Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.O>[Br:33][CH:25]([C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1)[CH3:26]
Reactant: CCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
In a 100 mL round bottom flask combined 4-[(3-chloro-2-methylphenyl)methyl]-5-ethyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.1 g, 10.13 mmol) (Example 75) and sodium acetate (1.246 g, 15.19 mmol) in acetic acid (30 mL). Bromine (0.782 mL, 15.19 mmol) in acetic acid (5 mL) was added dropwise over ˜3 min. The red colored reaction was stirred at room temperature for 16 hr. LC/MS indicated complete conversion to product. This reaction mixture was diluted with water (150 mL), producing a gummy yellow residue. The mixture was extracted with chloroform (100 mL), then concentrated to a thick yellow oil. This oil was triturated from ether (150 mL), to provide, after sonication a yellow solid that is consistent with 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.52 g, 9.34 mmol, 92% yield). The proton NMR is consistent for the desired product. LC/MS m/z MH+=484 (theoretical), found=484.9, 1H NMR (400 MHz, CHLOROFORM-d) S ppm 1.97 (d, J=6.57 Hz, 3H) 2.51 (s, 3H) 3.52-3.64 (m, 4H) 3.71-3.84 (m, 4H) 4.53-4.65 (m, 1H) 5.43 (d, J=17.43 Hz, 1H) 5.95 (d, J=17.43 Hz, 1H) 6.38 (d, J=7.83 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:13])[CH:10]=2)[CH2:5]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[NH2:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH2:5][CH:4]([NH:3][S:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:12]2
Reactant: Nc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
2,5-Diaminoindan dihydrochloride and 4-chlorophenylsulfonyl chloride are treated similarly as in Reference example 1 - (4) to give 5-amino-2-(4-chlorophenyl)sulfonylaminoindan.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
Step F (3): Dichloromethane (125 mL) was added to a flask charged with 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (4.00 g, 19.59 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (4.55 g, 19.59 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (0-5% EtOAc/chloroform) linear gradient to afford 1-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.91 g, 15.88 mmol, 81% yield) as a white solid. LC-MS (M+H)+ 247.0. 1H NMR (500 MHz, chloroform-d) δ ppm 8.64 (s, 1 H) 7.78 (d, J=8.55 Hz, 1 H) 6.96 (dd, J=8.55, 2.14 Hz, 1 H) 6.90 (d, J=2.14 Hz, 1 H) 3.94 (s, 3 H) 2.48 (s, 3 H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])[C:23]4[S:27][CH:26]=[N:25][C:24]=4[CH:28]=3)=[N:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[O:47]1[CH2:50][C:49](=O)[CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.C([O-])(O)=O.[Na+].CCOC(C)=O>[O:47]1[CH2:50][CH:49]([N:11]2[CH2:10][CH2:9][N:8]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:21]=[C:22]([O:29][C@@H:30]([C@H:32]5[CH2:36][NH:35][C:34](=[O:37])[CH2:33]5)[CH3:31])[C:23]5[S:27][CH:26]=[N:25][C:24]=5[CH:28]=4)=[N:18][CH:19]=3)[CH2:13][CH2:12]2)[CH2:48]1
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C4COC4)CC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
The crude TFA salt of (R)-4-((R)-1-(5-(5-(piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.23) described above (0.06 mmol) was dissolved in THF (1 mL) and iPr2NEt (21 μL, 0.12 mmol) was added followed by oxetan-3-one (12 μL, 0.21 mmol) and sodium triacetoxyborohydride (55 mg, 0.26 mmol). The reaction mixture was stirred at 40° C. for 1.5 h and was diluted with water (1 mL), saturated aqueous NaHCO3 (1 mL), and EtOAc (2 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-25% MeOH in DCM) to yield (R)-4-((R)-1-(5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.25). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H30N5O3S: 480.2; found: 479.8. 1H NMR (400 MHz, Chloroform-d) δ 9.00-8.95 (m, 1H), 8.43-8.37 (m, 1H), 8.21-8.15 (m, 1H), 7.79-7.69 (m, 2H), 7.31 (dd, J=8.4, 3.8 Hz, 1H), 5.81 (s, 1H), 4.89-4.75 (m, 1H), 4.75-4.63 (m, 4H), 3.65-3.43 (m, 2H), 3.41-3.30 (m, 5H), 3.01-2.81 (m, 1H), 2.62-2.41 (m, 6H), 1.48-1.38 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:5]([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O)[CH:6]=1>C(O)(=O)C.[Fe]>[NH2:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[CH2:7][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc(Br)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)cn1Cc1cc(Cl)ccc1N
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a well-stirred solution of ethyl 4-bromo-1-(5-chloro-2-nitrobenzyl)-1H-pyrrole-2-carboxylate (9.1 g, 23.48 mmoles) in acetic acid (60.00 mL) at 70° C., add iron (5 equiv; 6.56 g, 117.38 mmoles) in portions over 0.5 h. Halfway through the addition, observe an exotherm to maintain a temperature of 85° C. with the oil-bath removed. The reaction mixture will get thicker as the exotherm dissipates and the rest of the iron can be added. Stir at 85° C. for 0.5 h. Cool to room temperature and pour onto water (200 mL). Extract into chloroform (2×200 mL). Combine organic layers and wash with water (2×100 mL) then saturated aqueous NaHCO3 solution. Dry over Na2SO4, filter and evaporate to the title compound as an orange oil (7.7 g, 92% yield). MS (m/z): 358.98 (M+1).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][NH:3]1.O=S(Cl)[Cl:21]>CN(C=O)C>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Temperature: 80 °C

Procedure:
A mixture of the compound of formula (IX) (3 g, 12 5 mmol), SOCl2 (30 mL) and one drop of DMF was heated at 80° C. until the reaction was complete (TLC analysis). The volatile components were evaporated (including SOCl2) to provide crude compound of formula (Xa) that was purified by column chromatography (eluting with EtOAc/DCM, 1:8, v/v) to give free base of the compound of formula (Xa). The compound of formula (Xa) 1H NMR (300 MHz, d6-DMSO): δ 7.53 (d, J=3.3 Hz, 1H), 7.68 (d, J=3.3 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.90 (s, 1H), 9.64 (s, 1H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.CN(C)C=O.[CH2:14]([N:21]1[C:25]2[C:26]([Cl:31])=[N:27][NH:28][C:29](=O)[C:24]=2[N:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(OCC)(=O)C>[CH2:14]([N:21]1[C:25]2[C:26]([Cl:31])=[N:27][N:28]([CH3:29])[C:1](=[O:4])[C:24]=2[N:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]nc(Cl)c2c1ncn2Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(Cl)c2c(ncn2Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.7 %

Procedure:
0.604 g of potassium carbonate and 0.297 ml of methyl iodide were added to a 30 ml N,N-dimethylformamide solution of 1.035 g of 1-benzyl-7-chloro-1,5-dihydroimidazo[4,5-d]pyridazin-4-one (J. A. Carbon Journal of the American Chemical Society, 80, pp. 6083, 1958), and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate and 100 ml of water were added to the solution, and the organic layer was washed twice with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.280 g of the title compound was obtained from the fraction eluted with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN1CCCC1=O>[Br:8][C:4]1[N:3]=[C:2]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[O:9])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccccn1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=c1ccccn1-c1cccc(Br)n1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
2,6-dibromopyridine (4.74 g), 2-hydroxypyridine (2.85 g), potassium carbonate (4.15 g) and N-methylpyrrolidone (1 mL) were stirred at 150° C. for 6 hours. The reaction solution was cooled to room temperature, then ethyl acetate and aqueous sodium hydrogencarbonate solution were added thereto, the insoluble matter was removed through Celite filtration, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give the entitled compound as a white solid (1.63 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([N:7]([N:5]1[CH:6]=[C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[N:3]=[CH:4]1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:16]
Reactant: CCN(C(=O)OC(C)(C)C)n1cnc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
tert-Butyl (4-bromo-1H-imidazol-1-yl)(ethyl)carbamate (253.7 mg, 0.874 mmol), pyridin-3-ylboronic acid (113 mg, 0.918 mmol), potassium carbonate (329 mg, 2.39 mmol), water (0.870 mL), absolute ethanol (1.74 mL), and toluene (3.50 mL) were placed into a 10 mL round bottomed flask equipped with condenser and magnetic stirrer. The atmosphere was flushed with nitrogen and tetrakis triphenylphosphine palladium (30.0 mg, 0.026 mmol) was added. The mixture was heated to 110° C. and stirred for 16 hours. The reaction was cooled, the organic layer set aside, and the aqueous layer was extracted with ethyl acetate. All organics were combined, dried over sodium sulfate, and concentrated. The residue was purified using silica gel chromatography (0-25% methanol/dichloromethane) to afford the title compound (81 mg, 0.28 mmol, 32%) as a yellow oil: 1H NMR (400 MHz, CD3CN) δ 9.00 (d, J=2.5 Hz, 1H), 8.46 (d, J=4.8 Hz, 1H), 8.11 (m, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.36 (m, 1H), 3.76 (q, J=7.1 Hz, 2H), 1.45 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 289 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[Cl:13]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester (example 15 d]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:19]#[N:20])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[C:19]([C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1)#[N:20]
Reactant: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1C#N)C(C)CNCC2
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A solution of N-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (10 mg, 0.032 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred 1 hour at 50 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 6.0 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.33 (s, 1 H), 6.93 (s, 1 H), 3.91 (s, 3 H), 3.18-2.97 (m, 5 H), 2.80 (m, 1 H), 2.60 (m, 1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C13H16N2O+H: 217, observed: 217.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:25])[C:18]=2[CH3:33])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:31]([O:30][C:28]([CH2:27][CH2:26][C:24]([NH:23][C:19]1[C:18]([CH3:33])=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:29])[CH3:32]
Reactant: CCOC(=O)CCC(=O)Nc1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(=O)Nc1cccc(N2CCNCC2)c1C
Yield: 93.7 %

Procedure:
In 50 ml of methanol was dissolved 1.50 g of 1-benzyloxycarbonyl-4-(3-(2-ethoxycarbonylethyl)carbonylamino-2-methylphenyl)piperazine, and 1.0 g of 10% palladium-on-carbon was added thereto, followed by stirring at room temperature in a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the solvent was evaporated to yield 0.99 g of 3-(2-ethoxycarbonylethyl)carbonylamino-2-methylphenylpiperazine, which was used in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:18])([F:19])[F:20])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCCOC(F)(F)F
Temperature: 60 °C
Yield: 82 %

Procedure:
Methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate (crude from Step 1) was dissolved in THF (5 mL) and a suspension of LiOH (550 mg, 23 mmol) in water (5 mL) was added. The mixture was stirred vigorously and heated at 60° C. for 6 h before it was concentrated to half volume. Water (5 mL) was added and the mixture was extracted with diethyl ether (1×10 mL). The aqueous layer was acidified with 4N HCl to pH 2. The resulting mixture was extracted with ethyl acetate (3×10 mL) and the combined organics were washed (1×10 mL H2O, 1×10 mL brine), dried over MgSO4 and evaporated to give 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid (1.0 g, 82%) as a white solid. ESI-MS m/z calc. 280.1, found 281.3 (M+1)+; Retention time: 1.34 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][N:36]([C:39]1[S:40][C:41]([CH2:49][CH2:50][CH2:51]I)=[C:42]([C:44]([O:46]CC)=[O:45])[N:43]=1)[CH2:35][CH2:34]2)=[O:28]>CN(C=O)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][N:36]([C:39]1[S:40][C:41]([CH2:49][CH2:50][CH2:51][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9]([C:13]#[N:14])=[CH:10][S:11][CH:12]=4)=[CH:6][CH:7]=3)=[C:42]([C:44]([OH:46])=[O:45])[N:43]=1)[CH2:35][CH2:34]2)=[O:28]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: N#Cc1cscc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
To compound 51A (0.095 g, 0.015 mmol) in DMF (4 mL) was added 60% sodium hydride (0.036 g, 0.9 mmol) at 0° C. The solution was stirred for 10 minutes. To this solution was added compound 2C. The solution was stirred at rt for 2 hours. The reaction was quenched with MeOH (1 mL). Conc. HCl (0.5 mL) was added, and the solution was filtered through a syringe filter. The filtrate was then purified by Prep HPLC to provide the desired product 51: 1H NMR (DMSO-d6): δ 8.57 (d, J=3.38 Hz, 1H), 7.95 (d, J=7.98 Hz, 1H), 7.71-7.72 (m, 2H), 7.60 (d, J=7.36 Hz, 1H), 7.45-7.48 (m, 2H), 7.26-7.41 (m, 4H), 6.95-6.97 (m, 214), 4.77 (s, 2H), 3.97 (t, J=6.29 Hz, 2H), 3.66 (t, J=5.98 Hz, 2H), 3.11-3.14 (m, 2H), 2.96 (t, J=5.98 Hz, 2H), 1.93-2.00 (m, 2H); MS (ESI(+)): m/z 678 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:14]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:14][CH2:12][C:7]1[C:6]([CH3:13])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][N:8]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1c(C(C)(C)C)cc[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(C(C)(C)C)ccnc1CCl

Procedure:
A solution of 9.8 g of 4-tert-butyl-2,3-dimethylpyridine N-oxide in 120 ml of abs. chloroform is boiled at reflux under argon and treated through the condenser with 25.5 ml of trichloroacetyl chloride. After 22 hours the reaction mixture is poured on to ice, whereupon 10% sodium bicarbonate solution is added, the mixture is extracted with methylene chloride and the methylene chloride solution is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel (solvent: methylene chloride/ether [10:1]). The 2-chloromethyl-4-tert-butyl-3-methylpyridine obtained is processed directly.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.Cl.[CH2:37]([OH:39])[CH3:38]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:37](=[O:39])[CH3:38])[CH2:17][CH:16]=3
Reactant: CCO
Reactant: C[C@H](CCCN)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-24-amino-5α-chola-8,14-diene (0.50 g) is acetylated in a mixture of 20 ml of pyridine and 7 ml of acetic anhydride and hydrolysed with HCl/ethanol. After aqueous work-up and crystallisation from ethanol/water, the title compound (0.24 g) is isolated. Melting point: 219-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N+:30]([O-:32])=[O:31])=[CH:22][CH:23]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(C)ccnc2[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of 0.913 g (5.2 mmol) of 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine in 10 mL of anhydrous dimethylformamide was added 0.210 g (5.7 mmol) of a 60% mineral oil dispersion of sodium hydride. The reaction mixture was magnetically stirred under a nitrogen atmosphere for 2 hours, at which point 1.675 g (5.7 mmol) of 4-bromomethyl-2'-nitrobiphenyl was added as a solid. The reaction mixture was stirred an additional 1 hour at room temperature, then partitioned between ethyl acetate and water. The organic layer was extracted, washed with brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 75% ethyl acetate-hexane, which after evaporation of the pure fractions and drying in vacuo afforded 1.009 g (50%) of the product as a tan solid: NMR (CDCl3) δ 0.97 (t, J=8 Hz, 3H), 1.70-1.83 (m, 2H), 2.66 (s, 3H), 2.81 (t, J=10 Hz, 2H), 5.52 (s, 2H), 7.02 (d, J=6 Hz, 1H), 7.14-7.25 (m, 4H), 7.36 (d, J=10 Hz, 1H), 7.42-7.48 (m, 1H), 7.56-7.61 (m, 1H), 7.82 (d, J=10 Hz, 1H), 8.20 (d, J=6 Hz, 1H); MS (FAB) m/e 387 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[C:3]=1[C:30](=[O:31])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCc1ccncc1
Reactant: O=c1cc(O)c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Product: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 53.9 %

Procedure:
The procedure of Synthetic Example 1 was repeated using a mixture of 4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2 (1H)-one (2.5 g, 8.83 mmol), 3-(pyridin-4-yl)propionic acid (19.87 g, 131 mmol, 15 eq.; prepared in Synthetic Example 1-(1)) and polyphosphoric acid (about 100 ml) to obtain 4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2 (1H)-one (1.98 g, 54%).