Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24](Br)[C:23](O)=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37].C[Si](Br)(C)C.C(O)(C(F)(F)F)=[O:47].C(Cl)Cl>>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19]([C:20]1[CH:21]=[C:22]([C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:47])=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(O)c(Br)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O

Procedure:
The resin-bound 3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acid methyl ester (50 mg, 0.3 mmol) was reacted with 3-chloro-4-fluorophenylboronic acid (240 mg, 1.5 mmol) following general procedure D, cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography to give 35 mg of title compound.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[O:58]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59]1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:60]3[CH:61]=[CH:62][O:58][CH:59]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccoc1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-furansulfonyl chloride (43 mg, 0.256 mmol), the title compound was obtained as a white solid (71 mg, 61% yield). MS (ESI): 474.0 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@@H:11]([OH:24])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O-:22])=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CCC1CN2CCC1CC2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([O-])c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 1.22 g dihydroquinidine (0.0037 mol) in 30 mL of CH2Cl2 was added 0.78 mL of Et3N (0.0056 mol; 1.5 eq). followed by 0.71 mL of p-chlorobenzoyl chloride (0.005 mol; 1.2 eq) in 1 mL CH2Cl2. After stirring 30 minutes at 0° C. and 1 hour at room temperature, the reaction was quenched by the addition of 10% Na2CO3 (20 mL). After separation, the aqueous layer was extracted with three 10 mL portions of CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent removed under vacuum. The crude product was purified as described above. Dihydroquinidine p-chlorobenzoate (1) was obtained in 91% yield (1.5 g) as a white foam.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[C:12]([Cl:13])=[N:11][C:9]([Cl:10])=[N:8][C:6]=1Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:10][C:9]1[N:11]=[C:12]([Cl:13])[N:5]=[C:6]([NH:3][CH2:2][CH2:1][NH:4][C:6]2[N:5]=[C:12]([Cl:13])[N:11]=[C:9]([Cl:10])[N:8]=2)[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(Cl)nc(NCCNc2nc(Cl)nc(Cl)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 15 g (0.25 mole) of ethylenediamine in 125 ml of cold acetone is added dropwise, at 0° to 5° C., to 92.2 g (0.5 mole) of cyanuric chloride, dissolved in 500 ml of acetone. The mixture is subsequently stirred for 30 minutes and a solution of 20 g (0.5 mole) of NaOH in 125 ml of water is then slowly added at 0° to 5° C. After stirring the mixture at the same temperature for four hours, it is diluted with 500 ml of ice-water and the solid is filtered off. The desired compound is obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1.C(N(CC)CC)C>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[NH2:33][C:29]1[CH:28]=[C:27]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]3[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=3[C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])=[CH:3][C:2]=2[F:1])[CH:32]=[CH:31][N:30]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1cnc(Nc2ccc(O)c(F)c2)c(C(=O)Nc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
365 mg of a mixture of 2-(3-fluoro-4-hydroxyphenylamino)-5-methyl-N-phenylnicotinamide and the des-methyl analog and 4-chloropyridin-2-amine (264 mg, 2054 μmol) were dissolved in NMP (5.0 ml) and triethylamine (0.75 ml, 5381 μmol) was added. The flask was fitted with a reflux condenser, placed in a preheated oil bath (185° C.-190° C.), and stirred under argon. After about 22 hours, more 4-chloropyridin-2-amine (250 mg, 1.95 mmol), DMAP (171 mg, 1.40 mmol), triethylamine (0.30 ml, 4.1 mmol), and NMP (1 ml) were added, and stirring was continued at 190 C for another day. The reaction was then cooled to room temperature and quenched with water (20 ml). The water was decanted, and the residual solid was collected with DCM and MeOH, concentrated, and purified on silica gel (50:1→25:1 DCM/MeOH→15:1 DCM/2 N ammonia in MeOH) to afford the desired 2-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-5-methyl-N-phenylnicotinamide along with the des-methyl analog. This mixture was taken to the last step.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([N:4]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:2][CH3:1])[CH:30]=[CH2:29]
Reactant: CSC(=Nc1ccccc1)NN1C(=O)c2ccccc2C1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(=Nc1ccccc1)SC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To 50 ml of dry acetone, 4.0 g (0.013 m) of the above product (IV), 2.2 g (0.016 m) of powdered anhydrous potassium carbonate, and 1.4 ml (0.016 m) of allyl bromide was added in succession and the mixture stirred overnight at room temperature. The mixture was poured into 300 ml of ice water with stirring. The aqueous layer was decanted and the residue suspended in fresh ice cold water, stirred and filtered to give a yellow semisolid product. This was purified by stirring in hexane to give a yellow powder 1.8 g (39%), m.p. 78°-81°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH2:20][C:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[C:30]([O:29][C:28](=[O:34])[NH:27][C:21]([CH3:26])([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][O:19][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Yield: 34.3 %

Procedure:
8-Chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.580 mmol), prepared as described in Example 16, Part G, and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.161 g, 0.696 mmol) were subjected to the Buchwald coupling as described in Example 16, Part H, to afford tert-butyl(1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (0.22 g, 0.199 mmol, 34% crude yield). Crude product was used for next step without further purification. LC/MS (ESI) m/e 454.1 [(M+H)+, calcd for C26H36N3O4, 454.3]; LC/MS retention time (method D): tR=0.93 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[C:5]2[N:10]([CH:13]([F:15])[F:14])[CH:11]=[N:12][C:4]=2[CH:3]=1.[CH:16]1C=C(Cl)C=C(C(OO)=O)C=1.[S:27]([O-:31])([O-])(=[O:29])=S.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([S:27]([CH3:16])(=[O:31])=[O:29])[C:5]2[N:10]([CH:13]([F:14])[F:15])[CH:11]=[N:12][C:4]=2[CH:3]=1
Reactant: CSc1nc(Cl)cc2ncn(C(F)F)c12
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1nc(Cl)cc2ncn(C(F)F)c12
Reaction time: 4 h

Procedure:
To a solution of 6-chloro-3-(difluoromethyl)-4-(methylthio)-3H-imidazo[4,5-c]pyridine (431 mg, 1.73 mmol) in DCM (12 mL) was added m-CPBA (max. 77%, 1.1 g, 4.9 mmol). After stifling 4 h, saturated aqueous sodium thiosulfate (30 mL) was added and the biphasic mixture was stirred 15 min. The mixture was diluted with EtOAc (30 mL) and water (30 mL). The phases were separated, and the organic layer was washed with saturated NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated to afford 6-chloro-3-(difluoromethyl)-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.63 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H7ClF2N3O2S: 282.0; found: 282.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.CCOCC>[CH2:17]([NH:16][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:7][CH:6]=3)[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOCC
Product: CCCCNc1nccc(-c2c(-c3ccc(NC4CCCCC4)cc3)nn3c(NCCCC)cccc23)n1
Yield: 70.4 %

Procedure:
A solution of N-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine (62 mg, 0.15 mmol) in 1,2-dichloroethane (2 mL) was treated with cyclohexanone (0.02 mL, 0.22 mmol), acetic acid (0.04 mL, 0.72 mmol), and sodium triacetoxyborohydride (61 mg, 0.29 mmol). The resultant solution was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added dropwise followed by ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine (54 mg, 73%) as an orange oil. 1H NMR (CDCl3): δ 7.94 (d, 1 H), 7.73 (d, 1 H), 7.39 (d, 2 H), 7.23 (m, 1 H), 6.59 (d, 2 H), 6.41 (d, 1 H), 6.03 (m, 1 H), 5.91 (d, 1 H), 5.11 (broad, 1 H), 3.66 (broad, 1 H), 3.44 (m, 2 H), 3.30 (m, 3 H), 2.05 (m, 2 H), 1.75–1.12 (m, 16 H), 0.95–0.92 (m, 6 H); MS m/z 512 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].CO[C:9](OC)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1C=CC=CC=1>[C:10]1([C:9]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:1][CH2:2][CH:3]([CH2:4][OH:5])[O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC(O)CS
Reactant: COC(OC)(c1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: OCC1CSC(c2ccccc2)(c2ccccc2)O1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
3-Mercapto-1,2-propanediol(3.26 g, 30.00 mmol) was dissolved in benzene (60 mL). Benzophenone dimethyl ketal (13.48 g, 60.0 mmol, 2 equiv.) and CSA (0.70 mg, 3.00 mmol, 0.1 equiv.) were added. The solution was heated with an oil bath to reflux. Benzene/methanol was collected and removed while more benzene was added to the refluxing reaction. After about 200 mL benzene/methanol was distilled out, the reaction was cooled to room temperature, applied directly onto a silica gel column. The column was then eluted was 20%-40% ether/petroleum ether to afford a thick oil as the desired product (3.78 g, 46). Rf =0.25, 20% ether/petroleum ether. 1H NMR (400 MHz, C6D6) δ=2.56 (dd, J=6.3, 10.2 Hz, 1H), 2.83 (dd, J=7.7, 10.2 Hz, 1H), 3.35 (br dd, J=5.3, 11.6 Hz, 1H), 3.44 (br dd, J=3.5, 11.6 Hz, 1H), 3.88-3.95 (m, 1H), 6.94-7.20 (m, 6H), 7.54 (d, J=7.5 Hz, 2H), 7.70 (d, J=7.5 Hz, 2H). 13C NMR (100 MHz, C6D6) δ=35.90, 63.97, 83.29, 100.20, 126-129 (m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][CH2:13][CH2:14][NH2:15]>CO>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]=[C:6]1[C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: CNCCN
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: CO
Product: CN1CCN=C1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4-aminobenzonitrile (5.1 g, 43 mmol) in dry methanol (60 mL) at 0° C., hydrogen chloride gas was bubbled through until saturation was reached. The mixture was then stirred at room temperature overnight. It was concentrated in vacuo. The residue was dissolved in dry methanol (60 mL). To the solution, N-methyl ethylenediamine (19 mL, 216 mmol) was added. The mixture was then heated to reflux for 3 h. After being cooled in fridge overnight, the precipitated product was collected by filtration, then was dried on vacuum to give white solids (3.7 g). MS 176.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([C:14]([NH2:16])=O)=[CH:8]2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([C:14]#[N:16])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2cc(C(N)=O)[nH]c(=O)c12
Product: COc1cccc2cc(C#N)nc(Cl)c12
Yield: 82 %

Procedure:
A solution of 8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (800 mg, 3.66 mmol) in POCl3(40 mL) was heated to reflux for 1 hour. The reaction mixture was subsequently concentrated in vacuo to give the title compound (660 mg, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1H), 7.78 (t, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=8.0 Hz), 4.05 (s, 3H); ESI-MS m/z [M+H]+ 219.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na].O>C(O)C>[O:24]=[C:3]([CH2:2][S:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:4]=[P:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Sc1ccccc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CSc1ccccc1
Yield: 74.1 %

Procedure:
3-Bromo-2-oxopropylidenetriphenylphosphorane (17.85 g) was added to a solution of thiophenol (5.22 g; 4.86 ml) in anhydrous ethanol (70 ml) containing sodium (1.09 g). The mixture was heated at reflux for 150 minutes and was then poured into a mixture of ice and water (250 ml). The mixture was then extracted with dichloromethane and the extract was washed with dilute aqueous sodium hydroxide solution (2 N) and then with water, and was dried over magnesium sulphate. Evaporation of the solvent gave a residual oil which was triturated with petroleum ether (b.p. 40°-60° C.), and the resulting crude solid was recrystallised from a mixture of toluene and petroleum ether (b.p. 60°-80° C.) to give 2-oxo-3-phenylthiopropylidenetriphenylphosphorane (14.2 g) in the form of cream prisms, m.p. 132°-134° C. [elemental analysis: C, 76.4; H, 5.3; P, 7.3; S, 7.7%. C27H23OPS requires C, 76.0; H, 5.4; P, 7.3; S, 7.5%. νmax 715, 740, 750, 1110, 1385, 1440, 1485 and 1550 cm-1 ].
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.[OH:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:24]1>>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:19]([OH:21])[CH2:20][O:22][CH:23]2[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:24]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: ClCC1CO1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Product: CON1C(C)(C)CC(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)CC1(C)C

Procedure:
The title compound is prepared by reaction of 2,4-dihydroxybenzophenone with epichlorohydrin followed by reaction with 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:22][CH2:23][OH:24])[C:5]1[N:6]=[N:7][C:8]([N:11]2[C:15]([NH2:16])=[C:14]([C:17]([O:19]CC)=O)[CH:13]=[N:12]2)=[CH:9][CH:10]=1.O.[NH2:26][NH2:27]>O1CCOCC1>[OH:24][CH2:23][CH2:22][N:4]([CH2:3][CH2:2][OH:1])[C:5]1[N:6]=[N:7][C:8]([N:11]2[C:15]([NH2:16])=[C:14]([C:17](=[O:19])[NH:26][NH2:27])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1cnn(-c2ccc(N(CCO)CCO)nn2)c1N
Solvent: O
Solvent: C1COCCO1
Product: NNC(=O)c1cnn(-c2ccc(N(CCO)CCO)nn2)c1N

Procedure:
A mixture of 6.72 g. (20 mmoles) of 3-[bis(hydroxyethyl)-amino]-6-(4-ethoxycarbonyl-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 2), 34 ml. of 72% hydrazine hydrate and 34 ml. of dioxane is stirred at reflux temperature for 12 hours. After cooling the separated crystals are filtered, washed with water and ethanol and then recrystallized from 30 ml. of ethanol. Yield: 5.7 g. (88.5%); m.p.: 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 0 °C
Yield: 70.7 %

Procedure:
The amide derivative 1 (5.0 g, 16.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. To this solution was added triethylamine (5.0 mL) followed by dropwise addition of methanesulfonyl chloride (2.05 g, 17.9 mmol). The reaction was stirred at 0C for 1 h, and then at room temperature overnight. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to give 2 (4.45 g, 71%) as a tan gum; C18H24ClNO4S, LRMS (m/z)=386 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1Br)=[O:4].[CH2:19](O)C.[NH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[C:29]1[CH:30]=[CH:31][C:26]([S:23](=[O:25])(=[O:24])[NH2:22])=[CH:27][CH:28]=1)=[O:4])[CH3:19]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1Br
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of methyl-3-bromo-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (compound 1a, 2.2 g, 6.3 mmol) in a mixture of toluene:ethanol (10:30 ml) were added 4-aminosulfonylbenzene boronic acid (prepared according to the procedure given in EP 1012142, 1.28 g, 6.3 mmol) and potassium carbonate (1.76 g, 12.7 mmol) at 25° C. in a sealed tube and nitrogen gas was bubbled through the reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.370 g, 0.318 mmol) under nitrogen and the reaction mixture was heated at about 95-about 100° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.3 g, 48%).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].Cl[C:15]1[N:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[CH:12]=[O:13])[N:16]=[N:17][CH:18]=1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1O
Reactant: COc1cnnc(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2c(C=O)c(C(F)(F)F)nn2C)c1
Yield: 55.8 %

Procedure:
5-Hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (3.0 g, 0.015 mole), 3-chloro-5-methoxypyridazine (2.3 g, 0.015 mole), 2,6-lutidine (2.8 g, 0.025 mole), and toluene (80 mL) were heated in a flask equipped with a short Vigreux column until 5 mL of solvent had distilled. The mixture was then held at reflux for 4 hours, cooled, poured into 1% hydrochloric acid, and extracted with a mixture of ether and ethyl acetate. The combined extracts were washed with 1% hydrochloric acid, 1% sodium hydroxide, 5% sodium chloride, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/cyclohexane to give 5-[(5-methoxy-3-pyridazinyl)oxy]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (2.53 g, 55% yield) as a yellow solid.