Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9](SC)[S:8][CH2:7][C:6]=2[CH:13]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1>C(O)CCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[S:8][CH2:7][C:6]3[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CSC1=Nc2ccc(Cl)cc2CS1
Solvent: CCCCO
Product: CC(=O)c1ccc(NC2=Nc3ccc(Cl)cc3CS2)cc1
Yield: 39.1 %

Procedure:
A mixture of 6-chloro-2-methylthio-4H-3,1-benzothiazine (57.5 g, 0.25 mole) and p-aminoacetophenone (33.8 g, 0.25 mole) in n-butanol (200 ml) was refluxed overnight. After cooling in a refrigerator for three days, the solid was collected by filtration and recrystallized from ethanol-water mixture to yield 31 g (39%) of product. Recrystallization from ethanol-water mixture gave an analytical sample, m.p. 174°-175°.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:27]C(=O)OC(C)(C)C)[N:15]=[CH:14]2.Cl>O1CCOCC1.ClCCl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:27])[N:15]=[CH:14]2
Reactant: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (21 mg, 0.045 mmol) and 4M HCl in Dioxane (0.5 mL) in dichloromethane (1 mL) was stirred at room temperature for 16 h. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated and used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Yield: 70.8 %

Procedure:
A mixture of 28.8 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (as prepared in Example XIV of U.S. Pat. No. 4,219,559), 33.9 parts of ethyl 5-chloromethyl-2-furancarboxylate, 15.9 parts of sodium carbonate and 282 parts of N,N-dimethylformamide was stirred for 2 nights at 70° C. The reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was stirred in 1,1'-oxybisethane. The precipitate was filtered off and dried, yielding 31.2 parts (70.8%) of ethyl 4-[[1-[[5-(ethoxycarbonyl)-2-furanyl]-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 136.0° C. (interm. 1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([N:23](CC)CC)C.ClC(OCC(C)C)=O.[N+](=C)=[N-]>C1COCC1.CCOCC>[NH:23]=[CH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: CCN(CC)CC
Agent: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: N=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (144 mg, 0.535 mmol, described in Intermediate 16) in THF (5 mL) at −10° C. was added triethylamine (0.097 mL, 0.695 mmol), followed by isobutyl chloroformate (0.090 mL, 0.695 mmol) and the resulting mixture was stirred at −10° C. for 3 h. A cold solution of diazomethane (ca. 1.0 mmol) in Et2O (3 mL) was added, and stirring was continued for 16 h, allowing the mixture to warm slowly to ambient temperature. The mixture was cooled to −10° C. and a cold solution of diazomethane (ca. 1.5 mmol) in Et2O (5 mL) was added, and the resulting mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was removed in vacuo and the residue was partitioned between Et2O (20 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted further with Et2O (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH to give a pale solid. This solid was further purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=266 (M−N).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[CH2:1]([O:8][CH:9]([CH3:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(OCc1ccccc1)C(=O)O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A mixture of residue containing methyl 2-(benzyloxy)propanoate compound of formula-12 obtained in step-a) and water (500 ml) was cooled to 0-5° C. A solution of sodium hydroxide (51.5 g) in water (375 ml) was added to reaction mixture at 0-5° C. and stirred the reaction mixture for 1 hour at the same temperature. Temperature of the reaction mixture was raised to 25-30° C. and stirred for 4 hours at this temperature. After completion of the reaction, washed the reaction mixture with dichloromethane. Both dichloromethane and aqueous layers were separated and pH of aqueous layer was adjusted to 2.5 using 50% hydrochloric acid solution. Extracted the aqueous layer with dichloromethane. Distilled off the solvent from dichloromethane layer under reduced pressure to get the title compound as a residue. The obtained residue can be taken into next step without isolation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[C:4]([N+:16]([O-])=O)[CH:3]=1>CCO.O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CN(C)CCCN(C)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (4.0 g, 15 mmol) in EtOH (80 ml) and water (10 ml) was added Raney-Ni (10 g). The mixture was stirred for 5 hours at RT, filtered through a pad of Celite and concentrated to yield 4-chloro-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine as a deep red oil. MS m/z=242 [M+H+. Calc'd for C12H29ClN3: 241.77.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cccc(O)c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3)c12
Temperature: 110 °C
Yield: 40.3 %

Procedure:
3-methyl-1,2-benzisoxazol-4-ol (Intermediate 10, 137 mg) was stirred with 1-fluoro-4-nitrobenzene (130 mg, 0.92 mmol) in DMF (3.0 ml) with potassium carbonate (381 mg, 2.8 mmol). The reaction mixture was heated at 110° C. for 1 hour under microwave irradiation After removal of the volatiles, the residue was purified by silica gel chromatography eluting with CyHex/EtOAc (100%/0% to 0%/100%) to afford the title compound (100 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:49][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][C:45]=1[F:48]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: C=C(CN1CCOCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4ylmethyl-2-propenoic acid in 50 ml ThF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:16][O:15][N:14]([CH3:13])[C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: CNOC
Reactant: Cc1cccc(CC(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a solution of (3-methylphenyl)acetic acid (1.0 g, 6.7 mmol) in DMF (20 mL0 were added N,O-dimethylhydroxylamine hydrochloride (0.78 g, 8.04 mmol), EDC (1.54 g, 8.04 mmol), HOBt (1.06. g, 8.04 mmol), and N,N-diisopropylethylamine (7.0 mL, 40.2 mmol). The solution was stirred at RT for 18 h then diluted with EtOAc (150 mL) and washed with HCl 1M (100 mL), water (100 mL), saturated solution of NaHCO3 (100 mL), and brine (100 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to afford the desired amide (1.2 g, 98%) used in the next step without further purification. Rf 0.8 (EtOAc/hexanes 1/1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]1[S:27][C:26]([CH2:28][OH:29])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>COCCOC>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1ccc(F)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cn12
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (285 mg), (5-fluorothiophen-2-yl)methanol (109 mg), potassium tert-butoxide (93 mg) and DME (5 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional potassium tert-butoxide (93 mg) and (5-fluorothiophen-2-yl)methanol (109 mg) in DME (0.5 ml) were added to the reaction mixture, and the resulting mixture was heated at 120° C. for further 30 min under microwave irradiation. The mixture was quenched with water and extracted with EtOAc/MeOH. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was crystallized from EtOH-IPA to give the title compound (120 mg) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:40]=[C:20]1[C@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: N#Cc1cccc(CBr)c1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1cccc(CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-(bromomethyl)benzonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile was obtained (75%) as a colorless solid: mp 94-96° C. (isopropyl alcohol); 1H NMR (300 MHz, CDCl3) δ 7.65-7.52 (m, 4H), 7.49-7.42 (m, 2H), 7.23-7.15 (m, 1H), 7.08-7.01 (m, 1H), 6.75-6.70 (m, 1H), 6.49 (s, 1H), 6.18 (s, 1H), 5.03 (d, J=15.8 Hz, 1H), 4.95-4.84 (m, 2H), 4.66 (d, J=9.0 Hz, 1H), 4.20-4.07 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4, 29.7; MS (ES+) m/z 411.0 (M+1). Anal. Calcd. for C25H18N2O4: C, 73.16; H, 4.42; N, 6.83. Found: C, 72.92; H, 5.05; N, 6.50.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]=[N:8][C:4]=2[CH:3]=1.[CH2:30]([N:37]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47](B)[CH:46]=1)[CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(Cl)Cl>O1CCOCC1.C(OCC)C>[CH2:30]([N:37]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:7]=[N:8][C:4]=3[CH:3]=2)[CH:46]=1)[CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Bc1cccc(CN(CCCN(C)C)Cc2ccccc2)c1
Reactant: Brc1ccc2c(c1)nnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCN(Cc1ccccc1)Cc1cccc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 90 °C
Yield: 21.2 %

Procedure:
A mixture of 5-bromo-1-trityl-1H-benzotriazole (220 mg, 0.5 mmol), N-benzyl-N-(3-boranyl-benzyl)-N′,N′-dimethyl-propane-1,3-diamine (180 g, 0.55 mmol), and cesium carbonate solution in water (2M, 1 mL, 2 mmol) taken altogether in 10 mL of dioxane was degassed (evacuate in vacuo and pressurize with argon, two times) and PdCl2(dppf).DCM (21 mg, 0.025 mmol) was added and the mixture was degassed two more times as described above. The resulting mixture was heated at 90° C. for 3 h, then it was allowed to cool to room temperature and the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over MgSO4, filtered and evaporated to give the crude product. Chromatography on silica gel (elution with methanol/dichloromethane) followed by trituration of the material obtained with diethyl ether gave 68 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].BrCBr>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[O:10][CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: COc1cc(Br)cc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCBr
Product: COc1cc(Br)cc2c1OCO2
Yield: 52 %

Procedure:
To dimethylfonrnamide (400 mL) was added 1-bromo-3,4-dihydroxy-5-methoxybenzene (40 g, 182 mmol), potassium carbonate (75.7 g, 548 mmol), and dibromomethane (95.2 g, 548 mmol), followed by heating to reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was taken up into ethyl ether, filtered, washed with saturated potassium carbonate solution, brine, 1N citric acid solution, and brine. The organic phase was dried over anhydrous magnesium sulfate and filtered through charcoal. The filtrate was concentrated in vacuo giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid. This material was distilled at 2 mm Hg, 125° C., giving a crystalline solid, 21.7 g, 52% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:9]([CH3:16])=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[CH3:14])[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=O)[CH2:19][CH2:20][CH3:21].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:26][N:27]=[C:18]([C:3]1[C:4](=[O:17])[CH2:5][CH:6]([C:8]2[C:9]([CH3:16])=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[CH3:14])[CH2:7][C:2]=1[OH:1])[CH2:19][CH2:20][CH3:21])[CH3:25]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)nc(C)nc2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)nc(C)nc2C)CC1=O

Procedure:
3-Hydroxy-5-(2,4,6-trimethylpyrimidin-5-yl)-2-butyrylcyclohex-2-en-1-one (0.29 g) was stirred with O-ethylhydroxylamine hydrochloride (0.1 g) and sodium acetate trihydrate (0.14 g) in ethanol (30 ml) at room temperature for 15 hr. The mixture was poured into a saturated aqueous salt solution (50 ml), which was subsequently extracted with ethyl acetate. The dried (Na2SO4) organic extract was evaporated to give 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(2,4,6-trimethylpyrimidin-5-yl)cyclohex-2-en-1-one as a colourless oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.01 (3H, t); 1.34 (3H, t); ca 1.64 (2H, m); ca 2.3-3.8 (7H, m); 2.59 (6H, s); 2.63 (3H, s); 4.13 (2H, q); 10.66 (1H,s).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:11][C:5]3[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=3[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C1NCCc2cc(Br)sc21
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2cc(-c3ccc(F)cc3)sc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Add tetrakis(triphenylphosphine) palladium(0) (0.075 g, 0.065 mmol) to a degassed solution of 2-bromo-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.5 g, 2.15 mmol), 4-fluorophenylboronic acid (0.30 g, 2.15 mmol), and sodium carbonate (0.46 g, 4.30 mmol) in N,N-dimethylformamide (21 mL), methanol (5 mL) and water (1 mL). Heat the reaction at 90° C. for 16 h. Allow the reaction to cool to RT and pour into water (75 mL). Filter the resulting solid and dry in vacuo at 80° C. to give 0.40 g (75%) of the title compound. MS/ES m/z 248.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C@H:65]([C:75]([O:77][CH3:78])=[O:76])[CH2:66][CH2:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71].Cl>CN(C=O)C>[CH3:78][O:77][C:75](=[O:76])[C@@H:65]([NH:64][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[O:30])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=1)=[O:29])[CH2:66][CH2:67][C:68]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:74]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 1.50 g 5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 22 ml DMF were added 0.60 ml DIPEA, 1.38 g HATU and 923 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using DCM/MeOH 97:3 as eluent. Yield: 2.0 g.
Reaction SMILES: [OH:1][C@@H:2]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.C(Cl)(Cl)Cl.C=O.N1CCNCC1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][C@@H:2]([OH:1])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:19][CH2:20]1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc([N+](=O)[O-])c3)CC2)cc1
Agent: [Pd+2]
Agent: C1CNCCN1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc(N)c3)CC2)cc1

Procedure:
Pd(OH)2/C at 20% [1.54 g, 2.2 mM Pd(OH)2] is suspended in a solution of (S)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)-1-(3-nitrophenoxy)propane (3.30 g, 7.73 mM) (Example 27) in ethyl acetate (43 ml). The mixture is maintained in agitation in atmosphere of H2 (10 atm) for 30 hours. The catalyst is then removed by filtering the reaction mixture on Celite, and the solvent is distilled under vacuum. A white solid is obtained (97% of yield). Pf 138.5-139.6° C.s. [α]D=−10.7 (c 1.06, CHCl3). FT-IR (KW): 3456, 3371, 3100, 3063, 2945, 2916, 2853, 1597, 1576, 1497, 1456, 1343, 1328, 1302, 1263, 1195, 1161, 1096, 948, 839, 809, 773, 737, 694, 660 cm−1. 1NMRs (300 MHz CDCl3, δ): 7.71-7.67 (m, 2H, aromatic protons); 7.05-6.98 (m, 3H, aromatic protons); 6.30-6.29 (d, 1H, J=2.2 Hz, aromatic proton); 6.27-6.26 (m, 1H, aromatic proton); 6.23-6.22 (t, J=2.2 Hz, 1H, aromatic proton); 4.05-3.97 (m, 1H, CHOH); 3.89-3.88 (m, 5H, CH2O and OCH3), 3.70-3.10 (bs, 2H, NH2); 3.10-2.85 (bs, 5H, 2 CH2N of piperazine and OH); 2.79-2.69 (m, 2H, CH2N of piperazine); 2.58-2.45 (m, 41-1, CH2N of piperazine and CHOHCH2N). 13C NMRs (75 MHz CD3OD, δ): 163.39, 159.95, 148.03, 130.35, 130.16, 127.15, 114.51, 108.55, 104.67, 101.90, 70.09, 66.07, 60.46, 55.87, 52.69, 46.28. MS-ESI m/z (%): 444 [M+Na]+(100). Anal. Calc. for C20H27N3O5S: C, 56.99; H, 6.46; N, 9.97. Found: C, 56.91; H, 6.41; N, 9.69.