Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:6]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c1
Temperature: 115 °C

Procedure:
46.6 g (0.3 mol) of 3-methylbenzoyl chloride were warmed to 85° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin were added dropwise while stirring. The temperature was then increased in steps to 115° C. When the reaction was complete, 50 ml of toluene were added at room temperature. After crystallization, 85 g (84% of theory) of the abovementioned compound of melting point 108° to 111° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:10][SH:11].[H-].[Na+].Cl[CH2:22][S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:10][S:11][CH2:22][S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: OC(CS)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(CSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(2,4-Dichlorophenyl)-1-mercapto-3-(1H-1,2,4-triazol-1-yl)-propan-2-ol (0.304 g) was stirred in tetrahydrofuran (5 ml) whilst sodium hydride (58 mg of a 50% dispersion in oil, 1.2 equiv.) was added in one portion. After stirring a further five minutes, N-(chloro-methylsulphonyl)piperidine (0.296 g, 1.1 equiv.) was added and heated under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature then poured into an ice/water mixture (20 ml), and extracted with ethyl acetate (3×15 ml). The organic extracts were combined, dried (Na2SO4) and evaporated to a gum, 0.71 g.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.CCCCCC.[CH2:30]1[O:33][CH:31]1[CH3:32].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH2:30][CH:31]([OH:33])[CH3:32])=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)Cc1cnc([Si](C)(C)C(C)(C)C)n1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.426 g (18.7 mmol) of 1-(N,N-dimethylsulphamoyl)-2-tert-butyldimethylsilylimidazole are dissolved in 100 ml of freshly distilled THF under nitrogen and cooled to −78° C., and a solution of n-butyl-lithium in hexane (2.5M; 15 ml; 37.5 mmol) is added dropwise over a period of 10 min. The mixture is stirred for 30 min at −78° C. The solution is warmed to 0° C. with rapid stirring, and a solution of 3.0 ml (2.49 g; 42.9 mmol) of propylene oxide in 20 ml of freshly distilled THF is added dropwise over a period of 15 min. The mixture is stirred for 18 hours with heating at 20° C., and the mixture is then hydrolysed by adding 100 ml of saturated NH4Cl solution. The THF is removed under reduced pressure and the mixture obtained is extracted three times with 100 ml of dichloromethane. The organic layers are combined, dried (MgSO4) and evaporated under reduced pressure to yield an oil, which is subjected to column chromatography with diethyl ether as eluent to yield 1-(N,N-dimethylsulphamoyl)-2-tert-butyldimethylsilyl-5-(2-hydroxypropyl)imidazole in the form of a viscous yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=C(C#N)[CH:9]=2)[N:4]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[OH-:32].[Li+].Cl.[CH2:35]([OH:37])[CH3:36]>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:36]([C:35]([OH:32])=[O:37])[CH:9]=2)[N:4]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Agent: Cl
Agent: [Li+]
Product: O=C(O)c1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Temperature: 25 °C

Procedure:
To a suspension of 3.0 g of 3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile obtained by Production example 431 in 20 mL of ethanol was added 20 mL of 4N lithium hydroxide aqueous solution at room temperature, and heated at reflux for a day. After cooling to room temperature, the solution was neutralized with 5N hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration. The crystals were washed successively with water and diethyl ether, to afford 3.0 g of the title compound as colorless crystals.
Reaction SMILES: C1C=C2C(N)=NC(=N)C2=CC=1.[C:12]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])=[O:16])#[N:13].[NH:26]1[C:33](=O)[CH2:32][C:30](=[O:31])NC1=O.C1C(=NNC2C=CC(/C=C/C3C=CC(NN=C4C=CC(=O)C=C4)=CC=3S([O-])(=O)=O)=C(S([O-])(=O)=O)C=2)C=C[C:37](=[O:38])[CH:36]=1.[Na+].[Na+]>O.C(O)(=O)C>[C:23]([CH2:22][C:21]([NH:20][CH2:19][CH2:18][NH:17][C:15](=[O:16])[CH2:14][C:12]#[N:13])=[O:25])#[N:24].[CH2:19]([NH2:20])[CH2:18][NH2:17].[C:33]([CH2:32][C:30]([O:38][CH2:37][CH3:36])=[O:31])#[N:26]
Reactant: O=C1C=CC(=NNc2ccc(/C=C/c3ccc(NN=C4C=CC(=O)C=C4)cc3S(=O)(=O)[O-])c(S(=O)(=O)[O-])c2)C=C1
Reactant: O=C1CC(=O)NC(=O)N1
Agent: N#CCC(=O)NCCNC(=O)CC#N
Agent: N=C1N=C(N)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC#N
Product: NCCN

Procedure:
3.87 g of 1-amino-3-imino-isoindolenine and 1.95 g of bis-cyanoacetylethylenediamine are heated in 50 ml of water for 2 hours to reflux temperature. Then 2.56 g of barbituric acid and 20 ml of acetic acid are added and the mixture is refluxed for a further 5 hours. The pigment is collected hot with suction and washed with water and dried, affording 5.1 g of a yellow colourant powder. When incorporated in lacquers without further treatment, this pigment produces brilliant, strong colourations of outstanding fastness to overstripe bleeding. For incorporation in printing inks or plastics, the pigment is advantageously brought into the form of a preparation. This is accomplished by known methods by coating the finely dispersed pigment with substrate-compatible resins. When the pigment is used in printing, brilliant yellow colourations of excellent lightfastness are obtained. The bis-cyanoacetylethylenediamine (m.p. 191° C.) is obtained by conventional methods by reaction of ethylenediamine with ethyl cyanoacetate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37]CCCO)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+](C1C=CC=CC=1S([NH:57][C@@H:58]([CH3:62])[C:59]([NH2:61])=[O:60])(=O)=O)([O-])=O.[N+]([C:66]1[CH:71]=CC=C[C:67]=1S(NCC(N)=O)(=O)=O)([O-])=O>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:67][CH2:66][CH2:71][NH:57][C@H:58]([C:59](=[O:60])[NH2:61])[CH3:62])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(N)=O
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN[C@@H](C)C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Example 39 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and (S)-2-(2-nitrobenzenesulfonylamino)propionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-(2-nitrobenzenesulfonylamino)acetoamide, respectively.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7][C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:15][N:14]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]=2[N:11]=[CH:12][N:13]=1>O.C(O)(=O)C>[C:30]([N:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH2:7])[C:9]=2[C:16]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:2])=[CH:21][CH:22]=2)=[CH:15]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)n1cc(-c2ccc(Sc3ccccc3)cc2)c2c(N)ncnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)n1cc(-c2ccc(S(=O)c3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A solution of sodium periodate (0.60 g) dissolved in water (16 ml) was added to a solution of 4-amino-5-[4-(phenylthio)phenyl]-7-(tert-butyl)pyrrolo[2,3-d]pyrimidine (1.0 g) in glacial acetic acid (30 ml) with stirring whilst keeping the temperature below 5° C. The mixture was stirred for 66 hours at ambient temperature. The mixture was filtered and the filtrate was added to water (300 ml). This mixture was basified with solid sodium bicarbonate, filtered to remove a small amount of solid which was discarded and the filtrate extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) as the mobile phase, to give a solid which was rechromatographed under the same conditions to give 7-tert-butyl-5-(4-phenylsulphinylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 180-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(=O)([O-])O.[Na+].[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53](Cl)=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>O1CCOCC1.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:53]([O:52][CH2:51][CH:49]3[C:48]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[C:42]4[C:50]3=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:54])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 37.7 mg, 0.0876 mmol) and sodium hydrogen carbonate (9.5 mg, 0.113 mmol) were dissolved in 1,4-dioxane (0.5 mL)-water (0.5 mL), and then 9-fluorenylmethoxycarbonyl chloride (25.6 mg, 0.0990 mmol) was added thereto under ice cooling. After the reaction mixture was stirred at room temperature for 3 hours, it was diluted with ethyl acetate (10 mL). The mixture was washed with 1N aqueous HCl solution (10 mL), water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (19.7 mg) as a colorless amorphous product. (Yield 34%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[CH:5]=[CH:38]/[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reactant: O=Cc1cccnc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(/C=C/c2cccnc2)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To diethyl 3-bromobenzylphosphonate (Kennedy, G. Perboni, A. D. Tetrahedron Lett. 1996, 37, 7611-7614; 1.91 g, 6.22 mmol) in dimethylformamide (20 mL) was added sodium methanolate (0.672 g, 12.44 mmol) followed by 18-crown-6 (0.658 g, 2.488 mmol) and nicotinaldehyde (0.666 g, 6.22 mmol). The reaction mixture was heated to 120° C. for 2 h at which time the heating bath was turned off and the reaction mixture was allowed to reach ambient temperature over 18 h. The mixture was poured into water and extracted with 3×75 mL ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to 1.7 g amber liquid which was loaded onto a 90 g silica gel cartridge and eluted with 5 to 60% ethyl acetate/hexanes over 1300 mL. The major spot (Rf=0.45; 50% ethyl acetate/hexanes; UV) was collected and concentrated to 939 mg as a colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.72 (1H, d, J=1.83 Hz), 8.50 (1H, dd, J=4.73, 1.68 Hz), 7.81 (1H, dt, J=8.01, 1.95 Hz), 7.67 (1H, t, J=1.68 Hz), 7.37-7.46 (2H, m), 7.29 (1H, dd, J=7.93, 4.88 Hz), 7.20-7.25 (1H, m), 7.07 (2H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2[nH]1
Yield: 58.9 %

Procedure:
The procedure of Method A was followed in that -indolesulfonamide (10.2 mmol) was reacted with 4-chlorophenylisocyanate (10.2 mmol) to obtain 2.1 g of title product as a solid. The 2-indolesulfonamide was prepared by procedures well known in the art. See, e.g., European Patent Application 070698 (published Jan. 26, 1983). 1H NMR (CD3SOCD3): δ12.14 (s, 1 H), 10.82 (bs, 1 H), 9.07 (s, 1 H), 7.73 (d, J =8 Hz, 1 H), 7.56 (d, J =8 Hz, 1 H), 7.43 (d, J =9 Hz, 2 H), 7.34 (d, J =9 Hz, 2 H), 7.32 (m, H), 7.19 (m, 1 H), 7.15 (dd, J =6, 8 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F-].[Cs+].C[CH:13]([OH:17])[CH:14](O)[CH3:15]>C(OCC)C.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>[CH:13]([C:14]1[CH:15]=[CH:7][C:6]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:5][CH:4]=1)=[O:17]
Reactant: N#Cc1ccnc(Br)c1
Reactant: CC(O)C(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Product: N#Cc1ccnc(-c2ccc(C=O)cc2)c1

Procedure:
Benzaldehyde-4-boronic acid (1.36 g), 2-bromo-4-cyano pyridine (1.5 g), cesium fluoride (2.72 g) and tetrakis(triphenylphosphine)palladium(0) (285 mg) were mixed together in dimethyl ethylene glycol (30 ml ). The reaction mixture was refluxed for 16 hrs under a atmosphere of nitrogen after which time the cooled mixture was diluted with diethyl ether (40 ml ) and washed with water (40 ml), the organic layer was separated and washed with saturated brine, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography eluting with Dichloromethane/Diethyl ether (97.5/2.5, v/v) to afford the title compound (0.81 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]2[CH:11]=1.[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[C:24]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:17]([CH:14]([CH2:12][CH3:13])[CH2:15][CH3:16])[C:18]2=[N:26][C:25]=1[CH3:27]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cn2cccc(C)c2n1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C)cccn34)c(C)nc12
Yield: 64.6 %

Procedure:
Using a procedure analogous to Example 16B, 2,8-dimethyl-imidazo[1,2-a]pyridine (J. Chem. Soc. 1951; 2411, 2415), (0.30 g, 2.06 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.71 g, 2.06 mmol) give the title compound (0.48 g, 1.33 mmol, 65%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.81-1.95 (m, 4H), 2.41 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 2.70 (s, 3H), 3.35-3.43 (m, 1H), 6.65 (t, J=6.6 Hz, 1H0, 6.72 9s, 1H), 7.03 (d, J=6.6 Hz, 1H), 7.40 9d, J=6.6 Hz, 1) ppm. ES-MS (m/z): calcd for C22H27N5 (M+H)+: 362.5. found: 362.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O.[OH-].[Li+]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:15]3[CH2:16][CH2:17][O:13][CH2:14]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CCOC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCOC1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), tetrahydrofuran-3-carboxylic acid (202 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred for 60 minutes, and the solvent was removed in vacuo. The resulting residue was dissolved in THF (10 mL) and treated with lithium hydroxide hydrate (109 mg, 2.61 mmol) in water (1 mL). After 30 minutes, the mixture was concentrated in vacuo, and water (5 mL) was added to the residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide (210 mg, 74% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.07 (br s, 1H), 9.65 (s, 1H), 8.35 (d, 1H), 7.59 (s, 1H), 3.95 (t, 1H), 3.81-3.68 (m, 3H), 3.26-3.18 (m, 1H), 2.11-2.05 (m, 2H); LCMS (APCI+) m/z 327.9, 329.9 (M+H)+, Retention time=2.44 min (Method 2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[S:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:20]1[CH3:29]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sccc1Sc1ccncc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2sccc2Sc2ccncc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
A mixture of 3-(pyridin-4-ylsulfanyl)thiophene-2-carbaldehyde (1.3 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.3 g) and 1,2-dichloroethane (30 mL) at −10° C. was treated with a mixture of triethylsilane (5.8 mL), trifluoroacetic acid (2.4 mL) and 1,2-dichloroethane (20 mL), and the resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound as yellow foam (2.4 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([NH2:23])[CH2:16][CH2:17][CH2:18][C:19](O)([CH3:21])[CH3:20].Cl>>[NH2:23][CH:15]([CH3:14])[CH2:16][CH2:17][CH2:18][C:19]([C:7]([C:19]([CH3:21])([CH2:18][CH2:17][CH2:16][CH:15]([NH2:23])[CH3:14])[CH3:20])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:21])[CH3:20]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CC(N)CCCC(C)(C)O
Agent: Cl
Product: CC(N)CCCC(C)(C)C(c1ccccc1)(c1ccccc1)C(C)(C)CCCC(C)N

Procedure:
16.8 parts of diphenylmethane were reacted with 36.4 parts of heptaminol hydrochloride according to the procedure of Example 2. Distillation gave 22.4 parts of bis-(6-amino-2-methylhept-2-yl)diphenylmethane b0.4 230°-44° C. Analysis of this fraction showed it to contain 73% of the 4,4'-isomer with the following percentage composition by weight
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][C@H:38]([CH3:42])[CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH3:32])[CH2:37][C@H:38]5[CH3:42])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCCN1CCN[C@H](C)C1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@H](C)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(2-methoxyethyl)-2-(R)-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-Methoxy-ethyl)-3-(R)-methyl-piperazine following general procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:12][C:9]1[CH:8]=[C:4]([C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:7])[CH:3]=[C:2]([Cl:1])[C:10]=1[OH:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 3,5-dichloro-4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 32% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=362/364/366 (Cl) [M+H]+.