Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl.[CH2:24]([SH:26])[CH3:25]>CCOCC.C(#N)C>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([S:26][CH2:24][CH3:25])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Reactant: CCS
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CCSC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Yield: 73.2 %

Procedure:
A solution of 3.00 g (9.20 mmol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl)urea, the compound of Example 1a, in 75 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, washed with anhydrous ether and suspended in a mixture of 1.8 ml (25 mmol) of ethyl mercaptan and 30 ml of acetonitrile. After heating under reflux for 1 hr, the reaction mixture was evaporated in vacuo. The crystalline residue was dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol/water afforded 2.20 g (73%) of the title compound. Recrystallization from ether/hexane and finally ethanol/water gave an analytical sample mp 102°-104° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:6]=1)=[N+]=[N-]>CO.[Ni]>[I:16][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][NH2:1])=[N:6]2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1ccn(-c2ccc(I)cc2)n1
Agent: [Ni]
Solvent: CO
Product: NCc1ccn(-c2ccc(I)cc2)n1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A mixture of 3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (100 mg, 0.31 mmol) and Ra—Ni (50% aq. slurry, 150 mg) in MeOH (8 mL) was hydrogenated under balloon H2 for 3 hrs. It was filtered through celite. The filtrate was concentrated in vacuo to give (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]Cl)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:45][CH:44]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 97.6 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted to yield the title compound as yellow needles (yield: 97.6%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[S:13](Cl)([Cl:16])(=[O:15])=[O:14]>C(#N)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:13]([Cl:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CNS(=O)(=O)Cl)cc1

Procedure:
The intermediate 4-nitrobenzylaminosulfonyl chloride was prepared from 4-nitrobenzylamine hydrochloride and sulfuryl chloride at reflux in acetonitrile. The solvent was evaporated and the crude material used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([N:14]1[CH2:10][CH2:11][CH2:3][CH2:4]1)[CH2:8]2
Reactant: COc1cc2c(cc1OC)CC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CC(N1CCCC1)C2
Temperature: 100 °C

Procedure:
To a solution of 5,6-dimethoxy-2-aminoindan (Preparation 5, 4.5 mmol) in dimethylformamide/acetonitrile (1:6, 49 mL) was added sodium carbonate (1.43 g, 13.5 mmol) and was heated (100° C.) overnight. The mixture was diluted with ethyl acetate, filtered and the filtrate concentrated. The oily residue was chromatographed (400 g silica gel) eluting with methylene chloride/methanol (9:1) to yield a yellow oil. The oil was converted into the HCl salt and recrystallized from methanol/ethyl acetate: mp 267°-269° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.CC(C)=[O:19]>>[C:13]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([CH3:10])([CH3:12])[CH3:11])[N:6]=1)[C:2]([OH:19])=[O:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)n1
Reactant: CC(C)=O
Product: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1

Procedure:
Jone's reagent was added dropwise to a solution of 4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B, 302 mg 1.37 mmol) in 5 ml of acetone until the solution changed color from light yellow to orange (55 drops of Jone's reagent were consumed). After 5 minutes 2 ml of isopropanol were added to the reaction mixture, and a green precipitate of Cr3+ salt was formed. The precipitate was removed by filtration and the solution was diluted with ethyl acetate, then washed with brine, water and dried over MgSO4. After filtration, the solvent was removed to give the desired product as a white solid (227 mg). 1H NMR δ 7.71 (s, 2H), 1.34 (s, 18H).
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]2)=[N:15][CH:16]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[N:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:24]=3)[C:19]([C:34]([OH:36])([CH3:1])[CH3:35])=[CH:18]2)=[N:13][CH:12]=1
Reactant: C[Mg]I
Reactant: CC(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Solvent: C1CCOC1
Product: CC(C)(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3M solution in diethyl ether, 0.14 mL, 0.439 mmol, 1.5 eq) was added at −50° C. to a stirred solution of 184a) (130 mg, 0.292 mmol, 1.0 eq) in dry THF (10 mL). The reaction mixture was stirred for 2 h at −30° C., then quenched with ammonium chloride solution, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The remnant was purified by preparative TLC using ethyl acetate/pet ether (7:3) as eluent. White solid. Yield: 50 mg (37% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([C:17]1[C:18]([C:31]([F:34])([F:33])[F:32])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27](=[NH:30])[NH:28]O)[CH:21]=[CH:20]2)#[N:16]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:30]=[C:27]([CH2:26][N:22]3[C:23]4[C:19](=[C:18]([C:31]([F:34])([F:32])[F:33])[C:17]([C:15]#[N:16])=[CH:25][CH:24]=4)[CH:20]=[CH:21]3)[N:28]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)benzoic acid (0.016 g, 0.071 mmol) and CDl (0.012 g, 0.071 mmol) were combined in in CH3CN (3 mL). 2-[5-Cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) was added after 5 min. After stirring at rt for 1 h, the reaction was heated at 150° C. in a microwave for 10 min. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.022 g): MS (ESI): m/z 471 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[OH:27][CH:28]1[CH2:32][CH:31]([CH3:33])[NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH:31]([CH3:33])[CH2:32][CH:28]([OH:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: CC1CC(O)CN1
Product: CC1CC(O)CN1c1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3ccc(F)cc3F)c2c1F
Yield: 64 %

Procedure:
The condensation of 5-Amino-1-(2′,4′-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-hydroxy-5-methylpyrrolidine in a similar manner as described in example 1 gave the titled product. Yield 64%, m.p ° C., C21H17F4N3O4, m/z 453. (M+1)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1>[Rh].C(O)C>[F:1][C:2]([F:10])([F:11])[C@H:3]1[CH2:4][CH2:5][C@H:6]([OH:9])[CH2:7][CH2:8]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [Rh]
Solvent: CCO
Product: O[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
A mixture of 0.3 mol of 4-trifluoromethylphenol, 1000 ml of ethanol and 20 g of rhodium/activated charcoal (5%) is hydrogenated for 2 hours at a pressure of 5 bar and a temperature of 60° C. Removal of the solid components by filtration and removal of the solvent by distillation give the cyclohexanol as a cis/trans mixture (30%/70%). From this, the pure trans-compound is obtained by heating with aluminium triisopropylate in toluene in the presence of 3,3-dimethyl-2-butanone and subsequent recrystallization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: COC(=O)c1ccc(N)cc1
Product: CCCCNc1ccc(C(=O)OC)cc1
Yield: 87.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-aminobenzoic acid methyl ester (Aldrich, 500 mg, 3.31 mmol) and butyraldehyde (300 μL, 3.31 mmol) were converted to the title compound (600 mg, 82%). 1H NMR (CDCl3) δ 7.91-7.80 (m, 2H), 6.59-6.46 (m, 2H), 3.86 (s, 3H), 3.18 (t, J=7.0 Hz, 2H), 1.67-1.58 (m, 2H), 1.48-1.37 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 208.1 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:1]([N:5]1[C:9]([NH:10][C:12](=[O:14])[CH3:13])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Product: CC(=O)Nc1cc(C)nn1C(C)(C)C

Procedure:
To 1-(tert-butyl)-3-methyl-1H-pyrazol-5-amine (110 g, 0.71 mol), acetic anhydride (73 ml, 0.71 mol) was added dropwise with stirring. The reaction mixture was stirred for 1-2 h at 20-35° C. Thereafter the reaction mixture was washed with excess of hexane and filtered to obtain the title compound as a yellow solid. MP: 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10]/[C:11](=[CH:15]\[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)/[C:12]=2[O:13]C)=[CH:4][CH:3]=1.[Li+].[Br-].OS(O)(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10]/[C:11](=[CH:15]\[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)/[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: COC1=C(c2ccc(Cl)cc2)C(=O)O/C1=C\c1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O/C(=C\c2cccc3ccccc23)C(O)=C1c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 78 %

Procedure:
A stirred mixture of 3-(4-chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one (380 mg, 0.998 mmol) and LiBr (86.6 mg, 0.998 mmol) in DMF is heated at 150° C. for 10 min., cooled to room temperature, poured into 5 mL H2SO4, diluted with water and extracted with EtOAc. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant oil residue is passed through a silica gel pad, using a gradient elution of 100% EtOAc to 9:1 EtOAc:2.5% acetic acid in methanol, to afford the title product as a rust-yellow solid, 270 mg (78% yield), mp 220°-224° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl) benzoic acid (100 mg, 0.2369 mmol) was dissolved in methylene chloride (20 ml), then p-anisidine (58 mg, 0.4715 mmol), triethylamine (48 mg, 0.4752 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (80 mg, 0.4733 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (68 mg, 0.1290 mmol, 54%).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][S:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[BH4-].[Na+]>C(O)C>[OH:1][C:2]([CH3:27])([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][S:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCC(C)(O)CSC1CCC(=O)N1CC(=O)CCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(C)(O)CSC1CCC(=O)N1CC(O)CCCCC(=O)OC
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 16 (about 4 mg) in ethanol (0.5 mL) at 0° was added sodium borohydride (3 mg). The mixture was stirred at 0° for one hour and then quenched with one drop of acetic acid. After removing ethanol, the residue was diluted with methylene chloride and washed with saturated sodium chloride. The separated aqueous layer was extracted with methylene chloride twice and the combined organic layer was dried over magnesium sulfate. Removal of the solvent gave 2.7 mg of methyl 7-[2-(2-hydroxy-2-methylheptylthio)-5-oxopyrrolidin-1-yl]-6-hydroxyheptanoate, 17. By comparison of TLC mobility, this product was determined to be identical in element content to that of Example 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>CN1C(=O)CCC1.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Fc1cc2[nH]ccc2cc1Br
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: Fc1cc2c(ccn2-c2ccc(Cl)cc2)cc1Br
Temperature: 170 °C
Reaction time: 6 h
Yield: 60.4 %

Procedure:
A mixture of 0.07 g (5 mmol) 5-Bromo-6-fluoro-1H-indole (1, 1-chloro-4-iodobenzene (2.5 g, 10.5 mmol), 250 mg (1.31 mmol) CuI, 80 mg (0.9 mmol) ZnO, and 1.75 g (12.67 mmol) K2CO3 in degassed NMP was stirred at 170° C. during 6 hours in a pressure tube. After cooling to room temperature, the mixture was poured into 50 ml of saturated aqueous NaCl and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4, evaporation of the solvent, and column chromatography on silica gel with CH2Cl2/hexane 1:2 gave 0.98 g (60%) 5-Bromo-1-(4-chloro-phenyl)-6-fluoro-1H-indole as a yellowish-grey solid, MS: 323 (M, 1Cl, 1Br). (Analogously to Jens Perregaard et. al. J. Med. Chem. 1992, 35, 4813-4822.)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])(C)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28](=[O:33])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:33])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CON(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Reactant: COc1ccc(Br)cn1
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
5-Bromo-2-methoxypyridine (247 mg, 1.31 mmol) was dissolved in toluene (6 mL) and cooled to −75° C. t-Butyl lithium (0.77 mL of 1.7 M in pentane, 1.3 mmol) was added dropwise. Stirring was continued at the same temperature for 15 min and then in an ice bath for 5 min. The reaction was cooled to −75° C. and a solution of (S)-2-(methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (300 mg, 1.09 mmol) in toluene (3 mL) was added dropwise over 5 min. The reaction was stirred at 0° C. for 1.25 h and then poured onto water. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (1:1 EtOAc/heptane eluent) to afford (S)-2-(6-methoxy-pyridine-3-carbonyl)-morpholine-4-carboxylic acid tert-butyl ester (315 mg, 89%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.97-3.25 (m, 2H) 3.63-3.76 (m, 1H) 3.85-3.97 (m, 1H) 4.02 (s and overlapping m, 4H) 4.10-4.32 (m, 1H) 4.50-4.66 (m, 1H) 6.80 (dd, J=8.87, 0.54 Hz, 1H) 8.17 (dd, J=8.87, 2.42 Hz, 1H) 8.91 (d, J=2.42 Hz, 1H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[ClH:28]>CO>[ClH:28].[ClH:28].[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: Cl
Solvent: CO
Product: C[C@]1(CN2CCN(N)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]carbamate prepared in Example 503 (300 mg, 0.78 mmol), concentrated hydrochloric acid (2 ml) and methanol (4 ml) was stirred at 50° C. for 30 minutes. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The residue was recrystallized from methanol/ether to afford (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine dihydrochloride (265 mg, yield 91%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([C:4]1[C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Temperature: 75 °C
Reaction time: 0.83 h

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (23.7 g, 0.110 mol) in carbon tetrachloride (90 ml) was added with concentrated nitric acid (17.2 ml). The mixture was left under stirring at 75° C. for 50 minutes, then left to cool at room temperature. The precipitated solid was recovered by filtration washing with cold carbon tetrachloride. After drying under vacuum, 20.9 g of the title product were obtained as a light yellow solid (73% yield).
Reaction SMILES: [CH3:1][C:2]1[S:29][C:5]2=[N:6][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:8]([C@@H:10]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:11])[CH:9]=[C:4]2[CH:3]=1.O.NN>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[S:29][C:5]2=[N:6][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:8]([C@@H:10]([NH2:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)nc2s1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2cc([C@H](C)N)c(-c3ccccn3)nc2s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Slurried (S)-2-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (60 mg, 0.150 mmol) in 3.5 mL of ethanol was warmed to 60° C. and hydrazine monohydrate (73.0 μL, 1.502 mmol) was added. The reaction was stirred at 60° C. for 2 h, cooled to RT and diluted with ethyl acetate. The reaction was filtered and concentrated. The resulting residue was redissolved in ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated to afford crude (S)-1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine. 1H NMR (400 MHz, CDCl3) δ 8.67 (ddd, J=4.9, 2.7, 1.2 Hz, 1H), 8.19 (s, 1H), 7.85 (m, 2H), 7.32 (ddd J=7.0, 4.9, 1.8 Hz, 1H), 6.93 (q, J=1.2 Hz, 1H), 4.60 (q, J=6.6 Hz, 1H), 2.63 (d, J=1.2 Hz, 3H), 2.20 (br s, 3H), 1.43 (d, J=6.6 Hz, 3H) ppm. LC/MS (M+1, found=270.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[C:5]([C:7]#[C:8][C:9]([O:11]C)=[O:10])=[O:6].[OH-].[K+].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[C:5]([C:7]#[C:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: COC(=O)C#CC(=O)c1ccc(OC)c(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)C#CC(=O)O)c(OC)c1OC
Reaction time: 1.5 h

Procedure:
A solution of 2.7 g (9.7 mmol) of methyl 3-(2,3,4-trimethoxybenzoyl)propiolate in 30 ml of tetrahydrofuran was treated slowly at 0° with 27 ml of 3% potassium hydroxide solution and subsequently stirred at 0° for a further 1.5 hours. The reaction mixture was treated with water and extracted once with ether. The ether phase was discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded 3-(2,3,4-trimethoxybenzoyl)-propiolic acid of melting point 119°-121°.