Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](Cl)=[O:10])[C:5](=[O:12])[C:4]1=[O:13])[CH3:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C)C>>[CH3:14][O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40]([C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]4=[O:12])=[O:10])[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Product: CCN1CCN(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)[C@H]4CC=CC[C@H]4C3=O)CC2)C(=O)C1=O

Procedure:
Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride and starting compound A1 as described for compound 1. Crystallisation from ethyl acetate/diethyl ether. M.p. 226-228° C.
Reaction SMILES: [P:1]([O:13][CH2:14]Cl)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I-:16].[Na+].CC(C)=O>C(#N)C>[P:1]([O:13][CH2:14][I:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [I-]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(C)OP(=O)(OCI)OC(C)(C)C

Procedure:
The title compound was prepared by halogen exchange reaction of di-tert-butyl chloromethyl phosphate (Intermediate 1) with sodium iodide in suitable solvent such as dry acetone or acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[NH:26][CH:27]=[CH:28][N:29]=4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Na+].I[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[N:29]([CH3:36])[CH:28]=[CH:27][N:26]=4)=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: CI
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4nccn4C)c4cccnc43)CC2)ccc1Cl
Reaction time: 1 h

Procedure:
To the solution of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone (50 mg, 0.11 mmol, 1 eq) in THF was added 60% sodium hydride (5.7 mg, 0.14 mmol, 1.3 eq) and stirred for 1 hr, followed by the addition of iodomethane (25.8 mg, 0.16 mmol, 1.5 eq). 2 hrs later, LCMS indicated that the major peak is the desired product. preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1-methyl-1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 465.2.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2OC(=O)[S:9][N:8]=2)[CH:2]=1.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17]>ClC1C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1cccc(-c2nsc(=O)o2)c1
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2cccc(C)c2)c1C(=O)OC
Yield: 52.2 %

Procedure:
5-m-Tolyl-1,3,4-oxathiazol-2-one (19.32 g, 0.1 mol) and dimethyl acetylenedicarboxylate (28.42 g, 0.2 mol) were heated at reflux in 60 ml of chlorobenzene as given above. After the initial crystallization from cold methanol, three recrystallizations from diethyl ether/petroleum ether gave 15.18 g (0.0522 mol, 52.2%) of white solid, m.p. 53°-54.5°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][NH2:12]>[Cu].Cl>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CN
Agent: [Cu]
Agent: Cl
Product: CNc1ccccc1C(C)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2'-chloroacetophenone (309 g), industrial methylated spirit (252 ml), methylamine (33% w/w solution in industrial methylated spirit, 1085 ml) and copper lining powder (2.7 g) was stirred in a sealed pressure vessel for 3 hours at 80° C. The reaction vessel was allowed to cool to 40° and the mixture was washed out of the vessel with industrial methylated spirit (60 ml). The combined reaction mixture and washing were stirred at 50 to 55°, a solution of sodium sulphide trihydrate (6.6 g) in water (45 ml) was added dropwise and the stirring and heating were continued for 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name HYFLO SUPERCEL) and the filter bed washed with industrial methylated spirit (300 ml). The combined filtrate and washing were evaporated under reduced pressure to give an oil which was added to hydrochloric acid (5M, 900 ml) and then stirred and heated under reflux for 2 hours. The mixture was cooled to 30°, washed with hexane (2×990 ml) and then adjusted to pH 2 to 3 by addition of aqueous sodium hydroxide (5M, 750 ml) whilst maintaining the temperature at 30 to 35°. The mixture was then extracted with dichloromethane (990 ml) and the extract evaporated under reduced pressure to give the novel compound 2'-(methylamino)acetophenone, m.p. 34°-35°.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCc1ccccc1-c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzylcyanide (12.33 g) in tetrahydrofuran (85 ml) was added dropwise, at -70° C. in argon streams, a hexane solution (65 ml) of n-butyl lithium. The mixture was then stirred for 30 minutes at -50° C., to which was then added dropwise 2-bromopyridine (9.7 ml). The reaction temperature was gradually raised up to 0° C. Fifteen minutes later, a saturated ammonium chloride solution was added to the reaction mixture, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The concentrate was purified by means of a silica gel column chromatography to give the title compound (6.59 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:4]=1)=[O:1]
Reactant: CC(C)(C#N)c1cc(CO)cc(C(C)(C)C#N)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(C=O)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,2'-(5-hydroxymethyl-1,3-phenylene)di(2-methylpropiononitrile), (1.9 g), in dichloromethane (20 ml) was treated with pyridinium chlorochromate (2.15 g) and stirred at room temperature for 1.5 h. The reaction mixture was subjected to flash column chromatography, eluting with dichloromethane, to give 2,2'-(5-formyl- 1,3-phenylene)di(2-methylpropiononitrile), mp. 145°-147°.
Reaction SMILES: CO[C:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])=O.S[CH:20]([OH:22])C>CO>[OH:22][CH2:20][CH2:3][S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(O)S
Reactant: COC(=O)SSCC(=O)NC(CC(=O)O)C(=O)O
Solvent: CO
Product: O=C(O)CC(NC(=O)CSSCCO)C(=O)O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 74.6 %

Procedure:
A round bottomed flask was charged with 399.6 mg (1 eq., 1.495 mmole) (methoxycarbonyldithio)ethylamidosuccinic acid dissolved in 5 ml methanol, cooled to 0° C., purged with argon, and then treated dropwise with a solution of 110.9 mg (0.95 eq., 995.9 μl, 1.42 mmole) mercaptoethanol in 4 ml methanol over a 30 min period. The stirred solution was allowed to warm to room temperature over 1 hour and then stirred at this temperature for an additional 3.5 hours, after which, the solvent was evaporated on the rotary evaporator (bath temp. 30° C.). The residue was subjected to vacuum transfer for 0.5 hours to ensure that all mercaptoethanol was removed. The resultant white solid was then titurated with 3 ml ether and then the solid was pumped on the high vacuum for 10 min. (bath temp. 40° C.) to yield approximately 0.3 g of (2-hydroxyethyldithio)ethylamidosuccinic acid as a pure white solid. 1H NMR (d6DMSO/TMS) δ: 2.31 (2H, t, J=6.02 Hz, CH2), 2.41 (2H, t, J=6.39 Hz, CH2), 2.77 (4H, q, J=6.86 Hz, 2×CH2), 3.35 (2H, t, J=6.75 Hz, CH2), 3.60 (2H, t, J=6.46 Hz, CH2), 8.06 (1H, t, NH). 13C NMR (d6DMSO/TMS) δ: 30.53 (CH2), 31.62 (CH2), 38.46 (CH2), 39.68 (CH2), 42.11 (CH2), 61.27 (CH2), 174.76 (Q), 176.63 (Q).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]1(=O)[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCO1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2[nH]c(CCCCO)nc2c1
Temperature: 100 °C
Yield: 79.3 %

Procedure:
A mixture of 4-tert-butyl-benzene-1,2-diamine (1 g, 6.09 mmol) and valerolactone (0.67 g, 6.70 mmol, 1.1 eq.) in 4N HCl aq (5 ml) was sealed and heated for 2 h at 100° C. LCMS analysis shows remaining diamine. Completion was achieved using excess of valerolactone (˜1.3 ml, 2 eq.) heating at 100° for 4 h. The reaction was cooled to RT and basified to pH 12 with a saturated solution of Na2CO3. EtOAc (100 ml) was added and organic separated, washed with saturated solution of Na2CO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography over silica gel, eluted with DCM-MeOH from 2% to 5% gradually to yield 1.19 g (79%) of a beige solid; MS (ESI+) for C15H22N2O m/z 1 [M+H]+, 247.15; HPLC purity 100% (ret. time, 1.42 min). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.38 (9H, s), 1.65-1.75 (2H, m), 2.00 (2H, quin, J=7.17 Hz), 2.98 (2H, t, J=7.09 Hz), 3.72 (2H, t, J=5.99 Hz), 7.31 (1H, dd, J=8.51, 1.58 Hz), 7.48 (1H, d, J=8.20 Hz), 7.56 (1H, d, J=1.26 Hz).
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C(OC(OCC)C[N:24]=[C:25]=[N:26][CH:27]1[CH2:32]CCCO1)C.CCOCC.Cl>C(Cl)Cl>[CH3:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:25]3[NH:24][CH:32]=[CH:27][N:26]=3)[C:17](=[O:18])[N:4]2[C:5]=1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CN=C=NC1CCCCO1)OCC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 7-amino-3-methylceph-3-em-4-carboxylate (810 mg.) and 1-(2,2-diethoxyethyl)-3-(tetrahydropyran-2-yl)carbodiimide (726 mg.) in dry CH2Cl2 (8 ml.) under nitrogen at room temperature was dropwise added a 2N ether solution of HCl (1.5 ml.) in CH2Cl2 (4 ml.) over 30 minutes. The mixture was allowed to stand for a further 30 minutes and then evaporated to dryness. To a solution of the residue, t-butyl 7-[2-(2,2-diethoxyethyl)-3-(tetrahydropyran-2-yl)guanidino]-3-methylceph-3-em-4-carboxylate (1.7 g.) in acetonitrile (8 ml.) was added 3N aqueous HCl (1 ml.) and the mixture was heated at 50° for 2 hours, then evaporated to dryness at 30°. The residue was purified by chromatography on silica gel using CH2Cl2 /MeOH/HOAc 89:10:1 v/v/v as eluant to give, after precipitation from CH2Cl2 solution will ether, t-butyl 3-methyl-7-[5-hydroxy-1-(tetrahydropyran-2-yl)imidazolin-2-yl]aminoceph-3-em-4-carboxylate (900 mg.) as a mixture of diastereoisomers. A solution of this product in trifluoroacetic anhydride was allowed to stand at room temperature under nitrogen for 6 hours, and then evaporated to dryness. The residue was purified by chromatography on silica to give t-butyl 3-methyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate. This compound was treated with trifluoroacetic acid to give the free acid, identical to the product obtained in Example 7.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10](=[O:19])(=[O:18])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]1=2.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10](=[O:19])(=[O:18])[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]2=3)=[CH:27][CH:26]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: O=S1(=O)Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Product: O=S1(=O)Cc2ccccc2N(C[C@@H]2CCCN2CCc2ccc(O)cc2)c2ccccc21

Procedure:
This was obtained by reacting (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine-10,10-dioxide (see Preparation 20) and 4-hydroxyphenethyl bromide by a similar method to that described in Example 28. The title compound was obtained as a colourless oil, (60 mg, 29%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]4[N:24]([C:30](=[O:32])[NH2:31])[CH2:25][CH2:26][CH2:27][C:28]=4[CH:29]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[N:16]1[CH:17]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23](=[N:22][CH:21]=2)[N:24]([C:30]([NH2:31])=[O:32])[CH2:25][CH2:26][CH2:27]3)[CH:19]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C4CCNCC4)c3)cnc21
Reaction time: 16 h
Yield: 122.3 %

Procedure:
To the 5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (19.3 mg, 0.04 mmol) in 1 mL of CH2Cl2 is added 1 mL of 4 M HCl in dioxane. The mixture is stirred for 16 h. The mixture is concentrated to give 16.5 mg of 6-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([O:16][SiH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:15]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[CH2:14]([O:16][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[CH2:3][CH2:2][CH2:1][N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:11])([CH3:13])[CH3:12])[CH2:6][CH2:5]1)[CH3:15]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCN1CCN([Si](C)(C)C)CC1
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN1CCN([Si](C)(C)C)CC1)(OCC)OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 99.2 g (0.5 mole) of 1-allyl-4-trimethylsilylpiperazine and 0.65 g of a toluene solution of platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (platinum content 3 wt %) and heated at 70° C. Once the internal temperature became constant, 82.2 g (0.5 mole) of triethoxysilane was added dropwise over 4 hours. Stirring was continued for a further one hour at the temperature. The reaction solution was distilled, collecting 137.5 g of a fraction having a boiling point of 119-122° C./50 Pa.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[F:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH:37][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1
Reactant: Nc1cccc(N2CCN(CCCF)CC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCN(CCCF)CC5)c4)nc23)cc1

Procedure:
187 a) To a suspension of 1-(3-nitro-phenyl)-piperazine; hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) was added 1-fluoro-3-iodo-propane (0.85 g, 4.5 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. 1-(3-Fluoro-propyl)-4-(3-nitro-phenyl)-piperazine was isolated as a viscous orange oil (0.886 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.71 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H), 4.54 (ddd, J=47.2, 5.9, 5.9 Hz, 2H), 3.32-3.27 (m, 4H), 2.65-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=268 (MH)+. 187 b) 3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenylamine was prepared from 1-(3-fluoro-propyl)-4-(3-nitro-phenyl)-piperazine (0.20 g, 0.75 mmol) in a manner analogous to Example 111a. Product isolated as a tan waxy solid (0.18 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.04 (t, J=8.1 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 6.26 (s, 1H), 6.21 (d, J=7.9 Hz, 1H), 4.62-4.44 (m, 2H), 3.60 (br s, 2H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.53 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=238 (MH)+. 187 c) {3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenyl}-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (220.0 mg, 0.7148) and 3-[4-(3-fluoro-propyl)-piperazin-1-yl]-phenylamine (180.0 mg, 0.7585 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (60.0 mg, 0.110 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.264 g, 73%). MP=157-169° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.7 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.46 (br s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.64-4.48 (m, 2H), 3.30 (br s, 4H), 3.11 (s, 3H), 2.93-2.40 (m, 6H), 2.08-1.90 (m, 2H). MS=509 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CCN2CCCC2)cc1

Procedure:
A solution of 0.300 g (1.06 mmol) of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione and 0.222 g (1.17 mmol) of 4-(2-pyrrolidin-1-yl-ethyl)-phenylamine in 1.8 mL of N,N-dimethylformamide (DMF) is heated at 120° C. for 1 h. The reaction is placed in a freezer and the precipitated material is collected, washed with cold N,N-dimethylformamide (DMF) (2×), cold MeOH (2×) and Et2O and dried in vacuo to give 0.307 g (66%) of brick red crystals: mp 212-214° C. (dec);
Reaction SMILES: CN(C)CCN.[CH2:7]([O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)[CH3:8].C(O)(=O)C.[C:25]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH2:26][CH2:27][CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:25](=[N:10][O:9][CH2:7][CH3:8])[CH2:26][CH2:27][CH3:28])[CH:35]=1
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCCC(=NOCC)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 22 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-ethoxyphthalimide (287 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (330 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1), the solvent evaporated under reduced pressure and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-ethoxyiminobutyl)phenyl]trifluoromethanesulfonamide 193 (82 mg, 22%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 12.10, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.32, dd, J=2.4 and 8.8 Hz, 1H; 4.27, q, J=7.2 Hz, 2H; 2.78, m, 2H; 1.59, sextet, 2H; 1.37, t, J=7.2 Hz, 3H; 1.02, t, J=7.6 Hz, 3H. HRMS (M+) 372.0514.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=O)[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][C:11]1[C:10]([C:13]#[N:15])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCn1ncc2c(O)c(C(N)=O)cnc21
Reactant: O=S(Cl)Cl
Product: CCn1ncc2c(Cl)c(C#N)cnc21

Procedure:
10.3 g. of 1-ethyl-4-hydroxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxamide (0.05 mol.) and 125ml. of thionyl chloride are refluxed for 3.5 hours. After cooling, the thionyl chloride is removed in vacuo and the residue is extracted twice with 400ml. of refluxing hexane. The combined extracts are treated with charcoal, filtered and evaporated. The product, 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, is recrystallized from a small amount of hexane, yield 2.9 g. (28%), m.p. 100°-102°.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([I:19])=[CH:4][N:3]=1.[CH3:20]I>C(Cl)(Cl)Cl>[I:19][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([O:1][CH3:20])=[N:3][CH:4]=1
Reactant: O=C(Nc1cc(I)cnc1O)OCc1ccccc1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: COc1ncc(I)cc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of benzyl (2-hydroxy-5-iodopyridin-3-yl)carbamate (16 g, 43 mmol) in CHCl3 (250 mL) was added Ag2CO3 (16.1 g, 58.4 g) and methyl iodide (27.0 mL, 434 mmol) in the dark, and the mixture stirred at RT for overnight. The solid was removed by filtration and the solvent was concentrated and purified by combi-flash (ISCO, 40g silica, UV254, 5:1 pet ether/ethyl acetate) to afford benzyl (5-iodo-2-methoxypyridin-3-yl)carbamate (8.85 g, 53% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.61 (br, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.35-7.42 (m, 5H), 7.12 (s, 1H), 5.21 (s, 2H), 3.95 (s, 3H); MS (ES) m/z 385 (M+H).