Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]([CH2:22][CH:23](OC)OC)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][CH:7]=1>ClCCl>[Br:5][C:6]1[CH:29]=[C:28]2[C:9](=[CH:8][CH:7]=1)[CH:10]=[N:11][CH:22]=[CH:23]2
Reactant: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Brc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
To a mechanically stirred suspension of 95.2 g (699.5 mmol) of AlCl3 in 400 ml of dichloromethane a solution of 59.9 g (139.8 mmol) N-(4-bromo-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2) in 400 ml of dichloromethane was added and the reaction was stirred at room temperature for 4 h. After standing overnight, the reaction mixture was poured onto ice, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane solutions were washed with 1 N NaOH (2×) and saturated sodium hydrogen carbonate-solution (2×). After drying with magnesium sulfate and evaporation of the solvent, the crude product was purified by silica gel chromatography (heptane/ethyl acetate 1:1) to yield 17.5 g of the title compound. Rt=0.68 min (Method C). Detected mass: 208.1/210.1 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[N:13]([CH2:47][C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[O:49])[C:12](=[O:14])[C@H:11]1[NH:15][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Yield: 75.8 %

Procedure:
(3S,4S)-4-t-Butyldimethylsilyloxymethyl-3-tritylaminoazetidinone (IV), (1.67 g) [H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190] as a suspension in acetonitrile (40 ml) was treated with DMF (20 ml) to obtain a clear solution. Cesium carbonate (1.29 g) followed by 4-methoxybenzyl bromoacetate (1.19 g) were added and the mixture vigorously stirred overnight. T.l.c. analysis showed no starting material, the solution was diluted with ethyl acetate and washed with water (4×), brine and then dried. Removal of solvent in vacuo and purification by flash chromatography afforded the title compound as a pale yellow foam, (1.744 g, 76%), νmax (CH2Cl2) 1760 and 1744 cm- ; δH (CDCl3) -0.06 and -0.13 (6H, 2s), 0.81 (9H, s), 1.60 (1H, brs), 2.44 (1H, dd, J 3.3, 11.7 Hz), 3.10 (1H, dd, 2.2, 11.7 Hz), 3.29 (1H, m), 3.41 (1H, d, J 18.0 Hz), 3.80 (3H, s), 4.36 (1H, d, J 18.0 Hz), 4.45 (1H, m), 4.97 and 5.05 (2H, ABq, J 11.8 Hz), 6.85 (2H, d, J 8.7 Hz), 7.16-7.30 (15H, m) and 7.52 (2H, d, J 8.7 Hz); [mass spectrum: MH+ (651)].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a3) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:20]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[C:22]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:21]=1>ClCCl.C(OCC)(=O)C>[OH:11][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][C:20]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[C:22]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:21]=1
Reactant: NCC(O)Cc1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(NCC(O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 1-amino-3-phenyl-propan-2-ol (0.51 g, 3.3 mmol) and triethylamine (0.45 mL, 3.3 mmol) in 20 mL dichloromethane was added (0.92 g, 2.6 mmol) 2-chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one. The solution was stirred for 18 h at room temperature. The solution was diluted with ethyl acetate and washed with 5% sodium bicarbonate. The organic layer was dried over magnesium sulfate and purified on 10 g silica eluting product with 0 to 5% methanol/dichloromethane to give a pale yellow solid. M+1=463.2.
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[N:21]([C:25]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:34])=[CH:27][C:26]=2[OH:35])[N:22]=[N:23][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:31]([C:29]1[CH:30]=[C:25]([N:21]2[C:20]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[CH:12][CH:13]=3)=[CH:24][N:23]=[N:22]2)[C:26]([OH:35])=[CH:27][C:28]=1[OH:34])([CH3:33])[CH3:32]
Reactant: CC(C)c1cc(-n2nncc2N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c(O)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(-n2nncc2Nc2ccc(N3CCOCC3)cc2)c(O)cc1O
Yield: 45 %

Procedure:
A solution of the intermediate from Step E in DCM/TFA (1/1 5 ml) was stirred for 12 hours at RT. The reaction mixture was concentrated under reduced pressure and the crude reaction mixture was purified by column chromatography (DCM/MeOH: 95/5). The title compound was obtained as slightly brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N:11]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:15]=2)[CH3:12])[CH:5]=1.Cl.O1CCOCC1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:15]=3)[N:11]([CH3:12])[C:6]=2[CH:5]=1)=[O:29]
Reactant: CCCN(CCC)Cc1cccc(C(=O)N(C)c2cc(C(=O)OC)ccc2N)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)Cc1cccc(-c2nc3ccc(C(=O)OC)cc3n2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
The compound (83.0 mg) obtained in Example 18-4 was dissolved in methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol to generate a free compound therefrom through an anion-exchange resin (Amberlite IRA-410). The resin was separated by filtration and the filtrate subjected to distillation of the solvent under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (44.0 mg) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[CH3:15].[OH-].[K+].[CH2:18](I)[CH3:19]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])([CH3:14])[CH2:7][C:8](=[O:12])[N:9]2[CH2:18][CH3:19])=[CH:4][C:3]=1[CH3:15]
Reactant: CCI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of 8.5 g of 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one (31.7 mmol), prepared according to WO 03/075924, in 15 mL dry DMSO was added to a prestirred solution of crushed potassium hydroxide (3.56 g, 63.4 mmol) in 15 mL of dry DMSO, followed by addition of 7.68 mL (95.2 mmol) of ethyl iodide. The reaction was stirred overnight before quenching with 100 mL of water and extracted with dichloromethane (3×150 mL), the extracts were dried with sodium sulfate, filtered, stripped and purified via flash chromatography (5% EtOAc/hexanes) to afford 8.3 g of product (88%) as a white solid. MS (electrospray): mass calculated for C14H18BrNO, 295.06; m/z found 296, [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=3)[N:12]=[C:6]2[C:5]=1[NH:20][C@H:21]1[C@@H:25]([CH2:26][F:27])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)(=[O:3])[NH2:2].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[CH2:18]([N:16]1[CH:17]=[C:13]([C:11]2[N:12]=[C:6]3[C:5]([NH:20][C@H:21]4[C@@H:25]([CH2:26][F:27])[CH2:24][NH:23][CH2:22]4)=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]3[CH:10]=2)[CH:14]=[N:15]1)[CH3:19].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4CF)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CNC[C@@H]4CF)c3n2)cn1

Procedure:
A solution of (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (15 mg, 0.032 mmol) in DCM (0.5 ml) was treated with TFA (0.024 ml, 0.317 mmol) at room temperature for 2 h. The reaction mixture was concentrated to give 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (15.1 mg, 0.025 mmol, 79% yield) as a white solid. ESI-MS (Method A): m/z 373.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:20]
Reactant: Cc1coc(N)n1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1coc(NC(=O)CCCCl)n1
Temperature: 25 °C
Yield: 23.92 %

Procedure:
2-Amino-4-methyloxazole (5.0 g., 0.0509 mol) was dissolved in dry benzene (100 mls.) and triethylamine (5.70 g., 0.0563 mol) was added. The mixture was stirred vigorously at room temperature and 4-chlorobutyrylchloride (7.88 g., 0.0558 mol) in dry benzene (50 mls.) was added rapidly. After the addition the mixture was heated under reflux for 2 hours. The mixture was then cooled and fltered. The filtrate was placed in a separating funnel and washed successively with water (1 × 100 mls.), 10% Na2CO3 (2 × 100 mls.) and water (3 × 100 mls.). The organic layer was driec over magnesium sulphate and evaporated under vacuum. The product was recrystallised from ethyl acetate/hexane. Wt. = 2.47 g. m.p. 98° C. (Yield = 23.92%).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:25][C:6]2[C:7]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.O.[OH-].[Na+]>C(O)(C)C>[Cl:2][C:3]1[S:25][C:6]2[C:7]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Temperature: 45 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
37% Hydrochloric acid (74.12 mL, 789.78 mmol) is added to a solution of tert-butyl 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-carboxylate (60 g, 157.96 mmol) in isopropyl alcohol (420 mL) at 45° C. The resulting solution is stirred at 45° C. for 15 h. Then, the mixture is concentrated to 1/4 volume to afford a white suspension. Water (100 mL) is added and the suspension is basified with 6N aqueous solution of sodium hydroxide to obtain a two-layer mixture that is extracted with methyl t-butyl ether (3×100 mL). Combined organics are washed with brine (50 mL), dried over sodium sulfate and concentrated to afford a light brown solid which is dried under vacuum till constant weigh to yield 97% of the title compound. MS (m/z): 280 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=4)[CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(C(F)(F)F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(Br)cnc32)cc1
Yield: 46.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (300 mg, 0.629 mmol) was coupled with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole (Intermediate 4) (310 mg, 0.88 mmol) in sodium carbonate (200 mg, 1.88 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (22 mg, 0.0314 mmol) and toluene/ethanol/water (30/10/2.5 ml) to afford 167 mg (46.2% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=577.00 (M+2).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1.[N:11]([O-])=[O:12].[Na+].C([O-])(O)=O.[Na+]>O>[NH2:3][C:4]1[C:9]([N:11]=[O:12])=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ncnc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 250 mL of 2N HCl was added 8.0 g (55 mmoles) of 4,6-diaminopyrimidine hydrochloride (34). The 4,6-diamino-pyrimidine hydrochloride was allowed to dissolve. The solution was then cooled to 0° C. and a solution of 4.2 g (61 mmoles) of NaNO2 dissolved in 15 mL of H2O was added dropwise within 20 minutes while stirring. Stirring was continued for another 30 minutes at 0° and then 2 hours at room temperature. The violet solution was neutralized by NaHCO3, the precipitate collected, washed with H2O and ethanol and dried to give 35 as 6.3 g (82% yield) of a blue-violet crystal powder (m.p. >350° C.).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])([CH3:5])[CH2:3][OH:4].Cl.N.[C:16](O)(=O)[CH3:17]>>[CH3:16][C:17]1[N:6]([C:2]([CH3:1])([CH3:5])[CH2:3][OH:4])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)O
Reactant: CC(C)(CO)Nc1ccccc1N
Agent: Cl
Agent: N
Product: Cc1nc2ccccc2n1C(C)(C)CO

Procedure:
A mixture of 2-(1,1-dimethyl-2-hydroxyethyl)aminoaniline (from Preparation 2(a)) (8.4 g), acetic acid [4.2 g], and 4N hydrochloric acid [50 ml] were refluxed for 30 hours. The reaction was cooled and neutralised with concentrated aqueous ammonia. The solution was extracted with a mixture of tetrahydrofuran (1 part) and dichloromethane (3 parts) (3×100 ml). The organic phases were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was recrystallised from ethyl acetate yielding the title compound as a white solid 3.8 g (40%), m.p. 180°-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
3.0 g of 3-hydroxy-4-nitrobenzaldehyde, 30 ml of acetonitrile, 5.9 g of caesium carbonate and 4.1 ml of 2-iodopropane are successively introduced into a three-necked round-bottomed flask under argon. The reaction mixture is heated at 70° C. for 17 h. After cooling to ambient temperature, the mixture is filtered through a sintered glass filter and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 50 ml of ethyl acetate and 15 ml of water, and then separated by settling out. The aqueous phase is separated and the organic phase is washed with 10 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure, so as to obtain 3.6 g of 3-isopropoxy-4-nitrobenzaldehyde in the form of a dark brown liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:10][N:8]([CH3:9])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])(=[O:22])=[O:21])=[O:25])[N:7]=1
Reactant: COc1nc(N)nc(N(C)C)n1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C)nc(N(C)C)n1
Reaction time: 24 h

Procedure:
To a stirred solution of 0.85 g of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine in 40 ml of methylene chloride was added, dropwise, 1.0 g of 2-methylbenzenesulfonyl isocyanate in 10 ml of methylene chloride. After stirring 24 hours, the resulting solution was evaporated to yield a solid. Recrystallization from benzene/hexane yielded the product named above melting at 194°-198°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1OC1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C(C)(C)C)cc1OC1CCOCC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]acrylic acid methyl ester (14.4 mg, 0.045 mmole) and 10 wt. % palladium were added in MeOH. The reaction mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered with celite pad. The filterate was concentrated in vacuo and purified with column chromatography to yield a syrup (14.1 mg, 97.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[N:13][N:12]2[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:11]2[C:10]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:36]=1)[C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[N:13][N:12]2[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:11]2[C:10]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:36]=1)[C:26]([OH:28])=[O:27])[CH3:2]
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(=O)O)c1
Yield: 100.6 %

Procedure:
A mixture of benzyl 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate (330 mg) and 10% palladium on carbon (33 mg) in methanol (10 mL) was stirred under 4 atm hydrogen atmosphere at ambient temperature for 2 hours. The catalysts were filtered off and washed with chloroform. The filtrates were evaporated in vacuo to give 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid as yellow oil (272 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 =ml) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was then washed once with water, and the organic portion was separated. The aqueous portion was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g (27%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:12]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)Cc1ccc(-c2ccccc2)nc1
Temperature: 67.5 °C

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), phenylboronic acid (0.16 gm, 1.3 mmole) and 50% water wet 10% Palladium carbon (0.08 gm, 0.036 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.15 gm, 1.4 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst washed with 20 ml×3 using the above mixture, the filtrate was dried under vacuum and crude mixture was used without any purification in the next step.