ESI) Calculated for C15H10N3O6 [M+H]+: 328.0564. Found: 328.0568. m.p.: 171° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1.C(Cl)Cl>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]1[CH2:19][O:30]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=NN(CCCl)C(=O)N(CC1CO1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 5.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-(L-arabinopyranosyl)urea, 5.9 g of meta-chloroperbenzoic acid, 50 ml of methylene chloride and 50 ml of benzene is stirred at room temperature for 3 hours. After the reaction, the mixture is condensed under reduced pressure. The residue obtained is washed with ether and then purified by silica gel chromatography (Solvent: ethyl acetate). 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-(oxiran-2-yl-methyl)-3-(L-arabinopyranosyl)urea is thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1cncc1C(=O)c1cccs1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1cccs1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(2-thienyl)methanone (10.14 g, 52.7 mmol) and hydroxylamine hydrochloride (12.8 g, 185 mmol) in pyridine (60 mL) was stirred for 9 h at 50° C., then for 8 h at 60° C. Hydroxylamine hydrochloride (6.40 g, 92 mmol) was added again and the reaction mixture was stirred for 6 h at 110° C. After removal of the solvent in vacuo and addition of water (200 mL), the pH of the aqueous solution was adjusted to pH>7 by addition of aq. NaOH (1 M), which resulted in precipitation of a yellow solid. After filtration, the solid was washed with water and pentane, and dried in vacuo to afford a first crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine. The combined aqueous phases were extracted with dichloromethane, the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified recrystallized from diisopropylether to afford a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The crops were combined and recrystallized from diisopropylether to afford final N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine [8.22 g, yield 71%; HPLC/MS: m/z=208 (M+H); log P(HCOOH)=0.45].
Reaction SMILES: CO.[CH:3]([O:8]C)([O:6][CH3:7])OC.OS(O)(=O)=O.[C:15]([C:23]1C(=O)[O:25][C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:30]1([C:26]2[O:25][C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][C:28](=[O:29])[C:27]=2[C:3]([O:6][CH3:7])=[O:8])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Yield: 84 %

Procedure:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 mls of methanol, 8.0 gms of trimethyl orthoformate, 5.2 gms of concentrated H2SO4 and 5.0 gms of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene chloride (300 mls). The organic extracts were combined and washed with water. Removal of the solvent provided 4.4 gms of 2,6-diphenyl-3-methoxycarbonyl-pyr-4-one (85%). Recrystallization from methylene chloride/ether provide material with a melting point=150°-1°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][CH:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 10 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazine (64 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z=550.11 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, m), 1.80 (7H, m), 2.25 (1H, m), 2.57 (4H, m), 2.98 (2H, m), 3.48 (2H, t, J=4.7 Hz), 3.65 (2H, m), 3.82 (1H, bs), 4.49 (2H, s), 4.59 (1H, m), 5.00 (1H, bs), 6.63 (1H, d, J=1.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz), 7.29 (1H, d, J=2.5 Hz), 37.38 (5H, m), 7.73 (1H, d, J=1.8 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)ccn2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)ccn2)on1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M10) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:39][O:38][C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:37]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Reactant: COC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)nc1

Procedure:
In a manner similar to that of Example 51, by reaction of 460 mg (1.06 mmol) of ethyl 6-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)nicotinate with 515 mg (2.17 mmol) of methyl 8-bromooctanoate and 295 mg of potassium carbonate in MEK (10 ml), 487 mg (78%) of a yellow oil are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1cccc2[nH]ncc12
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc4[nH]ncc34)ccn2c1=O
Yield: 87 %

Procedure:
Methyl 8-(1H-indazol-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-Indazole-4-boronic acid (67 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (110.5 mg, 79%).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=1)=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O.O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[N:16][C:15]=3[N:22]([CH2:23][CH3:24])[C:6](=[O:7])[N:5]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCNc1nc(CC)ccc1C(=O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2c(-c3cccc(Cl)c3)nc(=O)n(CC)c2n1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Chlorosulfonyl isocyanate (0.8 ml, 9 mmol) was added to a tetrahydrofuran (50 ml) solution of 3-(3-chlorobenzoyl)-6-ethyl-2-ethylaminopyridine (2.6 g, 9 mmol) under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction solution were added water and saturated sodium bicarbonate aqueous solution in that order, followed by 30 minutes of stirring at room temperature. This was adjusted to pH 10 with 1 N sodium hydroxide aqueous solution and extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.7 g, 60%) in the form of crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 29.9 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (27 mg, 30% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD TFA-d) δ 9.40 (br s, 1H), 8.28-8.15 (m, 2H), 8.06 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.66 (dd, J=9.1, 2.8 Hz, 1H), 7.16-7.05 (m, 3H), 4.53 (d, J=11.0 Hz, 1H), 4.01 (dd, J=13.4, 4.6 Hz, 1H), 3.41-3.23 (m, 3H), 2.86 (br s, 1H), 2.23-2.15 (m, 1H), 1.99-1.88 (m, 1H), 1.79-1.66 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.78 min.
Reaction SMILES: CN([CH:4]([N:8]([CH3:10])[CH3:9])N(C)C)C.[CH3:11][O:12][P:13]([NH:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH3:40])=[C:23]2[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])([O:15][CH3:16])=[O:14]>>[CH3:11][O:12][P:13]([NH:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH:40]=[CH:4][N:8]([CH3:9])[CH3:10])=[C:23]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:15][CH3:16])=[O:14]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C)CSC12)OC
Product: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C=CN(C)C)CSC12)OC

Procedure:
By following the procedure of Example 3, but replacing the bis-dimethylamino-t-butoxymethane by trisdimethylaminomethane (1.75 cc) and starting from 7-dimethoxyphosphorylamino-3-methyl-2-(4-nitrobenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.3 g), 7-dimethoxyphosphorylamino-3-(2-dimethylaminovinyl)-2-(4-nitrobenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (1.5 g) is obtained in the form of an orange crystalline powder, m.p.=236°-237° C. An analytically pure sample is obtained by recrystallisation from acetonitrile: yellow crystals, m.p.=252°-253° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:16]CC(C1C=CC(N2CCCCC2)=CC=1)=O>>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: O=C(CBr)c1ccc(N2CCCCC2)cc1
Product: O=C(CBr)c1ccc(N2CCOCC2)cc1

Procedure:
This compound was prepared from 1-[4-(4-morpholinyl)phenyl]ethanone (Aldrich) by procedures analogous to those used to prepare 2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (Example 7).
Reaction SMILES: [C:1]([CH:5]([CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])([O:3][CH3:4])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([CH:5]([CH2:11][CH:12]=[CH:13][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])([O:3][CH3:4])=[O:2]
Reactant: C=CCC(CCCC#N)C(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Temperature: 25 °C

Procedure:
A mixture of 23.5 g of 5-carbomethoxy-oct-7-enenitrile, 20.07 g of 3-bromopyridine and 0.79 g of tri-o-tolylphosphine in 200 mL of 2:1 acetonitrile and triethylamine is stirred at room temperature under nitrogen for one half hour. Palladium acetate (0.27 g) is added and the mixture is stirred under reflux for 40 hours. An additional 0.13 g of palladium acetate is added and the reaction mixture is further heated under reflux for 20 hours. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water, and then with 3N hydrochloric acid. The acid extract is washed with ethyl acetate, made basic to pH 8-9 with ammonium hydroxide solution and reextracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to dryness to yield 5-carbomethoxy-8-(3-pyridyl)-oct-7-enenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([OH:33])[CH2:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2ccc(C3(O)CCC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 1-(4-bromo-phenyl)-cyclobutanol (prepared as described in SYNLETT 2004, No. 8, pp 1440-1442). White solid. MS (ESI): 475.0 (MH+).