Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]1[N:24]=[C:25]([NH:28]C(=O)OC(C)(C)C)[S:26][CH:27]=1)(=[O:12])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:25]1[S:26][CH:27]=[C:23]([CH2:22][S:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:12])=[O:11])[N:24]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Yield: 88 %

Procedure:
A solution of tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate Compound 11 (62 mg, 0.11 mmol), TFA (0.2 ml) in CH2Cl2 (1 ml) was stirred overnight. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford the title compound (45 mg, 88%).
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C(C(C(O)=O)O)O.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[S:19][C:20]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][N:22]=1>O1CCCC1>[O:15]1[CH2:16][CH2:17][O:13][CH:14]1[C:18]1[S:19][C:20]([CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][N:22]=1
Reactant: CCOC(=O)C(=O)c1cnc(C2OCCO2)s1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1cnc(C2OCCO2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A suspension of sodium borohydride (6.18 g) and DL-tartaric acid (24.5 g) in tetrahydrofuran (250 mL) was stirred at 80° C. for 2 hr. The reaction mixture was cooled to 0° C., ethyl [2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl](oxo)acetate (10.49 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was slowly poured into ice (100 g), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO9) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (8.43 g, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 260 (MH+).
Reaction SMILES: [CH3:1][CH:2](C(C)=O)[C:3](OCC)=[O:4].N.[NH2:12]/[C:13](/[CH3:21])=[C:14](/[CH3:20])\[C:15]([O:17]CC)=O.CC(C(OCC)=O)C(OCC)=O>>[CH3:21][C:13]1[C:14]([CH3:20])=[C:15]([OH:17])[C:2]([CH3:1])=[C:3]([OH:4])[N:12]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CCOC(=O)/C(C)=C(/C)N
Agent: CCOC(=O)C(C)C(=O)OCC
Agent: N
Product: Cc1nc(O)c(C)c(O)c1C

Procedure:
U.S. Pat. No. 4,785,113 discloses the preparation of the title compounds from ethyl 2-methylacetoacetate by reaction with NH3 to give ethyl 3-amino-2-methylcrotonate, reaction with diethyl monomethylmalonate to give 2,3,5-trimethyl-4,6-dihydroxypyridine, chlorination to give 2,4-dichloro-3,5,6-trimethylpyridine, selective cleavage of the 2-Cl substituent and exchange of the 4-Cl substituent for a methoxy group, and then oxidation to give the N-oxide. The subsequent reactions are carried out analogously to the process described in U.S. Pat. No. 4,472,409.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)C=C.[CH2:24]1[CH:33]2C(CCCC2)CC[CH2:25]1>>[CH2:33]([C:6]1[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:8][C:9]2[C:14](=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: C1CCC2CCCCC2C1
Reactant: C=CCOc1cc(-c2ccccc2)cc2ccc([N+](=O)[O-])cc12
Product: C=CCc1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc2c1O
Temperature: 180 °C

Procedure:
31 g of 1-Allyloxy-3-phenyl-7-nitro-naphthalene prepared in step (3) were gradually heated to 180° C. in 390 ml of decaline, the solution being stirred and maintained under nitrogen. The temperature of 180° C. was maintained for about 1 hour. After cooling, the crystals formed were washed with petroleum ether, filtered off and dried at 80° C. under reduced pressure.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)[CH2:8][CH2:7]1)C.O[Li].O>>[Cl:21][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[C:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:7][CH2:8]1)=[O:22]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)c(Cl)c2)CC1
Agent: [Li]O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To a solution of [4-(3-chloro-4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.76 g, 2.24 mmol in 6 mL of THF and 2 mL of methanol) was added LiOH.H2O (0.47 g, 11.2 mmol in 3 mL of water) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. and lyophilized for 24 hours to yield the title compound (0.70 g, 2.1 mmol). MS (ESI) m/z 312.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.81 min.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Cl.CN([CH:33]=[O:34])C>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
nBuLi (1.3 mL, 2.05 mmol, 1.57 M in hexane) was added dropwise to a solution of 4,5-dichloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (842 mg, 2.05 mmol) in THF (30 mL) at −78° C. under N2. The mixture was stirred for 30 min and DMF (1.0 mL) was then added dropwise. The mixture was stirred for 20 min and then allowed warm up to room temperature and stirred for 20 min. Quenched by aqueous NH4Cl and extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][Si:5]1(C2C=CC=CC=2)[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH2:4][Si@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1F
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.3 g of 4-(4-(3-methylbutyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.OCC1SC(B(O)O)=CC=1>>[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Agent: OCc1ccc(B(O)O)s1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(-c3ccc(C=O)cc3)cc2)c1
Yield: 73 %

Procedure:
When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 73% yield, as pale solid. 1H-NMR (CDCl3) 10.07 (s, 1H); 7.98 (d, 2H, J=6.56 Hz); 7.75 (d, 2H, J=8.24 Hz); 7.7 (d, 2H, J=8.82 Hz); 7.66 (d, 2H, J=8.75 Hz); 7.19 (t, 1H, J=8.13 Hz); 6.81 (dd, 1H, J=8.30, 2.45 Hz); 6.74 (t, 1H, J=2.17 Hz); 6.65 (dd, 1H, J=7.96, 1.24 Hz); 3.76 (s, 3H); 3.20 (s, 3H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(NCC)C.[Cu]I>[C:9]1([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Ic1ccccc1
Reactant: C#CCCC(=O)O
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1
Yield: 28.1 %

Procedure:
A solution of pent-4-ynoic acid (1.0 g, 10 mmol), iodobenzene (2.3 ml, 20 mmol), copper(I) iodide (75 mg, 0.40 mmol) and dichlorobis(triphenylphosphine)-platinum(II) (140 mg, 0.20 mmol) in 20 mL of diethylamine was stirred at rt for 3 days. The volatile material are evaporated by a rotary evaporator and the resulting residue was dissolved in 50 mL dichloromethane and washed with 1 M HCl (50 mL). The dichloromethane layer was dried over sodium sulfate and evaporated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/dichloromethane) to afford 5-phenylpent-4-ynoic acid (0.49 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[C:5]([CH3:17])[O:4][N:3]=1.[I:18]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([NH2:11])=[C:12]([I:18])[CH:13]=2)=[C:5]([CH3:17])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc(N)c([N+](=O)[O-])c1
Reactant: II
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of compound 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (334 g, 1.43 mol, 1.0 eq) in ethanol (3.3 L) were added iodine (726 g, 2.8 mol, 2.0 eq) and silver nitrate (485 g, 2.8 mol, 2.0 eq). The reaction mixture was stirred at rt overnight, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in EtOAc (5 L) and washed with water and brine, and dried over sodium sulfate. The organic solvent was evaporated to give a residue, which was purified by flash column chromatography on silica gel (PE/EA=4:1-3:1) to give compound 393 g of 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C=O.[C:24]([BH3-])#N.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:24])[CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)[C@@H]1CNCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H]1CN(C)CCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
1-(3,5-Dichlorobenzenesulfonyl)piperazine-2(S)-carboxylic acid, methyl ester (55 mg, 0.16 mmol) was added to a 5 mL round bottom flask containing 2 mL of acetonitrile and 37% formaldehyde (63 mg, 0.78 mmol) at 0°. Sodium cyanoborohydride (30 mg, 3 equivalents) was added portionwise over 10 minutes. The mixture was stirred at 25° for 2 hours. The solvent was removed under reduced pressure and the residue partitioned between methylene chloride and 1N HCl. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. Flash chromatography on silica gel eluted with (98/2/0.1 methylene chloride/methanol/acetic acid) gave 38 mg of 1-(3,5-dichlorobenzenesulfonyl)-4-methyl-piperazine-2(S)-carboxylic acid, methyl ester. The methyl ester was hydrolysed and isolated as described in Example 39, Step F.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[CH2:15]Br.[CH3:18][NH2:19]>C1COCC1>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:15][N:19]([CH3:18])[C:3]2=[O:2]
Reactant: CN
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1CBr
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At room temperature, a solution of 2-Bromomethyl-3-methoxy-6-nitro-benzoic acid methyl ester (crude 7.0 g, 18.2 mmol) in 46 mL of THF is treated with 2M solution of methylamine in THF (27.3 mL, 54.6 mmol), and the mixture is stirred for 4 hours at the room temperature. The reaction mixture is quenched with a saturated ammonium chloride solution and partitioned between ethyl acetate. The organic layer is washed with brine and then dried over Na2SO4 following concentrated to give 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (3.1 g) as orange solid in 77% yields (2 steps). 1H-NMR (400 MHz, δ, ppm) CDCl3: 3.19 (s, 3H), 3.99 (s, 3H), 4.32 (s, 2H), 7.0 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N[C@@H](C(O)=O)C(C)C)(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:29])[CH3:30])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described for {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (example 1 (c)) but using Boc-D-valine (Fluka).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N:36]1([CH2:45][C:46](O)=[O:47])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:46](=[O:47])[CH2:45][N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)[CH2:8][CH2:7]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Cn2ccc3ccccc32)CC1

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (465 mg, 2.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (830 mg, 3 mmol.) was added to a solution of indol-1-ylacetic acid (350 mg, 2.0 mmol.) in abs. methanol (25 ml), and the reaction mixture was stirred for 2 d at RT. For working up, the mixture was concentrated, water (15 ml) was added to the residue, the pH was adjusted to 11 with 5M NaOH and extraction was carried out with EE (3×15 ml). The combined extracts were dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target products, which was separated by flash chromatography on silica gel (70 g) and purified (eluant: methanol/EE 500 ml 1:3, then 1000 ml 1:1). 244 mg of the non-polar diastereoisomer of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-2-indol-1-yl-acetamide were obtained in the form of a viscous oil. 50 mg (0.128 mmol.) thereof were dissolved in 2-butanone (2 ml), and chlorotrimethylsilane (24.4 μl, 0.193 mmol.) was added thereto. There immediately formed a pale precipitate, which turned a strong colour within a few minutes. The solid was filtered off with suction, washed with ether (3×0.5 ml) and dried in vacuo. The hydrochloride 7/8 of the non-polar target product was thus obtained in a yield of 52 mg (brick-red solid, m.p. 176–186° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O.Cl>C1COCC1>[OH:2][CH2:1][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C=O)cc3)nc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CO)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-formyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide (194 mg, 0.5 mmol), in THF (40 ml) was added sodium borohydride (19 mg, 0.5 mmol) and the mixture stirred for 2 h at r.t. Water was added (30 ml) followed by 1N HCl (4 ml) and the mixture agitated. The aqueous phase was then extracted twice with EtOAc (30 ml), the combined organic phases were then washed with saturated NaCl solution, dried with Na2SO4 filtered and evaporated. The crude residue was suspended in ether and ultrasonnicated for 10 min., the solid precipitate was filterted off, washed with ether then dried under vacuum (0.05 mmHg, 50° C.) to afford the title compound as a light yellow solid (150 mg, 77% yield), MS: m/e=390.0 (M+).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[N+:9]([C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23].O.Cl>O1CCCC1>[N+:9]([C:12]1[O:16][C:15]([CH:17]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])o1)C(C)=O
Reaction time: 1 h

Procedure:
A solution containing 2.43 g of 5-nitro-2-furanecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione and 0.1 g of water in 5 ml of tetrahydrofurane was saturated with hydrogen chloride gas at 20° C. The mixture was stirred for 1 h and evaporated to dryness in vacuo. The product was recrystallized from acetic acid. Yield 0.1 g, mp 117°-120° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][N:42]1[CH:46]=[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:3]=2)[CH:44]=[N:43]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(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: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (intermediate 66B) (200 mg, 0.322 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (147 mg, 0.483 mmol) using Pd(PPh3)2Cl2 (12 mg, 0.016 mol) and sodium carbonate (86 mg, 0.806 mmol) in toluene/ethanol/water (10/2/2 ml) to afford 200 mg (93.2% yield) of the titled compound after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=669.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:19])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)n1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid methyl ester was prepared according to Wells, G. J. et al. (WO 94/11398): A mixture of 6-methyl-pyridine-2-carboxylic acid methyl ester (6.5 g, 43.0 mmol), benzoyl peroxide (25 mg, 0.1 mmol) and NBS (8.5 g, 47.8 mmol) in carbon tetrachloride (250 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, filtered, evaporated, and purified by chromatography on flash silica gel, eluting with 15% ethyl acetate/hexane to give 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (2.0 g, 20%) as a white solid. 1HNMR (CDCl3): 6 8.06 (d, J=8.0 Hz, 1H), 7.87 (dd, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 4.65 (s, 2H MS (APCI+): 231 (45), 235 (42).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.075 g, 0.274 mmol) and lithium hydroxide (0.053 g, 1.37 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound: 30 mg, 42% yield. 1H NMR (400 MHz, METHANOL-d) δ ppm 2.05-2.15 (m, 1H), 2.50-2.60 (m, 1H), 2.60-2.65 (m, 2H), 2.75-2.85 (m, 2H), 3.21-3.28 (m, 1H), 6.30 (s, 1H), 6.85-6.95 (m, 2H), 7.00-7.05 (d, 1H), 7.25-7.35 (q, 1H); 19F NMR δ ppm (m, −116.7); LCMS-MS (ESI−) 258.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a stirred solution of 1-bromo-2,5-difluoro-4-nitrobenzene (1.100 g, 4.622 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.451 g, 4.65 mmol, Aldrich, used as received) in water (5.0 mL). The resulting solution was stirred overnight at 70° C. The solution was cooled to room temperature and the bright orange solid was filtered, washed with cold acetone (10 mL) and dried under vacuum to give 0.469 g (35%) of the title compound as a bright orange powder; 1H NMR (DMSO-d6): δ3.458 (d, 2H, J=3.9 Hz), 7.148 (d, 1H, J=6.0 Hz), 7.944 (d, 1H, J=9.3 Hz), 8.740 (s, 1H).