Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][C@H:9]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1>C(O)C.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][C@H:9]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(C[C@H](CC(=O)N2CCN(C)CC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C[C@H](CC(=O)N2CCN(C)CC2)C(=O)O)cc1
Yield: 56.9 %

Procedure:
A suspension of 0.55 g of benzyl 2(R)-(4-methoxybenzyl)-3-(N-methylpiperazinocarbonyl)propionate hydrochloride (prepared as described in Preparation 23) in 20 ml of ethanol was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 0.2 g of 10% w/w palladium-on-charcoal. After removing the catalyst by filtration, the filtrate was concentrated by distillation under reduced pressure. The residue was mixed with ethanol and, after the mixture had been allowed to stand, 0.25 g of the title compound was obtained as a colorless powder, melting at 117°-118° C. (with decomposition)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:30]1[C@H:36]2[NH:37][C@H:32]([CH2:33][CH:34]([OH:38])[CH2:35]2)[CH2:31]1>C1COCC1.O>[OH:38][CH:34]1[CH2:33][CH:32]2[N:37]([C:2]3[C:3]4[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:36]([CH2:30][CH2:31]2)[CH2:35]1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1-c1ccccc1
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc2ncnc(N3C4CCC3CC(O)C4)c2c1-c1ccccc1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a stirred solution of methyl 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (3.231 g, 10.59 mmol) and DIPEA (2.39 mL, 15.89 mmol) in THF (60 mL) at room temperature was added nortropine (1.682 g, 15.89 mmol) and the reaction left to stir overnight. The reaction was diluted with water (60 mL) and the layers separated. The aqueous layer was acidified to pH 3 and extracted repeatedly with 3:1 chloroform/IPA. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford methyl 4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (1.839 g, 44%). LCMS: Rt=4.23, 396 (M+1).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH:12]([C:17]([OH:19])=[O:18])[CH2:11][CH2:10]2.[CH3:24]O>>[CH3:24][O:18][C:17]([CH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:6](=[O:1])[C:5]3[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=3[Cl:3])=[C:15]([OH:16])[CH:14]=2)[CH2:10][CH2:11]1)=[O:19]
Reactant: [OH-]
Reactant: O=C(O)C1CCc2cc(Cc3ccccc3Cl)c(O)cc21
Reactant: CO
Agent: [Na+]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3Cl)c(O)cc21

Procedure:
Analogously to the description in Example 2, 8.7 g of 5-(o-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester and 27 ml of 2 N sodium hydroxide solution in 100 ml of methanol give 5-(o-chlorobenzyl)-6-hydroxy-indane-1-carboxylic acid of melting point 188°-190° C (from ethyl acetate-petroleum ether).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].CO[C:7](OC)([N:9]([CH3:11])[CH3:10])[CH3:8]>>[CH3:10][N:9]([CH3:11])/[C:7](=[N:4]\[C:1](=[O:3])[CH3:2])/[CH3:8]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(N)=O
Product: CC(=O)/N=C(/C)N(C)C

Procedure:
A slurry of acetamide (500 mg, 8.46 mmol, 1 eq.) was heated neat in 1,1-dimethoxy-N,N-dimethylethanamine (5 mL) for 16 hours. The 1,1-dimethoxy-N,N-dimethylethanamine was removed by roto-evaporation to afford (Z)-N-(1-(dimethylamino)ethylidene)acetamide (2-1) as a dark yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH:17]1[CH2:22][CH2:21][CH:20]([C@H:23]2[CH2:28][CH2:27][Si@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1>[Cu]I.C1COCC1>[CH2:29]([SiH:26]1[CH2:25][CH2:24][CH:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)[CH2:30][CH3:31]
Reactant: Fc1ccc(-c2ccc([Mg]Br)cc2)cc1
Reactant: CCC[Si@H]1CC[C@H](C2CCC(I)CC2)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[SiH]1CCC([C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
A 15 ml THF solution of 1.5M 4-(4-fluorophenyl)phenyl magnesium bromide (22.5 mmol) was dripped into a mixed solution of 7.0 g (20.0 mmol) of trans-4-(4-iodocyclohexyl)-1-n-propyl-1-silacyclohexane, 70 mg of copper (I) iodide and 50 ml of THF. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 2.29 g (yield 58%) of the target product, i.e. the trans, trans isomers. The obtained target product exhibited the same physical properties as the product of Example 8.
Reaction SMILES: [NH2:1][C@@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:6]([C@H:9]3[CH2:13][CH2:12][C@@H:11]([CH2:14][O:15][CH3:16])[O:10]3)[CH2:7][S:8][C@H:3]12>C(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]3[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH3:16])[O:10]3)[CH2:7][S:8][C@H:3]12
Reactant: COC[C@@H]1CC[C@H](C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1
Solvent: ClC(Cl)Cl
Product: COCC1CCC(C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1

Procedure:
A solution of 4-methoxybenzyl (6R,7R)-3-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-yl]-7-phenoxyacetamidoceph-3-em-4-carboxylate (1.93 g) in dichloromethane (25 ml) was cooled to -15 to -20° C., N-methylmorpholine (0.75 ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (26.5 ml of a solution containing 40 mg.ml-1). The mixture was stirred at the same temperature for 0.5 h and then methanol (6.8 ml) was added and the mixture stirred at room temperature for 0.5 h. Water (10 ml) was then added and the mixture vigorously stirred for 0.5 h. The dichloromethane was then removed on a rotary evaporator and the residue was partitioned between ether and water. The aqueous phase was stirred with ethyl acetate and the pH was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The products were separated by column chromatography of the residue using gradient elution (silica gel, 1:1 hexane : ethyl acetate going to neat ethyl acetate). The following were obtained in order of elution 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxy-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (388 mg); νmax (CHCl3) 3410, 1776 and 1725 cm-1 ; δH (CDCl3) 1.59-1.78 (2 H,m), 1.93-2.08 (1 H,m), 2.18-2.32 (1 H,m), 2.54 (2 H, br s), 3.33-3.54 (3 H,m), 3.38 (3 H,s), 3.80 (3 H,s), 4.00-4.11 (1 H,m), 4.76 (1 H,d, J 4.99 Hz), 4.90 (1 H,d, J 4.97 Hz) 4.96 (1 H,t, J 8.23 Hz) 5.17 (2 H,s), 6.88 (2 H,d, J 8.60 Hz) and 7.33 (2 H,d, J 8.61 Hz). [Mass spectrum: M+ (434)]; 4-methoxybenzyl (6R,7R)-7-amino-3-((2R,5S)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (305 mg); νmax (CHCl3) 3409, 1776 and 1725 cm-1 ; δH (CDCl3) 1.60-1.81 (2 H, m), 1.85-2.01 (2 H, m), 3.30-3.50 (2 H, m), 3.38 (3 H, s), 3.44 (1 H,d, J 17.78 Hz), 3.69 (1 H, d, J 17.75 Hz), 3.80 (3 H, s), 4.00-4.17 (1 H,m), 4.70 (1 H, d, J 4.92 Hz), 4.93 (1 H, d, J 4.95 Hz), 5.10-5.20 (1 H, m), 5.18 (1 H, d, J 11.88 Hz), 5.24 (1 H, d, J 11.89 Hz), 6.88 (1 H,d, J 8.65 Hz) and 7.35 (1 H, d, J 8.64 Hz). [Mass spectrum: M+(434)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2c(Cl)cccc2Cl)ccn1
Yield: 64.5 %

Procedure:
Using the method of Example 3, Step A, 2,6-dichlorophenol (2.06 g, 12.6 mmol), 60% sodium hydride in mineral oil (505 mg, 12.6 mmol), and 2-chloro-4-nitropyridine (2.00 g, 12.6 mmol) were reacted at 80° C. overnight to provide 2-chloro-4-(2,6-dichlorophenoxy)pyridine (2.23 g, 64% yield) as an oil. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.44 (d, 2H), 7.24 (t, 1H), 6.71-6.75 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6](C#N)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[CH:10]=[CH:9][CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: CNC
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a stirred mixture of 4-(bromomethyl)-3-nitrobenzonitrile (5.00 g, 20.74 mmol) (prepared according to the method described in WO 07/024,945 A1) and dimethylamine hydrochloride (2.03 g, 24.89 mmol) in CH2Cl2 (70 mL) was added triethylamine (6.30 g, 62.23 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with water (20 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-((dimethylamino)methyl)-3-nitrobenzene (3.58 g, 84%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (br s, 1H), 7.92 (br s, 1H), 7.85 (br d, 1H, J=7.2 Hz), 3.80 (s, 2H), 2.27 (s, 6 H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), tetrahydropyran-4-one (27 mg, 0.27 mmol) and AcOH (50 μL) in DCE (2 mL) was allowed to stir at r.t. for 20 min before the addition of sodium triacetoxyborohydride (104 mg, 0.49 mmol). The resulting mixture was allowed to stir for 18 h then partitioned between DCM and H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) then triturated with MeCN and H2O and the resulting solid dried in vacuo affording 827 (92 mg, 82%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.65-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.40-4.10 (4 H, brd s), 3.91 (2 H, d, J=8.05 Hz), 3.80-3.79 (6 H, m), 3.71 (3 H, s), 3.41 (2 H, d, J=8.07 Hz), 3.28-3.26 (4 H, m), 3.02 (3 H, s), 2.37-2.28 (1 H, m), 1.67-1.63 (2 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.23-1.10 (2 H, m)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.C([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]=O)=[CH:24][CH:23]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:1][CH2:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:13])[NH:8]3)=[CH:24][CH:23]=1
Reactant: NCCc1cccc2c1CC(=O)N2
Reactant: O=CCc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1Cc2c(CCNCCc3ccc(O)cc3)cccc2N1

Procedure:
A mixture of 0.9 g of 4-(2-aminoethyl)-2(3H)-indolone, 0.23 g of 4-benzyloxyphenylacetaldehyde, 0.25 g of 10% palladium-on-charcoal and 100 ml of ethanol is hydrogenated at 50 p.s.i. at 50° until the uptake of hydrogen is complete. After filtration, the mother liquors are evaporated to give 4-[2-(4-hydroxyphenethylamino)-ethyl]-2(3H)-indolone as the residue. This base in alcohol is treated with an excess of methanesulfonic acid to give the methanesulfonate salt.
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[CH3:35][C:36]1([CH3:44])[C@@H:41]2[C@H:37]1[C:38](=[O:43])[O:39][C:40]2=O>>[CH3:35][C:36]1([CH3:44])[C@H:41]([C:40]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([CH3:10])=[CH:34][CH:33]=3)[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=2)[C@@H:37]1[C:38]([OH:43])=[O:39]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@@H]3[C@H](C(=O)O)C3(C)C)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione followed by the hydrolysis according to Example 111. MS (ESI): mass calcd. for C28H29N3O3, 455.22; m/z found, 456.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.58 (d, J=8.9, 1H), 7.54-7.48 (m, 1H), 7.40 (d, J=7.9, 1H), 7.13 (d, J=7.9, 2H), 7.04 (dd, J=8.8, 2.3, 1H), 6.98-6.87 (m, 3H), 5.31 (d, J=16.5, 1H), 5.24 (d, J=16.6, 1H), 5.18 (s, 2H), 2.34 (s, 6H), 2.28 (d, J=8.2, 1H), 2.07 (d, J=8.2, 1H), 1.21 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[Li].O.Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.2 %

Procedure:
To a solution of methyl 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (110.0 mg, 0.29 mmol) in methanol (20 mL) and water (1 mL), was added LiOH.H2O (50 mg, 2.08 mmol,). After stirring for 2 days at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (1N) and filtered to give 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (47.4 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[CH:14]=[C:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH:18]1[CH2:19][CH2:20][C:15](=[CH:14][C:13]2[CH:12]=[C:11]([CH:30]=[CH:29][CH:28]=2)[CH2:10][C:6]2[C:7]([CH3:9])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:16][CH2:17]1
Reactant: COc1ccc(Cc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2cccc(C=C3CCNCC3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A 0° C. solution of tert-butyl 4-(3-((6-methoxy-2-methylpyridin-3-yl)methyl)benzylidene)piperidine-1-carboxylate (0.186 g, 0.487 mmol) dichloromethane (3 mL) was treated with trifluoroacetic acid (0.693 mL, 9.74 mmol). The resulting mixture was stirred for 1 h at room temperature. The solution was concentrated under reduced pressure to give the crude title compound (0.15 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:24])[NH:10][CH2:9]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+].O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[N:25]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:24])[NH:10][CH2:9]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Yield: 69.4 %

Procedure:
2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate 157 mg (0.42 mmol) were reacted with sodium azide (60 mg 0.924 mmol) in acetonitrile/DMF 10 ml/2 ml at 80° C. for 18 hours. The reaction was worked up with water, saturated NaHCO3 and extracted with ethyl acetate. The organic phase, dried on Na2SO4, was filtered and evaporated. The crude was dissolved with diethyl ether and after a while, a solid precipitated, which was filtered to give 92 mg (70%) of 4-(2-azidoethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[CH3:16].[CH3:23][I:24]>C1COCC1>[I-:24].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][N+:15]([CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)([CH3:23])[CH3:16]
Reactant: CN(CCOc1ccc2ccccc2c1Cl)Cc1ccco1
Reactant: CI
Solvent: C1CCOC1
Product: C[N+](C)(CCOc1ccc2ccccc2c1Cl)Cc1ccco1
Product: [I-]
Yield: 92 %

Procedure:
A solution of 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N-methylethanamine (38) (0.05 mmol) was dissolved in 3 mL of THF; then 0.10 mmol of MeI were added under stirring and allowed to react for 14 h at room temperature. The solvent was evaporated under vacuum and the resulting crude was triturated with 5 mL of n-hexane for 2 h. The solid was filtered and dried at 50° C. under reduce pressure to afford 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N,N-dimethylethanaminium iodide as a white solid (92% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:10]=2)[C:4]=1[OH:20].[N:21]([O-])=O.[Na+].[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([N:34]3[C:38](=[O:39])[CH2:37][C:36]([CH3:40])=[N:35]3)=[CH:31][CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[OH:20][C:4]1[C:3]([NH:2][N:21]=[C:37]2[C:36]([CH3:40])=[N:35][N:34]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[CH2:25][CH2:26][CH2:27]4)[C:38]2=[O:39])=[CH:8][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:10]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1=NNc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Yield: 18.9 %

Procedure:
3-Amino-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (188 mg, 0.74 mmol) was dissolved in 4 mL of 2 N hydrochloric acid upon cooling by an ice-water bath, followed by dropwise addition of 1 mL of aqueous sodium nitrite (57 mg, 0.82 mmol). After the mixture was reacted for 30 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (159 mg, 0.74 mmol) was added. The mixture was adjusted to pH 8 with saturated sodium bicarbonate, followed by addition of 0.5 mL of ethanol. The reaction mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in aqueous sodium hydroxide (3 N). The mixture was washed three times with dichloromethane. The layers were separated and then the aqueous layer was adjusted to pH 3 with 2 N hydrochloric acid to form a copious amount of precipitates. The mixture was filtered and the filter cake was purified by silica gel column chromatography to obtain the title compound 4-{[2-hydroxy-3′-(1H-tetrazol-5-yl)-biphenyl-3-yl]-hydrazono}-2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 27 (67 mg, yield 18.8%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:4][CH:3]=1.[C:14]([O:17][CH2:18][C@@:19]([NH:30][C:31](=[O:33])[CH3:32])([CH2:28][CH3:29])[CH2:20][CH2:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)(=[O:16])[CH3:15].C([O:37][CH2:38][CH3:39])(=O)C.O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH2:18][C@@:19]([NH:30][C:31](=[O:33])[CH3:32])([CH2:28][CH3:29])[CH2:20][CH2:21][C:22]1[N:23]([CH3:27])[C:24]([C:11]([O:12][C:38](=[O:37])[CH2:39][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:25][CH:26]=1)(=[O:16])[CH3:15]
Reactant: CC[C@@](CCc1cccn1C)(COC(C)=O)NC(C)=O
Reactant: CCOC(C)=O
Reactant: Cc1ccc(CCCC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@](CCc1ccc(C(=CCCc2ccc(C)cc2)OC(=O)CCCc2ccc(C)cc2)n1C)(COC(C)=O)NC(C)=O
Temperature: 110 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A solution of 4-dimethylaminopyridine (1.17 g, 11.8 mmol) and 4-(4-methylphenyl)butyric chloride (1.06 g, 5.90 mmol) in toluene (5 mL) was added to a solution of (2R)-1-acetoxy-2-acetylamino-2-ethyl-4-(1-methylpyrrol-2-yl)butane (444 mg, 1.60 mmol) obtained in Reference example 2 in toluene (15 mL) and the mixture was stirred at 110° C. for 72 hours. The temperature of the mixture was returned to room temperature and ethyl acetate and water were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:hexane, 3:2-2:1) to obtain the title compound (377 mg, yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([OH:33])[CH:3]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CN[C@H](C)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 79.1 %

Procedure:
Following General Procedure F, (R)-tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (43 mg, 0.09 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 4 mL, 4 mmol) to afford the desired product as a white solid (15 mg, 45%): 1H NMR (500 MHz, CD3OD) δ 7.69-7.59 (m, 3H), 7.45 (ddd, J=7.0, 5.8, 2.1 Hz, 2H), 7.30 (s, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.48 (q, J=6.9 Hz, 1H), 2.72 (s, 3H), 1.79 (d, J=6.9 Hz, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC 97.1% (AUC), tR=8.85 min.