Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:18][OH:19])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)COc1cccc(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)OC(=O)COc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
A solution of (3-formyl phenoxy)acetic acid isopropyl ester (3.7 g, 17 mmol) in methanol (55 mL) was stirred under nitrogen as hydroxylamine hydrochloride (1.2 g, 17 mmol) and pyridine (6 mL, 74 mmol) were added. The reaction was stirred for 15 h at room temperature. The volatiles were removed in vacuo and the residue was diluted with ethyl acetate. The resulting solution was washed with 1N HCl, and the resulting aqueous solution was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (4.13 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (d, 6H) 4.67-4.72 (m, 2H) 5.15-5.34 (m, 1H) 7.01-7.07 (m, 1H) 7.33-7.36-7.43 (m, 2H) 8.17 (s, 1H). LRMS m/z calcd. for C12H15NO4([M+H]+): 237.1. Found: 238.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.O.[NH2:20][NH2:21].O>C(O)CCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5](=[N:20][NH2:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: COc1ccccc1C(=NN)c1ccccc1OC
Temperature: 25 °C

Procedure:
A stirred suspension of 2,2′-dimethoxybenzophenone (20.72 g, 0.0855 mol) and 20 mL (0.412 mol) of hydrazine monohydrate in 25 mL of 1-butanol was heated to reflux overnight. After cooling to room temperature the two phase reaction mixture was poured into water and cooled to induce crystallization. The white precipitate was filtered, washed with water and petroleum ether and dried in vacuo to yield 2,2′-dimethoxybenzophenone hydrazone (1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.O=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(NC4CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #148, Step D, 2.4 g, 10.32 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (Aldrich, 2.0 g, 6.23 mmol) was stirred at 15° C. for 10 min and then acetic acid (7 mL) was added. The reaction mixture was stirred for 30 min and sodium cyanoborohydride (0.68 g, 11 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 100% EtOAc) to give 3-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.3 g, 53%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 6.20 (d, J=8.4 Hz, 1H), 5.63-5.53 (m, 1H), 4.73 (m, 1H), 4.52-4.41 (m, 2H), 4.06-3.99 (m, 1H), 3.62-3.37 (m, 2H), 3.15-2.92 (m, 1H), 2.10 (m, 1H), 1.64 (m, 1H), 1.38 (s, 9H), 1.30 (m, 3H). LCMS (Table 1, Method 2) Rt=1.059 min.; MS m/z: 424 [M+Na]+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=4[F:40])=[O:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([F:40])=[C:33]([C:31]([CH:28]2[CH2:29][CH2:30][N:25]([C:20]3[N:21]=[C:22]4[CH2:23][CH2:24][NH:15][CH2:16][C:17]4=[N:18][C:19]=3[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:26][CH2:27]2)=[O:32])[CH:38]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone TFA salt (41.7 mg, 0.066 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 0.036 mmol) in THF (328 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon). After 3 h, the mixture was diluted with MeOH, filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (36 mg, 100%) as a yellow film, which was used without further purification. ESI-MS m/z [M+H]+ 432.3.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:17](O)=[O:18])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[C:4]([C:3]1[C:2]([C:7]#[N:8])=[N:1][C:17]([OH:18])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)#[N:5]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cl
Product: N#Cc1nc(O)c(-c2ccccc2)nc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Diaminomaleonitrile (5.40 g; 0.05 mole) and 7.50 g (0.05 mole) of benzoylformic acid were put into 50 ml of a 2 N aqueous solution of hydrochloric acid. The mixture was stirred at 20° to 30° C. for 30 minutes, and further stirred at 70° to 80° C. for 2 hours. The mixture was then cooled to room temperature. The precipitate formed was collected by filtration, washed thrice with 40 ml of water, and dried under reduced pressure to afford 10.0 g (yield 90%) of 2,3-dicyano-5-hydroxy-6-phenylpyrazine.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]([OH:15])[CH2:13][CH3:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccn(-c2ccccc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(=O)c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
1-(1-Phenyl-1H-pyrazol-3-yl)-propan-1-ol (631 mg, 3.12 mmol) was dissolved in CH2Cl2 (16 mL) and Dess-Martin periodinane (1.6 g, 3.8 mmol) was added in one portion. After 40 minutes, TLC (2:1 hexanes:EtOAc) indicated a mixture of starting material and product. Additional Dess-Martin periodinane (800 mg, 1.88 mmol) was added and the mixture was stirred at ambient temperature. After 30 minutes, TLC indicated no further conversion to product. The reaction mixture was diluted with CH2Cl2 and washed with aqueous Na2S2O3 (1×) and saturated NaHCO3 (2×). The CH2Cl2 layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (2:1 hexanes:EtOAc) to provide the title compound as a colorless solid (487 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 1H, J=2.4 Hz), 7.73 (d, 2H, J=8.8 Hz), 7.48 (t, 2H, J=7.2 Hz), 7.35 (t, 1H, J=7.6 Hz), 6.96 (d, 1H, J=2.8 Hz), 3.13 (q, 2H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz). MS (ES) m/z 201.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[S:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:18]1
Reactant: OB(O)c1ccsc1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2ccsc2)CC1
Yield: 76 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (17 mg, 0.060 mmol), thiophene-3-boronic acid (9.2 mg, 0.072 mmol), tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 5 mol %), 0.5 M sodium carbonate (0.17 mL, 0.084 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (13 mg, 76%), LC-MS (ESI, 3.5 min) Rt 1.12 min, m/z 288 (100%, [M+H]+); m/z (ESI) C15H18N3OS requires 288.1165 found [M+H]+ 288.1163.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O.[O:7]=[CH:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])O.N#N>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:17]1[O:18][C@H:9]([CH2:8][OH:7])[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@H:15]1[OH:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COCCN
Agent: N#N
Solvent: O
Product: COCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
N-(2-methoxyethyl)glucosylamine (sugar adduct) is prepared starting with 1728.26 g of 50 wt. % 2-methoxyethylamine in water (11.5 moles, 1.1 mole equivalent of 2-methoxyethylamine) placed under an N2 blanket at 10° C. 2768.57 grams of 50 wt. % glucose in water (10.46 moles, 1 mole equivalent of glucose), which is degassed with N2, is added slowly, with mixing, to the methoxyethylamine solution keeping the temperature below 10° C. The solution is mixed for about 40 minutes after glucose addition is complete. It can be used immediately or stored 0° C.-5° C. for several days.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CC[N:21]([CH2:24][CH3:25])CC>CCCCCC>[CH:24]1([NH:21][Si:2]([CH3:18])([CH3:17])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([CH3:15])=[C:4]2[CH3:16])[CH2:25][CH2:5][CH2:4][CH2:3][CH2:14]1
Reactant: CCN(CC)CC
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Solvent: CCCCCC
Product: CC1=C(C)C([Si](C)(C)NC2CCCCC2)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 181 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)silane (5.00 g, 0.01806 moles) was stirred in hexane (80 mL) as NEt3 (3.29 g, 0.03251 moles) and t-cyclohexylamine (1.81 g, 0.01824 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.55 g, 90.9 percent).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)=[C:5]([C:11]([O:13]CC)=[O:12])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2].C1COCC1.[Li+].[OH-].C>CO>[C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)=[C:5]([C:11]([OH:13])=[O:12])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)c(CC)n1C
Agent: C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)O)n1C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Add ethyl 4-cyano-3-[4-(2-cyanophenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylate to a round bottom flask with a nitrogen inlet, thermocouple and magnetic stirring. Add THF (4.0 volumes). MeOH (1.0 volume) and 1.20 equiv. of 2N LiOH and stir the reaction mixture at RT. After stirring for 24 h no starting material remains. Add Darco (40 w %) and stir the slurry for 30 min. Then filter the reaction mixture through a plug of Hyflo Super Cel® (about ½″ thick) and rinse 2 times with 1 volume of water. Filter this initial filtrate again through a Whatman® GF/F filter to collect small black particulates that escape through the first filtration. Acidify the filtrate slowly with 1 N HCl (1.5 equiv as compared to the LiOH added) {slow addition is very important for polymorph control—about 90 min. addition on 100 g scale}. Stir the milky suspension for 15 min. Filter the thick suspension through a glass frit to obtain a wet solid. Wash this wet solid 4 times with 5 volumes of water (breaking vacuum and stirring the solids with the water each time). Place the wet solid in a vacuum oven at 40° C. overnight (˜15 h) to provide the title compound (92.2% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=12.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1ccc2nccn2c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Yield: 74.4 %

Procedure:
In 200 ml of N,N-dimethylformamide, 33.17 g of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone was stirred at 80° C. for 1 hour, together with 45.4 g of N,N-dimethylformamide dimethyl acetal. After cooling, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (eluted with chloroform-methanol=97:3) to obtain 32.46 g (74.5%) of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][CH:14]=[CH:15][CH2:16]1)[CH2:11][CH2:10]3.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@@H:14]2[O:30][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of compound 34 (160 mg, 0.55 mmol) in anhydrous dichloromethane (10 mL) was added m-CPBA (149 mg, 0.67 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. over a period of 3 h. The solution was subsequently diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/acetone: 9:1) to yield compound 35 (127 mg, 75%). 1H NMR (CDCl3) δ: 0.73 (s, 18-CH3), 0.76 (s, 19-CH3), 0.58-2.05 (residual CH and CH2), 3.12 and 3.15 (2 m, 2×CH of epoxide), 3.21 (t, J=8.2 Hz, 17α-CH), 3.34 (s, OCH3).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:3]12([CH2:2][NH:1][C:15]3[C:14]([Cl:13])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(NCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 65 °C
Yield: 8.3 %

Procedure:
A stirred mixture of 1-(aminomethyl)adamantane (0.31 g, 1.85 mmol), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (0.5 g, 1.85 mmol) and potassium carbonate (0.64 g, 4.63 mmol) in N,N-dimethylformamide (18 mL) and tetrahydrofuran (10 mL) was heated at 65° C. for 48 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with saturated aqueous ammonium chloride (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0 to 10% gradient of methanol in dichloromethane to afford the title compound as a pale yellow solid (0.064 g, 8%): 1H NMR (300 MHz, CDCl3) δ 8.55-8.08 (m, 2H), 7.51-7.40 (m, 1H), 6.58-6.43 (m, 1H), 3.44 (s, 3H), 2.84-2.75 (m, 2H), 2.02 (br s, 3H), 1.81-1.46 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 166.5, 162.5 (d, 1JC-F=255.0 Hz), 153.1 (d, JC-F=11.8 Hz), 130.9 (d, JC-F=3.2 Hz), 106.8, 106.2 (d, JC-F=19.5 Hz), 99.6 (d, 2JC-F=25.3 Hz), 55.7, 42.1, 40.6, 36.9, 33.8, 28.2; MS (ES+) m/z 414.8, 416.8 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C2N=C(CCC3N[C:43](=[O:45])CCCC3)NC2=NC=1.C(=O)([O-])[O-].[Na+].[Na+].COC1C=CC(B(O)O)=CC=1>>[CH3:43][O:45][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Agent: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) from 100 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 677 μl of aqueous sodium carbonate solution (strength 2.0 M), 52 mg of commercially available 4-methoxyphenylboronic acid, and 72 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 110° C. for 96 hours. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-20 vol. % ethanol) yields 99 mg of the title compound as a waxy solid. ESI-MS: 365.2 (MH+). TLC: Rf=0.32 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([I:24])=[CH:21][CH:22]=3)[C:17](=[O:25])[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[I:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH:13]1[CH2:10][CH2:11][CH2:12][NH:8][CH2:9]1)[CH:15]=[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]2=[O:25]
Reactant: CCOC(=O)c1cn(CC2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CCCNC2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 131, 3.0 g, 5.7 mmol) was dissolved in 1,4-dioxane (15 mL) and 4.0M hydrogen chloride in 1,4-dioxane (10 mL) was added. The reaction was stirred at 23° C. for 3 h, and the solvent was removed in vacuo. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 2.64 g (quant. yield) of ethyl 6-iodo-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)[CH2:3][CH2:2]1.BrCCCCBr.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=4)[CH2:30][CH2:29][N:28]3[C:41]=2[CH3:42])[CH:22]=[CH:23][CH:24]=1>CN(C=O)C>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][C:34]=1[O:37][CH3:38])[C:27]1=[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]4[CH2:3][CH2:2][CH2:1][CH2:11]4)[CH:20]=3)=[C:41]([CH3:42])[N:28]1[CH2:29][CH2:30]2
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: BrCCCCBr
Product: CCOC(=O)c1c(-c2cccc(N3CCCC3)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
168.5 mg (1.11 mmol) of DBU and 79.9 mg (0.37 mmol) of 1,4-dibromobutane were added to a solution of 150 mg (0.37 mmol) of ethyl 2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate obtained as described above in 3 mL of DMF. The mixture was stirred at 120° C. for 20 hours, the solvent was evaporated under reduced pressure, and the residue was taken up in an ethyl acetate/water mixture. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. Chromatography on a short silica gel column using a dichloromethane/ethyl acetate 10:1 mixture as eluant, followed by crystallization from diethyl ether gave the title compound.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:21][S:22]([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)(=[O:24])=[O:23]>>[OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:34][C:26]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)([CH3:33])[CH2:25][S:22]([CH3:21])(=[O:24])=[O:23])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(O)CCC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3(O)CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-hydroxycyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 129b) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 109d) as starting materials and isolated (25 mg, 37%); MS (ESI, m/z): 493.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16]CC3C=CC=CC=3)=[CH:14][CH:13]=[C:12]([O:24][C:25](=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]>CCOC(C)=O.CCO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:24][C:25](=[O:33])[NH:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cccc(-c2cc(OC(=O)NC3CCCCC3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(-c2cc(OC(=O)NC3CCCCC3)ccc2O)c1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred suspension of cyclohexylcarbamic acid 3′-carbamoyl-6-benzyloxybiphenyl-3-yl ester (222 mg; 0.5 mmol) in EtOAc (2.5 mL) and EtOH (2.5 mL), 10% Pd/C (22 mg) was added. The mixture was hydrogenated at 4 atm at 50° C. for 4 h, cooled, filtered on Celite and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:9) and recrystallization gave URB937 as a white solid. Yield: 92% (0.163 g). Mp: 128-130° C. (CH2Cl2/n-hexane). MS (ESI) m/z: 355.2 (M+H). 1H NMR (200 MHz, CDCl3) δ: =1.13-2.02 (m, 10H), 3.55 (m, 1H), 5.13 (br d, 1H), 5.85 (br s, 1H), 6.59 (br s, 1H), 6.74-6.95 (m, 3H), 7.07 (s, 1H), 7.34-7.41 (m, 1H), 7.56 (m, 1H), 7.68-7.75 (m, 2H) ppm. IR (Nujol) nmax: 3333, 1701, 1655 cm−1.