Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:37]1[O:41][C:40]([CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=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.CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:37]2[O:41][C:40]([CH2:42][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:39][CH:38]=2)=[C:3]([CH3:12])[CH:4]=1
Reactant: Brc1ccc(CN2CCOCC2)o1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CN3CCOCC3)o2)c(C)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A three necked flask was charged with methyl 4-bromo-3-methylbenzoate (2.18 mmol), bis(pinacolato)diboron (2.29 mmol), palladium acetate (0.065 mmol), potassium acetate (6.54 mmol) and DMF (10 ml). The solution was degassed by bubbling through N2 gas for 30 mins and was then heated to 80° C. under N2 for 3 h. Reaction was then cooled to room temperature and 4-(5-Bromo-furan-2-ylmethyl)-morpholine (2.18 mmol), cesium carbonate (3.27 mmol) and Pd(PPh3)4 (0.065 mmol) added. The reaction was heated to 80° C. and stirred for a further 17 h. Mixture was then diluted with EtOAc and water and filtered through a celite pad to remove black particulates. The organic layer was separated, washed with brine and dried over Na2SO4 and concentrated in vacuo. Flash chromatography of the residue (silica, 10-99% EtOAc in hexane) gave 3-Methyl-4-(5-morpholin-4-ylmethyl-furan-2-yl)-benzoic acid methyl ester as a grey powdery solid: m/z in MS ES+=316 [M+H]+, 0.51 mmol, 23%.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN(C)CCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylpropane-1,3-diamine according to general procedure 1 providing the intermediate (160 mg, 84%) as a clear oil: Rf=0.16 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.5 Hz, 1H), 3.40 (t, J=7.1 Hz, 2H), 2.48-2.45 (m, 2H), 2.27 (s, 6H), 1.93-1.88 (m, 2H); ES-MS: (M+H)=298, 300 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[Br:9].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[O:10][CH3:11]
Reactant: COc1cc(I)cc(OC)c1Br
Reactant: OB(O)c1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2ccco2)cc(OC)c1Br
Temperature: 60 °C
Yield: 91.2 %

Procedure:
2-(4-Bromo-3,5-dimethoxyphenyl)furan was synthesized according to the procedure reported in WO 2008/040669 as follows. To a round bottom flask containing 3,5-dimethoxy-4-bromo-iodobenzene (7.9 g, 85% purity, 19.6 mmol), 2-furylboronic acid (3.4 g, 30.4 mmol), triphenylphosphine (0.358 g, 1.37 mmol), tetrabutylammonium bromide (7.94 g, 14.6 mmol) and Na2CO3 (4.9 g, 46.2 mmol) was added THF (87 mL) and H2O (87 mL). The mixture was degassed by alternately putting under house vacuum and argon three times for several minutes each. 10% Pd/C (1.36 g) was added and the mixture was heated at 60° C. for 17 hrs under argon. After cooling to room temperature, the mixture was filtered through Celite and rinsed with THF and EtOAc. The filtrate layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by column chromatography (0-25% Et2O-hexanes) gave 2-(4-bromo-3,5-dimethoxyphenyl)furan as a white solid (5.06 g, 91% yield). Product TLC Rf 0.35 (15% EtOAc-hexanes TLC eluent).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1.BrC1C=CC=CN=1>[Pd]>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: Brc1cncnc1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Agent: [Pd]
Agent: Brc1ccccn1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 4-Methoxymethyl-thiazol-2-ylamine (CAS: [640768-40-7]; WO 2004081001) instead of 2-chloro-4-aminopyridine to yield [2-(4-Methoxymethyl-thiazol-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white gum, MS (ISP): m/e=379.4 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=279.3 (M+H+). Palladium catalysed arylation in accordance with the general method of example 20, using 5-Bromopyrimidine instead of 3 bromopyridine yielded the final compound as a light yellow solid, MS (ISP): m/e=357.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:19])[N:11]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:12][CH3:13].Cl>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][CH2:14][N:11]([CH2:12][CH3:13])[C:10]1=[S:19]
Reactant: CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Agent: Cl
Solvent: CC(C)=O
Product: CCN1CCC(=O)N(c2c(C)cccc2C)C1=S
Yield: 47.2 %

Procedure:
3-[3-(2,6-dimethylphenyl)-1-ethyl-thioureido]propionic acid (12 g) was dissolved in acetone (245 mL). Conc. HCl (5 mL) was added and the mixture was heated at reflux for 18 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in methylene chloride (100 mL), and washed with 1N NaOH. The organic phase was dried over anhydrous magnesium sulfate, then evaporated to dryness. The solid was recrystallized from ethyl acetate to give the title compound (5.3 g) as a white solid, m.p. 124°-126° C.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:19][CH2:20][O:10][CH:9]1[C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCNCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Product: O=C(c1ccccc1)C1OCCN1Cc1ccccc1
Yield: 90 %

Procedure:
Agami et al, Tetrahedron Lett., (1993) 34, 7061 describes the reaction of phenylglyoxal with (R)-N-methylphenylglycinol in refluxing acetonitrile to give (5R)-3,5-diphenyl-4-methyl-1,4-oxazin-2-one. Under the same conditions, however, we have found that the reaction of phenylglyoxal with N-benzylethanolamine gives predominantly (>90%) N-benzyl-2-benzoyloxazolidine. The desired product, N-benzyl-3-phenyl-1,4-oxazin-2-one was formed at a low level (5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[N:6]=[C:5]2[N:4]([CH3:14])[C:3]([CH2:2][O:1][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:11][C:10]2=[CH:9][CH:8]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.25 g of 2-hydroxymethyl-5-methoxy-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 69), 0.66 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.35 ml of tributylphosphine, 0.36 g of 1,1'-(azodicarbonyl)dipiperidine and 15 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.70 g of the title compound, melting at 80°-85° C. (softening).
Reaction SMILES: [CH2:1]1[S:10](=[O:12])(=[O:11])[NH:9][CH2:8][CH:7]2[CH2:13][CH2:14][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].CN(C=O)C.[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24]([CH2:23][N:9]1[CH2:8][CH:7]2[CH2:13][CH2:14][C:2]([C:4]2([CH3:6])[CH3:5])([CH3:3])[CH2:1][S:10]1(=[O:12])=[O:11])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC12CCC(CNS(=O)(=O)C1)C2(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2CCC(C)(CS1(=O)=O)C2(C)C
Reaction time: 8 h

Procedure:
Camphorsultam (3 g, 14 mmole) in DMF (25 mol) was mixed with NaH (1.1 equiv.) for 15 minutes, then tert-butyl bromoacetate (2.5 ml) was added and the reaction mixture was stirred overnight. The solvent was evaporated to dryness and the residue was partitioned between aq-citric acid and EtoAc. The organic layer was washed with sat. aq. NaHCO3, and water, dried and evaporated to give the ester. (3.5 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:11]2[N:10]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]([NH:23][CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:11]2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c3nc(-c4c(F)cccc4F)c4cc(F)ccc4c3nn2COCC[Si](C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCNCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
340 mg of 2-methylpropan-2-yl 4-{[5-(2,6-difluorophenyl)-7-fluoro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-carboxylate are introduced into 16 ml of methanol and 1.5 ml of THF. After cooling to 0° C. using an ice bath, 2.7 ml of a 4N solution of hydrochloric acid in dioxane are added and the mixture is stirred at RT for 5 h. It is poured into 200 ml of saturated sodium bicarbonate solution and then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/aqueous ammonia mixture (90/10/1 by vol.), to give 180 mg of 5-(2,6-difluorophenyl)-7-fluoro-N-(piperidin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid), LC-MS-DAD-ELSD: 528=(M+H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[NH2:24].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:24][C:15]3[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: Clc1nc2c(Br)cccn2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)cc1Nc1cccn2nc(Cl)nc12
Temperature: 100 °C
Yield: 67.8 %

Procedure:
A mixture of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.23 g, 0.99 mmol), 2-methoxy-5-trifluoromethyl-phenylamine (0.226 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.185 g, 0.2 mmol), dicyclohexyl-(2′-4′-6′-triisopropyl-biphenyl-2-yl)-phosphane (0.19 g, 0.4 mmol), and sodium tert-butoxide (0.29 g, 3.0 mmol) in toluene (10 mL) was degassed with nitrogen for 3 minutes, then heated at 100° C. for 2 hours under argon. The reaction was cooled to room temperature, diluted with dichloromethane, filtered through diatomaceous earth, and concentrated. The residue was diluted with dichloromethane, washed with 10% sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated. The crude product was triturated with ether and dichloromethane to give (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine (0.23 g, 68%). MP=144-146° C. MS=343 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:13])[N:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=C1NN=C(c2ccccc2)OC1c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(c2ccccc2)OC(c2ccccc2)=NN1c1ccccc1
Yield: 36.9 %

Procedure:
A mixture of 2,6-diphenyl-4H-1,3,4-oxadiazine-5-one (0.1 g), phenyl boric acid (0.13 g), copper acetate (0.18 g) and triethylamine (0.12 g) was stirred vigorously in methylene chloride (15 ml) overnight at room temperature. The reaction in solution was purified directly by silica gel chromatography (ethyl acetate/hexane, 1:2), to give the title compound as a white powder (0.048 g, 37%).
Reaction SMILES: CC([C:5]1[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[N:8]([CH3:10])[CH:9]=1)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[S:11]([C:7]1[N:8]([CH3:10])[CH:9]=[CH:5][C:6]=1[S:17]([NH2:20])(=[O:19])=[O:18])(=[O:12])=[O:13]
Reactant: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)c(C(C)(C)C)cn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.95 g (21 mmol) of N3 -(1,1-dimethylethyl)-N2,N2,1-trimethyl-1H-pyrrole-2,3-disulfonamide in 75 mL of methylene chloride under a nitrogen atmosphere was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the solid residue and removed by evaporation to remove residual TFA. The solids were suspended in diethyl ether and filtered to yield 4.52 g of the title compound as a solid, m.p. 146°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][C:13](=O)[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.CO>O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2c(c1)C[C@H](NC[C@@H](O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 3 g of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth 2-yl]-(S)-3-chloromandelamide, SR 58588, described in Example 8(b), in 40 ml of anhydrous tetrahydrofuran, heated with reflux under nitrogen stream, there is added 2.7 ml of a 10M solution of boranemethylsulfide in 20 ml of tetrahydrofuran, and the refluxing is maintained for 4 hours. To the solution cooled to room temperature, there is added 25 ml of methanol and the reaction mixture is left under stirring at first at room temperature for 30 minutes and then at reflux for 30 minutes. The solution is concentrated under reduced pressure and, after filtration, the product is crystallized twice from isopropanol. There is obtained 2.1 g (73%) of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine, SR 58590; m.p. 186°-188° C.; [alpha]=+76° (methanol, c=0.5%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19](Br)[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[CH3:27][OH:28]>C1COCC1>[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19]([O:28][CH3:27])[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(OC)nc(N)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Sodium hydride (9 mg) was dissolved carefully in methanol (0.5 ml) and this solution then added to a solution of (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 mg) in THF (0.5 ml) at room temperature. The reaction was stirred under nitrogen for 2 hours then the solution pre-absorbed directly onto silica gel. The mixture was purified by chromatography on an Isco Companion, eluting with ethyl acetate:heptane, increasing the gradient linearly from 20:80 to 60:40 over several column volumes. The desired fractions were combined and evaporated to provide the title compound (23 mg) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]=NC2C=CC=CC=2)[CH:5]=[CH:4][C:3]=1[OH:17]>C(O)C.[Pd]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:17])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: Oc1ccc(N=Nc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
61 g (0.26 mol) of 2,3-difluoro-4-(phenyldiazenyl)phenol from Example 3 and 1 g of Pd/C (10%) are initially charged in 800 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 18 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator, in the course of which the product already crystallized out. The resulting solid was filtered off, washed with a little cold ethanol and dried under high vacuum for 4 hours. 28 g (74%) of the desired compound were obtained as a light brown powder.
Reaction SMILES: C(O[C:4]([C:6]1([C:9]2([NH:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18]C)=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:18][O:17][C:15]([CH:14]1[C:4](=[O:5])[C:6]2([CH2:7][CH2:8]2)[C:9]2([CH2:10][CH2:11]2)[NH:12][C:13]1=[O:20])=[O:16]
Reactant: CCOC(=O)CC(=O)NC1(C2(C(=O)OCC)CC2)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)NC2(CC2)C2(CC2)C1=O
Temperature: 85 °C

Procedure:
1′-(2-Ethoxycarbonyl-acetylamino)-bicyclopropyl-1-carboxylic acid ethyl ester (1 g; 3.53 mmol) in toluene (15 ml) is added rapidly to a solution of sodium (81 mg; 3.53 mmol) in methanol (3 ml) under stirring. The reaction mixture is warmed to 85° C. for 40 minutes, cooled to room temperature and the precipitate (sodium salt of title compound) filtered, washed with toluene, then heptane, dissolved in water (0.6 ml) and acidified with 2N HCl (1.75 ml). The resulting resin is decanted from water and crystallized by triturating with TBME (1 ml) to deliver the title compound as colorless crystals (633 mg; 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1Br
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-{3-bromo4(methylthio)phenyl}-2-phenyl-ethan-1-one (1.54 g) in 50 ml THF, was added 232 mg of 60% oil dispersion of sodium hydride. The mixture was stirred for 1 hour at 0° C., which was followed by dropwise addition of 1.1 ml α-bromoisobutyryl cyanide diluted in 20 ml THF. The reaction mixture was then slowly warmed to room temperature and was stirred overnight. The solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 1.1 g of 5-{3-bromo-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.47 (s, 3H), 6.99 (d, J=8.7 Hz, 1H), 7.32 (m, 5H), 7.48 (dd, J=8.7, 2.1 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:24](=[CH:25][C:16]=2[N:15]=1)[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[C:21]3([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:29][C:21]1([CH3:30])[C:20]2[C:24](=[CH:25][C:16]3[NH:15][C:14]([S:13][CH2:2][C:3]4[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=4)=[N:18][C:17]=3[CH:19]=2)[C:23]([CH3:27])([CH3:26])[C:22]1=[O:28]
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 11,5 g (0.062 mol) of 2-chloromethyl-3 -methyl-4-nitropyridine and 16 g (0.06 mol) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]-imidazol-6(1H)-one in 200 ml of abs. acetone is treated with 13 g of finely ground potassium carbonate and the mixture is stirred at room temperature under argon for 18 hours, 100 ml of acetone are distilled off in vacuo, whereupon the residue is poured on to ice. The product which crystallizes out is filtered off and dissolved in methylene chloride; the solution obtained is washed with water, dried and concentrated. By recrystallization from ethyl acetate/ether there is obtained 5,7-dihydro-5,5,7,7-tetramethyl-2 -[[(3-methyl-4-nitro-2 -pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(1H)-one of melting point 181°-183° (decomposition).