Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@@H:6]([C:17]([OH:19])=[O:18])[NH:5]1)[CH2:2][CH3:3].C([C@H]1C2NC3C(=CC=CC=3)C=2C[C@H](C(OC)=O)N1)CC.[OH-].[Na+]>CO>[CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@H:6]([C:17]([OH:19])=[O:18])[NH:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Agent: CCC[C@@H]1N[C@@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 78 %

Procedure:
In the same manner as described above (2) using methyl (1RS,3SR)-trans-1-n-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (1.36 g), 1N NaOH (6 ml) and methanol (20 ml), there is obtained the title compound (1.01 g, 78%) as colorless needles, m.p. 210°-211° C.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:26])[CH2:4][C:5]([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:6]#[N:7].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH2:4][CH:3]([CH3:26])[CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:6]#[N:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(C#N)(CC(C)CCl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(C#N)(CC(C)CN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 17.6 %

Procedure:
The procedure of Example 2 is repeated using 4.0 g of α-(3-chloro-2-methylpropyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 3.5 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 0.985 g of the desired product as a yellow foam.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl>[N:28]([CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a stirred solution of Part A N-Boc-3-hydroxymethylpiperidine (27.0 g, 126 mmol) in 150 mL of dry dichloromethane under argon at 0° C. was added in order triethylamine (22.7 mL, 163 mmol) and methanesulfonyl chloride (11.7 mL, 151 mmol). The reaction was stirred at room temperature for 1.5 h and diluted with 450 mL of dichloromethane. The reaction was washed with 0° C. 1N HCl solution (2×100 mL) and brine (1×100 mL). The dichloromethane layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 200 mL of DMF and combined with sodium azide (24.5 g, 377 mmol). The mixture was stirred at room temperature for 33 h and the solid was filtered off. The filtrate was concentrated under pump vacuum at 45° C. The residue was partitioned between 400 mL of EtOAc and 10% sodium thiosulfate solution (2×100 mL) and brine (1×100 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. Purification was effected by a flash column chromatography on silica gel to give 19.5 g (65%) of title azide.
Reaction SMILES: [BH4-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][N:7]=1)=[O:5].[BH4-].[Na+].Cl>CO.CN(C)C=O.C(O)(=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][N:7]=1)=[O:5]
Reactant: COC(=O)c1ccc(N=CC=Cc2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCC=Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the stirred solution of 8 g of sodim borohydride in 300 ml of methanol the solution of 15 g of 5-cinnamylideneaminopyridine-2-carboxylic acid methyl ester in 60 ml of warm dimethylformamide is added during 1/2 hour while cooling with ice. Simultaneously a 5 g portion and a 3 g portion of sodium borohydride is added and the mixture stirred for 1 hour at 0°. It is warmed to about 20° until dissolution occurs and combined with 18 ml of 12 N hydrochloric acid, 5 ml of acetic acid and 600 ml of ice water. The mixture is cooled to -10°, filtered, the residue washed with water, dried and recrystallized from aqueous methanol, to yield the 5-cinnamylamino-pyridine-2-carboxylic acid methyl ester melting at 131°-133°.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:18]1[CH2:20][CH:19]1[CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CC(O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][CH2:21][CH:19]([OH:18])[CH2:20][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:24][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CCC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: CC(C)O
Solvent: O
Product: CCC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
tert-Pentyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.0 g; 4.16 mmol; from step (b) above) was dissolved in IPA:H2O (9:1; 4 mL) and 4-(2-oxiranylmethoxy)benzonitrile (1.46 g; 8.32 mmol; see Example A above) was added to the resultant solution. The reaction mixture was stirred at 60° C. for 3 h, concentrated and the residue subjected to column chromatography (DCM:MeOH; gradient 1:0 to 68:32) giving the title compound (1.45 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH3:18]
Reactant: O=C(O)Cc1cccc(Br)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a solution of (6-bromo-pyridin-2-yl)-acetic acid (34.0 g, 158.14 mmol) in ethanol (300 ml) was added conc. H2SO4 (5.0 ml) and heated to reflux for 12 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. Water was added to the residue and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to furnish the crude product. Column chromatography purification furnished the title compound as a brown liquid. Yield=31.2 g (82%). TLC (20% ethyl acetate in hexane) Rf=0.51; LCMS: RtH7=0.996, [M+1]+=244.0 and 246.0; HPLC: RtH9=3.87 min (97.2%); 1H NMR (400 MHz, CDCl3): δ 7.53 (t, 1H), 7.39 (d, 1H), 7.28 (d, 1H), 4.19 (q, 2H), 3.83 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A171) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].Cl>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:28][CH2:29][CH2:30][OH:31])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(N)C4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 50 mg (0.11 mmol) of 1-[4(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-3-ylamine and 14 μl (0.16 mmol) of 3-chloropropan-1-ol. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][N:40]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:39]#[N:40])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCCC1=O
Reactant: Nc1nccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: N#Cc1ccc2ccnc(N)c2c1
Reaction time: 2 h
Yield: 94 %

Procedure:
Palladium acetate (0.9 g) was added to a heated mixture of trifluoromethanesulfonic acid 1-amino-isoquinolin-7-yl ester (5.8 g), zinc cyanide (2.3 g) and triphenylphosphine (1.0 g) in 75 mL of N-methyl-pyrrolidone at 190° C. (exothermic!). Stirring was continued at 190° C. for 2 h. Precipitated material was removed by filtration and discarded. Ethyl acetate was added and the organic mixture washed with 2N aqueous ammonia, water and brine and dried (Na2SO4). Filtration and concentration afforded a brownish oil, which was purified by silica chromatography (ethyl acetate/isohexane=3/7, 4/6, 5/5, 6/4, 7/3, 8/2) to give 3.2 g (94%) of the title compound as yellow crystals. M.p. 183-186° C.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[O:23][C:24]([C:26]1[C:27]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])=[CH:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:25]>>[Cl:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH3:43])=[C:35]([C:27]2[C:26]([C:24]([OH:25])=[O:23])=[CH:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][CH:28]=2)[CH:40]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(Cl)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 93.8 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate (0.83 g, 2.6 mmol) to afford 0.75 g (95%) of 5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a yellow solid. Data for (5'-chloro-2'-methoxy-4-nitro-2-biphenyl)carboxylic acid: 1 H NMR (400 MHz, acetone-d6) 8.69 (d, J=2.5, 1 H); 8.46 (dd, J=8.3, 2.6, 1 H); 7.68 (d, J=8.5, 1 H); 7.41 (dd, J=8.9, 2.7, 1 H); 7.33 (d, J=2.8, 1 H); 7.08 (d, J=8.6, 1 H); 3.75 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[N:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
A mixture of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (110 mg, 0.28 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (45.6 mg, 0.44 mmol, 1.6 eq.), HATU (157.6 mg, 0.41 mmol, 1.5 eq.), and DIPEA (96.0 μL, 0.55 mmol, 2.0 eq.) in anhydrous DMF (4.2 mL) was stirred for 18 hours under N2 at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane) to afford the desired product as a yellow solid (24 mg, 18%). LCMS (method D1): RT=1.00 min, [M+H]+=484.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38](=[O:46])[NH:39][CH2:40][CH:41]([OH:45])[CH2:42][NH:43][CH3:44])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:46])[NH:39][CH2:40][CH:41]([OH:45])[CH2:42][N:43]([C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[C:29]([F:30])([F:31])[F:32])[N:8]=[CH:9]3)[C:18](=[O:26])[N:19]=1)[CH3:44])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC(O)CNC(=O)OC(C)(C)C
Product: CN(CC(O)CNC(=O)OC(C)(C)C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
[3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and (2-Hydroxy-3-methylamino-propyl)-carbamic acid tert-butyl ester following General Procedure
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[N:20]=[CH:21][S:22][CH:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1cscn1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cscn2)CCN(C)C1
Temperature: 120 °C
Yield: 5.4 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (163 mg, 0.731 mmol), 4-bromo-thiazole (100 mg, 0.60 mmol), dichlorobistriphenylphosphinepalladium(II) (12 mg, 0.01 mmol) and TBAF.3H2O (575 mg, 1.82 mmol) was heated at 80° C. (observed exothermic temperature was 120° C.) for 5 min by microwave. After completion of reaction (monitored by TLC&LCMS), the mixture was poured into water (20 mL) and saturated bicarbonate was added. The mixture was extracted with EtOAc (3×20 mL), the organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under vacuum to obtain 10 mg of 2,8-dimethyl-5-thiazol-4-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.80 (s, 1H), 7.56 (s, 1H), 7.44 (d, 2H), 7.18 (s, 1H), 7.08 (d, 1H), 3.64 (s, 2H), 3.0 (m, 2H), 2.90 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl.O>[CH2:9]([N:6]1[CH2:7][CH2:8][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][Cl:24])([OH:16])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 78.4 %

Procedure:
To a solution of compound 397 (39.7 g, 180 mmol) in dichloromethane (350 mL) was added triethylamine (50.0 mL, 359 mmol), followed by dropwise addition of chloroacetyl chloride (16.5 mL, 207 mmol) over 15 minutes. The resulting solution was stirred at room temperature for 1.25 hours. The crude mixture was diluted with DCM and water, and extracted with DCM twice. The combined organics were dried over Na2SO4 and concentrated in vacuo to give compound 398 (41.9 g, 78%). LCMS-ESI (POS), M/Z, M+1: Found 297.1, Calculated 297.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CC(N(C)C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
A solution of 3,5-dinitrobenzyl chloride (2.2 g, 10 mmol) in DMA (40 mL) was treated with potassium phthalimide (1.9 g, 10 mmol) and the mixture stirred 12 h. The mixture was then concentrated and the solid residue washed with ethyl acetate, dried, washed with water and dried to give 2.5 g (76%) of essentially pure adduct as a white solid: 1H NMR 400 MHz (DMSO) δ5.06 (s, 2H); 7.82-7.97 (m, 4H); 8.62 (s, 2H); 8.74 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (50 mL) was added 5-(3-aminophenoxy)pyridine-2-amine dihydrochloride (3.5 g, 12.7 mmol) produced in Example A1(ii), and the mixture was stirred at room temperature for 18 hr. 5% Aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) and triturated with ethyl acetate and hexane to give the title compound (3.44 g, 66%) as a colorless solid.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C1CCCCC1.C(OCC)(=O)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 91.7 %

Procedure:
A solution which contained 95.0 g R-(+)-thioctic acid and 5.0 g S-(-)-thioctic acid in a mixture of 225 ml cyclohexane and 25 ml ethyl acetate was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 87.1 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 93.5% with a melting range of 45 to 47° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]=[C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[CH3:7])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C=C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 18 h

Procedure:
To a degassed solution of 3-(1-trityl-1H-imidazol-4-yl)but-2-enoic acid ethyl ester (5 g, 11.8 mmol) in ethanol (100 mL) in a Parr bottle is added 5% palladium on carbon (0.5 g). The bottle is purged with nitrogen, evacuated, and hydrogen gas (15 psi) added. The bottle is placed upon a Parr hydrogenation apparatus and shaken for 18 h. The hydrogen is evacuated and the bottle purged with nitrogen gas. The reaction mixture is then filtered through diatomaceous earth and the clear liquid solution collected and the solvent removed in vacuo to give the crude oil, which is subject to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][C@H:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NC[C@@H](O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (200 mg, 1.070 mmol) in DCM (30 mL), was added HATU (489 mg, 1.283 mmol) and TEA (324 mg, 3.208 mmol). The solution was stirred at 15° C. for 30 minutes before (R)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (264 mg, 1.283 mmol) was added. The resulting solution was stirred for another 16 h at 15° C., until the reaction was complete by LCMS analysis. The mixture was then concentrated under vacuum to give the crude material which was purified by Preparative HPLC to give the title compound (118 mg, 29%). 1H NMR (400 MHz, METHANOL-d4) δ 8.33 (d, J=1.9 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (dd, J=2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.15-7.05 (m, 4H), 4.18 (quin, J=6.1 Hz, 1H), 3.79 (s, 2H), 3.63-3.55 (m, 2H), 2.95-2.90 (m, 4H), 2.76 (s, 3H), 2.76-2.68 (m, 2H). LCMS (m/z): 376.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: BrCCCBr
Reactant: CSc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]-ethanone (5.4 g; 30 mmol), K2CO3 (4.2 g), 1,3-dibromopropane (8 g, 39 mmol) in acetonitrile (150 ml) was heated at reflux for 3 hours and stirred at room temperature overnight. Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel column (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 l). The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p.=120°-122° C.