Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](C4C=CC=C5C=4CC(=O)N5C)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([CH3:54])[C:49](=[O:55])[CH2:48]2>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:45]4[CH:46]=[C:47]5[C:51](=[CH:52][CH:53]=4)[N:50]([CH3:54])[C:49](=[O:55])[CH2:48]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc5c4CC(=O)N5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CN1C(=O)Cc2cc(Br)ccc21
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(c4)CC(=O)N5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxoindolin-5-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid was prepared using in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxoindolin-4-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid, except 5-bromo-1-methylindolin-2-one was used instead of 4-bromo-1-methylindolin-2-one. LCMS-ESI+: calc'd for C34H31ClN3O4S: 612.1 (M+H+); Found: 612.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.61 (d, 1H), 8.36 (s, 1H), 7.94 (d, 1H), 7.89 (m, 1H), 7.84 (m, 2H), 7.61-7.59 (m, 1H), 7.54-7.50 (m, 3H), 7.03 (d, 1H), 5.18 (s, 1H), 3.55 (s, 2H), 3.14 (s, 3H), 2.53 (s, 3H), 0.89 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[F:8].[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[OH:19])=[O:18]
Reactant: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1F)CCC

Procedure:
N-(3-(3-bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 to give 2,2,2-trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide as a pale yellow oil. Yield (1.37 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.18 (t, J=9.0 Hz, 1H), 5.41 (d, J=4.8 Hz, 1H), 5.19 (s, 1H), 4.58-4.54 (m, 1H), 3.28-3.16 (m, 2H), 1.82-1.69 (m, 2H), 1.63-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[C:20]([NH2:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:20]1[C:9]([C:4]2[C:3]([Cl:22])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([S:17][CH3:18])=[N:13][C:12]=2[N:19]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
To a solution of 6-(3-amino-2,6-dichloro-phenyl)-2-methylsulfanyl-pyrido[2,3-d]-pyrimidin-7-ylamine (0.5 g, 1.42 mmol) in CH2Cl2 (40 mL) is added 3-(trifluoromethyl)benzoyl chloride (1.07 mL, 7.1 mmol). After the mixture is stirred for 24 hours at room temperature, the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by a flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(95/5%), to give the title intermediate as a solid (0.591 g, 79.4 %).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=[S:44])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CCC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Solvent: CO
Product: COc1ccc(CCC(=S)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Yield: 94 %

Procedure:
A mixture of N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-(4-methoxyphenylmethyl) acetamide (20 mg, 0.045 mmol) and Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial and mixed thoroughly with magnetic stirbars. The glass vial was then irradiated in a microwave oven (900 W, Whirlpool M401) for 8 min. Upon completion of the reaction, the yellow-colored material was transferred to an ion-exchange column with the aid of methanol (2 ml). The ion-exchange column was subsequently washed with CH2Cl2 (2 ml) and methanol (2 ml) and the product was thereafter eluted from the ion-exchange column (10% NH3 in methanol, 2 ml) to give N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylmethyl thioacetamide (20 mg, 97%) as a white solid; LC-MS: (M+H)+ 459, tr 9.60 min; TLC (CH2Cl2/methanol 20:1) Rf=0.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Li]CCCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(OC)c2ccccc2n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)nc2ccccc2c1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 2,4-dimethoxyquinoline (11.5 g, 60.8 mmol) in anhydrous THF was added dropwise n-BuLi (2.5 M in hexane, 48.6 mL, 122 mmol) at 0° C. After stirring for 1.5 h at 0° C., the mixture was added to a solution of ethyl chloroformate in anhydrous THF and stirred at 0° C. for additional 30 min and then at room temperature overnight. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (petroleum ether/EtOAc=50/1) to give ethyl 2,4-dimethoxyquinoline-3-carboxylate (9.6 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=O)[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:32][OH:33]>C(O)C>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[N:32][OH:33])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nonc1-c1nc2ccccc2n1CC(=NO)c1ccc(Br)cc1

Procedure:
A mixture of 4-[1-(4-bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.083 g, 0.21 mmol, prepared according to Example 1), sodium bicarbonate (0.021 g, 0.25 mmol) and hydroxylamine hydrochloride (0.014 g, 0.21 mmol) in ethanol (5 ml) is refluxed for 20 hours. Partitioning of the reaction mixture between ethyl acetate and water, separation of the organic phase followed by drying and evaporation of the solvent gives the crude product. Purification by chromatography on silicagel yields the title compound as an E/Z-mixture, m.p. 198-201° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH:29]=[CH2:30])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[N+:8]([O-:19])=[C:7]([NH:20][C:21](OCC(C)C)=[O:22])[N:6]=1)[CH:2]=[CH2:3].C(Cl)Cl.[OH-].[Na+]>O>[CH2:1]([N:4]([CH2:28][CH:29]=[CH2:30])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]2[O:19][C:21](=[O:22])[N:20]=[C:7]2[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)c1nc(NC(=O)OCC(C)C)[n+]([O-])c(NC(=O)OCC(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)OCC(C)C)n2oc(=O)nc2n1

Procedure:
18 g. of diisobutyl 6-diallylamino-s-triazine-2,4-dicarbamate-3-oxide are dissolved while stirring in 560 ml. of methylene chloride and treated with 1800 ml. of water and sufficient concentrated sodium hydroxide so that the pH value of the mixture amounts to 12.7. The mixture is then stirred for 75 minutes and the two phases are separated. The alkaline-aqueous phase is adjusted to pH 4 with 3-N hydrochloric acid and then extracted three times with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure isobutyl 5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate having a melting point of 161°-163° C.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]>CO>[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: C=CCS
Reactant: CC(C)CCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCC(C)C)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 150 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 10.03 g(0.05 mol) of 3-isopentyloxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:16]C1C=CC=C(C(OO)=O)C=1>ClCCl>[Cl:16][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=2)[N:1]=1
Reactant: CCOC(=O)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.8 g (29 mmol) of ethyl quinoline-6-carboxylate was stirred in 80 ml of dichloromethane. 6.2 g of m-chloroperbenzoic acid was added to the obtained mixture under cooling with ice, and they were stirred at room temperature overnight. The mixture was washed with 10% aqueous sodium sulfite solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated. 70 ml of dichloromethane and 35 ml of phosphoryl chloride were added to the residue, and they were stirred at 50° C. overnight. The solvent was evaporated, and the residue was treated with dichloromethane as the extracting solvent by an ordinary method. After the purification by the silica gel chromatography (ethyl acetate/hexane), the title compound was obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:23]=[C:24]([F:26])[CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1cc(F)cc(OCc2ccccc2)c1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reaction time: 8 h
Yield: 33.1 %

Procedure:
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.10 mmol 1.591 g), (3-(benzyloxy)-5-fluorophenyl)boronic acid (4.06 mmol 1.0 g), dppf (0,610 mmol, 338 mg) Potassium phosphate anhydrous (10.16 mmol, 2.157 g) were suspended in dioxane and the mixture was heated at 180 C for 25 min in a Mw reactor then poured in 100 ml of water. The mixture was stirred overnight then filtered on a buchner funnel washing with 30 ml of water. The crude material was purified by chromatography eluting with DCM\ MeOH (80/20) in DCM to give the title compound (450 mg, 1.342 mmol, 33% yield) as a beige solid.
Reaction SMILES: ClCl.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])([CH3:6])(C)C.[CH2:25](N(CC)CC)[CH3:26]>C(O)C>[CH2:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])[CH2:6][CH2:25][CH3:26]
Reactant: CCN(CC)CC
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: ClCl
Solvent: CCO
Product: CCCCOC(=O)N[C@H](C(=O)O)[C@@H](C)OCc1ccccc1

Procedure:
A mixture of 20 g. of chloromethylated polystyrene resin having 1.16 mmole of chlorine per gram, and 8 g. of Nα-t-butoxycarbonyl-O-benzyl-L-threonine in 500 ml. of ethanol is treated with 2.6 g. of triethylamine and refluxed for three days in excess ethanol. The resin is separated by filtration, washed with ethanol, water, methanol, dichloromethane and ether, successively, and then dried overnight at 40° C. giving the Nα-butoxycarbonyl-O-benzyl-L-threonine resin.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH2:21]O)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[N:10]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([CH:14]=1)[O:12][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][C:8]=1[CH3:23]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OCc1nc(-c2ccco2)oc1C
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OCc1nc(-c2ccco2)oc1C
Yield: 98.5 %

Procedure:
To a mixture of (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxyphenyl)methanol (7.0 g) and toluene (150 mL) was added thionyl chloride (3.16 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(5-chloromethyl-2-methoxyphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole as pale-brown crystals (7.30 g, yield 99%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]1[CH2:14][CH2:13][CH:12](OC)O1.[OH-].[Na+]>C(O)(=O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:1]1[CH:10]=[CH:14][CH:13]=[CH:12]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccn(-c2cnccn2)c1
Temperature: 105 °C

Procedure:
A mixture of 43 g (0.5 mole) 2-aminopyrazine and 66 g (0.5 mole) 2,5-dimethoxytetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. The reaction mixture is refluxed at 105°C for 30 minutes and, after cooling, it is made basic by the addition of 325 ml of 30% aqueous sodium hydroxide and steam-distilled.
Reaction SMILES: O.[CH2:2]([O:4][C:5](=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].CC[O-].[Na+].[C:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3]
Reactant: CCOC(=O)CCCCC(=O)OCC
Reactant: BrCc1ccccc1-c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(Cc1ccccc1-c1ccccc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Into a 3 neck flask, equipped with water cooler, were added 43.8 mL (0.22 mol) of diethyladipate and 220 mL THF. 16.3 g (0.24 mol, 1.1 equivalents) of NaOEt were added in small portions, at 20° C., and the reaction mixture was stirred at 60° C. for 16 hours. After cooling to 20° C., 48.6 g (0.20 mol) of 2-phenyl-benzyl bromide was added dropwise. The reaction mixture was stirred at 60° C., for 16 hours, to give 2-(2-phenyl-benzyl) adipic acid diethylester as a viscous oil, in a yield of 92%.
Reaction SMILES: CC(C[Al]CC(C)C)C.C([O:12][C:13](=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])C.O>C1COCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][CH2:13][OH:12])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CCOC(=O)C=Cc1ccc(C)cc1[N+](=O)[O-]
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=CCO)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 0.25 h

Procedure:
Dibal-H (0.0255 mol) was added at −35° C. to a mixture of 3-(4-methyl-2-nitro-phenyl)-acrylic acid ethyl ester (0.0085 mol) in THF (80 ml) under N2 flow. The mixture was stirred at −35° C. for 15 minutes. H2O (20 ml) was added drop wise at −35° C. under N2 flow. The mixture was half-evaporated. CH2Cl2 was added. The mixture was filtered over celite. Celite was washed with CH2Cl2. The filtrate was washed with H2O. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated. Yield: 2 g of 3-(4-Methyl-2-nitro-phenyl)-prop-2-en-1-ol (e-2) (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCC
Product: Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Yield: 100.5 %

Procedure:
To a solution of commercially available 1-bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) in anhydrous toluene (3 mL) was added CsCO3 (0.305 g, 0.94 mmol) followed by phenylboronic acid (0.062 g, 0.49 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3.]undecane as a 0.1M solution in toluene (0.200 mL, 4 mole %). Nitrogen was bubbled through the resulting suspension for three minutes then palladium acetate (0.0043 g, 4 mole %) was added, the reaction vessel sealed and immersed in an 80° C. oil bath and heated for 22 hours. Subsequent filtration through celite and removal of volatiles under vacuum gave the crude product (0.105 g, 100%), which was sufficiently pure for use as isolated.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH2:8][C:9]([CH3:11])=O)=O.[N+:12]([N:15]=[C:16]([NH:18][NH2:19])[NH2:17])([O-:14])=[O:13]>O>[CH3:5][C:6]1[CH:8]=[C:9]([CH3:11])[N:18]([C:16](=[N:15][N+:12]([O-:14])=[O:13])[NH2:17])[N:19]=1
Reactant: NNC(N)=N[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)n(C(N)=N[N+](=O)[O-])n1
Yield: 89 %

Procedure:
2.7 ml of acetic acid and 2,4-pentadione (0.785 mg, 7.83 mmol) are added to a mixture heated under reflux containing the N′-nitrohydrazinecarboximidamide compound isolated previously (0.5 g, 4.20 mmol) in 15 ml of water. The reaction medium is returned to ambient temperature then filtered. The solid obtained is washed with dichloromethane. A white solid in the form of white powder is obtained with a yield of 89%.
Reaction SMILES: CS(C1CCN([C@@H](C[NH:17][S:18]([C:21]2C=CC(OCC3C4C(=CC=CC=4)N=C(C)C=3)=CC=2)(=[O:20])=[O:19])C(OC)=O)CC1)(=O)=O.CS(C1[CH2:49][CH2:48][N:47]([C@@H:50]([CH2:54][NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[N:70]=[C:69]([CH3:77])[CH:68]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[C:51]([OH:53])=[O:52])[CH2:46][CH2:45]1)(=O)=O>>[CH3:21][S:18]([N:17]1[CH2:45][CH2:46][N:47]([C@@H:50]([CH2:54][NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[N:70]=[C:69]([CH3:77])[CH:68]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[C:51]([OH:53])=[O:52])[CH2:48][CH2:49]1)(=[O:20])=[O:19]
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCC(S(C)(=O)=O)CC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)O)N3CCC(S(C)(=O)=O)CC3)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)O)N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2n1

Procedure:
In a manner analogous to example 3.7, using 130 mg (0.2 mmol) of methyl (S)-2-(4-methanesulfonyl-piperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate, 120 mg (99%) of (S)-2-(4-methanesulfonylpiperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:23]3[N:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C([SiH](CC)CC)C>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:19]2[N:23]3[N:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cc(-c2ccc3ncc(C(=O)c4ccc(OCc5ccccc5)cc4)n3n2)cn1
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc(OCc5ccccc5)cc4)n3n2)cn1
Reaction time: 16 h

Procedure:
Sodium borohydride was added to a solution of (4-benzyloxy-phenyl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanone (Stage 5.2, 190 mg, 0.46 mmol) in ethanol (1.5 mL) and the reaction stirred for 16 h. Water was added to the reaction and the resulting solid was filtered off and dried under vacuum. The solid was dissolved in TFA (2 mL) and to this solution was added triethylsilane (0.18 mL, 1.16 mmol) and the mixture was stirred at rt for 30 min. Water was added and the mixture extracted with EtOAc. The EtOAc extract was dried, filtered and concentrated to give the title compound as red solid (tR 1.3 min (conditions 2), MH+=396).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Yield: 98.7 %

Procedure:
A mixture of 6-chloro-3-trifluoromethylpyridazine (0.666 g, 5.09 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P; Tarbit B. Tetrahedron 1999, 55, 15067-15070), N-Boc-piperazine (1.138 g, 6.11 mmol) and diisopropylethylamine (1.95 ml, 1.12 mmol) in acetonitrile (10 ml) was stirred at 180° C. for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; hexane/ethyl acetate) to yield D9 (1.67 g, 99%) as a light yellow solid. C14H19F3N4O2 requires 332; Found 333 (MH+).