Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as an orange oil (250 mg, 46%).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]=[O:31])=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:36])([CH3:35])[O:25]3)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]([OH:31])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:28]([CH:32]([CH3:33])[CH3:34])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:35])([CH3:36])[O:25]3)=[CH:16][CH:15]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.29 ml (1.15 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 300 mg (881 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) in 7 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. A 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.OS(O)(=O)=O>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NNc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3[nH]c4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
1-Benzyl-4-piperidone (1 mmol) was added dropwise to a stirred suspension of phenyl hydrazine (1 equiv.) in a solution of 7% H2SO4 (20 mL) in 1,4-dioxane (20 mL). The reaction mixture was heated at reflux for 18 h then cooled to RT. The solvent was evaporated and the residue recrystallized to afford 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[S:18][C:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[S:18][C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)s1
Solvent: O=S(Cl)Cl
Product: O=C(O)CCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)s1

Procedure:
Methyl 3-(5-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)thien-2-yl)propionate. A solution of the title compound of Example 2 (500 mg, 1.40 mmol) in ca. 1 ml of thionyl chloride was heated at reflux for 20 minutes. The excess thionyl chloride was then removed by distillation at slightly reduced pressure. Then, benzene (4 ml) was added to the pot and subsequently distilled to remove traces of thionyl chloride. The residue was dried in vacuo. The resultant solid was dissolved in ether (ca. 5 ml) containing a little THF. This solution was added dropwise to ethereal diazomethane (ca. 12 ml of ca 0.3M) at 0° C. An additional 6 ml of diazomethane solution was when added to complete formation of the diazoketone. After 5 minutes, the solvent was removed in vacuo. The residue was taken up in methanol (20 ml) and warmed to 60° C. Portions of silver (1) oxide (ca. 40 mg each) were added to the hot solution at 15 minute intervals. After 1.5 hours, the mixture was treated with Norit and filtered through Celite. The filtrate was concentrated in vacuo. The residue was then taken up in methylene chloride and passed through a short plug of silica eluting with 1:1 methylene chloride/ethyl acetate. The eluate was concentrated in vacuo to 399 mg of a solid. This material was combined with a material from a previous reaction (126 mg) and chromatographed (flash, silica, 25×15 cm, 40% ethyl acetate-hexanes) to provide 357 mg (47% yield) of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[OH:21])[CH:18]=3)[N:13]=[C:12]([O:34]C)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:21])([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:18]=3)[NH:13][C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 44.3 %

Procedure:
Following the same procedure as described in example 1F, [4-(3-ethoxy-phenyl)-2-methoxy-quinolin-6-yl]-di-pyridin-3-yl-methanol (212 mg, 0.457 mmol) was treated with HCl in aqueous THF to yield the title compound (91 mg, 44.3% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH3:11])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:11][C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)Cc1ccoc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1occc1CCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (2-methyl-furan-3-yl)-acetic acid ethyl ester (11.8 g, 70.2 mmoles) in tetrahydrofuran (50 ml) was added to a stirred suspension of lithium aluminium hydride (2.66 g, 70.2 mmoles) under a nitrogen atmosphere and with cooling to 0° C. When the addition was complete the mixture was stirred at room temperature for 3 hours, then quenched by the addition of excess acetone. After acidifying with 10% aqueous hydrochloric acid the mixture was extracted three times with diethyl ether. The combined extracts were dried and evaporated to afford crude 2-(2-methyl-furan-3-yl)-ethanol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([Cl:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Product: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
To a stirred suspension of 238 g of 1-(4'-chloro[1,1']biphenyl-4-yl)ethanol in 2 liters of anhydrous benzene add 200 ml. of thionyl chloride over 40 minutes. With stirring, reflux the reaction mixture for 4 hours. Concentrate the reaction mixture and dissolve the resulting solid residue in 2 liters of methylene chloride. Wash the methylene chloride solution with three 500 ml portions of water, dry the resulting solution over sodium sulfate, concentrate, and triturate the solid residue with petroleum ether to yield 4'-chloro-4-(1-chloroethyl)[1,1']-biphenyl m.p. 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](OC2C=CC(F)=CC=2F)=[C:4](C2C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(=O)N(C)C=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:39]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N:1]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[NH:8][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (31.0 mg, 0.058 mmol) in tetrahydrofuran (0.50 mL) was treated with ethyl orthoformate (28.8 μL, 0.173 mmol) followed by p-toluenesulfonic acid monohydrate (1.1 mg, 5.8 μmol) and stirred at 50° C. for 1 h. The reaction mixture was concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.0 mL), treated with 1.0 M sodium hydroxide in water (300 μL, 0.90 mmol), and heated at 60° C. overnight. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of methanol/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (6 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.72 (br s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.32-7.15 (m, 3H), 6.80-6.65 (m, 1H), 6.63-6.48 (m, 1H), 6.20-6.03 (m, 1H), 3.48 (s, 3H); LCMS calculated for C21H15F2N4O2 (M+H)+: m/z=393.1. found: 393.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:18]O)(C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:18][C@H:11]2[CH2:12][OH:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(/C=C/CO)cc1
Reactant: CC(C)(C)OO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc([C@@H]2O[C@H]2CO)cc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A flame-dried 50 ml three-necked flask was fitted with a thermometer and a dropping funnel, flushed with nitrogen, and charged with a mixture of powdered, activated 3 Å molecular sieves (0.45 g) and dry CH2Cl2 (15 ml). After cooling to −5° C., L-(+)-diethyl tartrate (92.8 mg, 0.45 mmol) and Ti(O-i-Pr)4 (88.5 ul, 0.30 mmol) were added sequentially. The mixture was cooled to −20° C. in a CCl4 dry ice bath, (E)-3-(4-nitrophenyl)-2-propenol 4 (1.074 g, 6 mmol) (dissolved in dry methylene chloride (15 ml) and dried with 3Å molecular sieves for 10-15 min prior to addition) was added and the mixture was stirred for 10 minutes. A 7.0 M solution of t-butylhydroperoxide (TBHP) in CH2Cl2 (1.72 ml, 12 mmol) was added, taking care to maintain the temperature around −20° C. After stirring, at −20° C. for 2 hrs, the cold (−20° C.) reaction mixture was quenched with a 10% aqueous solution of sodium hydroxide saturated with sodium chloride (0.48 ml). Ether in the amount of 10% of the total volume of the reaction mixture was added, the cold bath removed and the stirred mixture allowed to warm to 10° C. Stirring was maintained for an additional 10 minutes at 10° C., whereupon anhydrous MgSO4 (0.48 g,) and Celite® (0.06 g) were added. After a final 15 min. of stirring, the mixture was allowed to settle and the clear solution was filtered through a pad of Celite® and washed with ethyl ether. Concentration of the ether solution gave the crude product containing TBHP, which was dissolved in a minimum amount of ethyl acetate, filtered through a small pad of silica gel, and recrystallized from CH2Cl2-hexanes to yield compound 5, (2S, 3S)-3-(4-nitrophenyl) oxiranemethanol (1.13 g, 97%) as light yellow needles: mp 100-101° C. (literature value: 98-99° C.); Rf=0.62 (5% CH3OH—CH2Cl2); 1H NMR (300 MHz, CDCl3) δ: 8.22 (d, aromatic, 2H, J=8.7 Hz), 7.45 (d, aromatic, 2H, J=8.7 Hz), 4.10 (m, 2H) 3.89 (m, 1H), 3.20 (m, 1H), 1.74 (m, 1H); 13C NMR (CDCl3): d 147.88(C), 144.35(C), 126.41(CH), 123.82(CH), 62.94(CH), 60.62(CH2), 54.30(CH). Anal. Calcd for C9H9NO4: C, 55.38; H, 4.65; N, 7.18. Found: C, 55-65; H, 4.54; N, 7.17.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CC2
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@H](CCNC(C)=O)CC2

Procedure:
By substantially the same procedure as in Working Example 65, 1-[2-(acetylamino)ethyl]-6-methoxyindan was subjected to optical resolution by means of a high performance liquid chromatography to give the above-titled compound (119 mg), m.p.93-94° C. [α]Hg365 +80.7° (c 0.3, CHCl3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[N:20]1([C:29](N2C=C[N+](C)=C2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:29]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCc3ccccc32)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCc2ccccc21

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,3-dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to column chromatography(ethyl acetate/heptane, 1:5) (73%, crystals. HPLC-MS m/z=401.1) (M+1), Rt: 5.5 min.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN(C(C)C)C(C)C>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:22]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C#N)cc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzonitrile (1.0 eq), 3-(N-Boc-amino) piperidine (1.0 eq), and DIEA (2.4 eq) at 55° C. for 24 hours yielding tert-butyl 1-(4-cyano-2-nitrophenyl)piperidin-3-ylcarbamate (95%). LCMS (m/z): 347.2 (MH+); LC Rt=3.06 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(N)cc1

Procedure:
(3-Methyl-butyl)-(2-methyl-4′-nitro-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester (I-9a: 0.150 mg, 0.364 mmol) in methanol (12.1 ml) was hydrogenated employing an H-cube apparatus (atmospheric pressure, flow rate=1 mL/min, hydrogen level=full hydrogen, temperature=35° C.). The reaction mixture was allowed to proceed through a palladium on carbon cartridge and the contents collected and concentrated under reduced pressure. The resulting title compound (I-8b) was carried on to the next reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:11]1([C:21]2[N:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]3=[CH:23][N:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>ClCCl>[C:11]1([C:21]2[N:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]3=[C:23]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[N:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)c1nc(-c2cccc3ccccc23)n2ccccc12
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of butyroylchloride (100 μL, 1.13 mmol) in dichloromethane (10 mL) was added aluminum trichloride (195 mg, 1.47 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (276 mg, 1.13 mmol) in dichloromethane (5 mL) was added. The mixture was stirred for 30 min. at ambient temperature then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (25 mg, 8%). 1H NMR (DMSO-d6) δ 8.27 (1H), 8.19 (1H), 8.10 (1H), 7.95 (1H), 7.85 (1H), 7.68 (1H), 7.60 (2H), 7.55 (1H), 7.40 (1H), 6.95 (1H), 3.04 (2H), 1.70 (2H), 0.90 (3H); m/z (M+H)=315.2.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=c1[nH]ccc2scc(Br)c12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]ccc2scc(-c3ccncc3)c12
Temperature: 130 °C
Yield: 48.3 %

Procedure:
3-Bromothieno[3,2-c]pyridin-4(5H)-one (1000 mg, 4.35 mmol) from Example 202.3 was suspended in 2 mL of toluene and 2 mL of ethanol under argon. Then, an aqueous solution of sodiumcarbonate (691 mg, 6.52 mmol, 2 M) was added. To the suspension, pyridin-4-boronic acid (534 mg, 4.35 mmol) and then tetrakis(triphenyl phosphine)palladium(0) (502 mg, 0.435 mmol) were added. The reaction mixture was heated in a Biotage microwave at 130° C. for 30 min. Water and EA were added. The precipitate formed was collected to give 480 mg of the title compound. The filtrate was acidified with 2 M HCl and extracted with EA (twice). The aqueous phase was basified and extracted three times with EA. The organic phases were combined, washed with HCl, dried (MgSO4) and evaporated to give further 43 mg of the title compound. Total yield: 523 mg (52.4%). LC-MS: 229.1 [M+H]+; Rt: 0.427.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[CH:20]=[C:19]1[CH:27]([CH3:29])[CH3:28])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C>>[CH2:1]([O:4][NH:5][C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[CH:20]=[C:19]1[CH:27]([CH3:29])[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Product: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1C(C)C

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 41, 0.247 g, 0.58 mmol) following the procedure described for Intermediate 22. The desired product was obtained as a light yellow solid (98 mg, 71%)
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:20]=2)=[N:12]1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(C(F)(F)F)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([O:27][CH3:28])=[CH:20][N:19]=1.C(Cl)Cl>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)[C:21]([O:27][CH3:28])=[CH:20][N:19]=1
Reactant: Fc1cccc(CNc2cccc(Br)n2)c1
Reactant: COc1cnc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cnc(Cl)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 110 °C
Yield: 7.8 %

Procedure:
To a solution of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (555 mg, 1.974 mmol) and 2-chloro-5-methoxypyridin-4-ylboronic acid (518 mg, 2.76 mmol) in DME (4 ml) and 2M Na2CO3 aq (2 ml) was added PdCl2(dppf).CH2Cl2 adduct (81 mg, 0.099 mmol). This was then heated at 110° C. for 5 h. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The organics were combined, then washed with H2O (×3), saturated aq. brine (×3), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 15% to 25% EtOAc/hexane) to give 2′-chloro-N-(3-fluorobenzyl)-5′-methoxy-2,4′-bipyridin-6-amine (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
448 G. of 4-fluoro-phenol and 742 g. of 2-chloro-5-nitro-benzaldehyde are added to a solution of 184 g. of sodium hydroxide in 7.4 liters of water. The mixture is then left to cool to room temperature. The precipitate is removed by filtration, washed carefully with water, and there is obtained 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde, having a melting point of 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)=O)cc1
Product: COc1ccc(C(=O)C=CN(C)C)cc1

Procedure:
A mixture of 25 g. of p-methoxyacetophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 9 hours. Evaporation gives an oil which crystallized on the addition of hexane. Recrystallization from methylene chloride and hexane gives the desired compound, m.p. 92°-95° C.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][CH3:4].C[Si]([C:16]#[N:17])(C)C>>[Cl:11][C:7]1[CH:6]=[C:5]([CH:2]([CH2:3][CH3:4])[C:16]#[N:17])[CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)C#N
Reactant: CCC(Br)c1cccc(Cl)c1
Product: CCC(C#N)c1cccc(Cl)c1

Procedure:
rac-2-(3-chloro-phenyl)-butyronitrile was prepared from rac-1-(1-bromo-propyl)-3-chloro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.