Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO.C(Cl)Cl>O.C(Cl)Cl>[C:15]1([S:21]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)N1CC2CC(C1)CN(S(=O)(=O)c1ccccc1)C2
Reaction time: 17.5 h
Yield: 28.6 %

Procedure:
A 50-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, an ice bath, a 10-mL addition funnel, and a glass stopper. To a stirred, ice cold (5° C.) mixture of the amine (31, 1.03 g, 6.12 mmol) and NaOH pellets (97%, 0.76 g, 18.4 mmol) in H2O (7 mL) and CH2Cl2 (5 mL) was added dropwise a solution of benzenesulfonyl chloride (2.16 g, 12.2 mmol) in CH2Cl2 (5 mL) over 30 min. Stirring of the mixture was continued for an additional 17.5 h at RT. The reaction mixture was then partioned between H2O (30 mL) and CH2Cl2 (30 mL) followed by basification (pH~12) of the aqueous phase. Extracts (CH2Cl2,3×30 mL) of the remaining water layer were combined with the initial organic layer. The solution was washed with 10% NaOH (30mL) and then saturated NaCl (30 mL); it was dried (Na2SO4, overnight), filtered, and concentrated to give an orange viscous oil. Chromatography of the oil was performed on silica gel (39 g, 1.6 cm×62 cm) using 10% CH3OH/CH2Cl2. Fractions (Rf =0.44) were saved, concentrated, and reeluted on neutral alumina (90 g, 2.5 cm×18 cm) employing ethyl acetate as eluant. Fractions (Rf =0.53) were saved and concentrated. A colored impurity persisted which was removed by again eluting over silica gel (21 g, 1.6 cm×33 cm) using 5% CH3OH/CH2Cl2 as eluant. Fractions (Rf =0.34) were combined and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.54 g (28.6%) of white solid (36); mp 85.5°-86.5° C. IR (KBr) cm-1 3060 (Ar C--H), 2960, 2910, 2890, 2865, 2820 (C--H), 1585 (C=C), 1340, 1170 (S=O), 760, 720 (C--H out of plane, mono); 1H NMR (DMSO-d6) δ0.88 (d, 6H, CH3, J=6.5 Hz), 1.40 [bs, 2H, H(9)], 1.94 [bs, 2H, H(1,5)], 2.35 [bd, 2H, H(6,8)ax, J=10.3 Hz], 2.53 [heptet, 1H, CH(CH3)2, J=6.5 Hz], 2.69 [bd, 2H, H(6,8)eq, J=10.3 Hz], 2.89 [dd, 2H, H(2,4)ax, J=11.2 Hz, J'=4.5 Hz], 3.36 [d, 2H, H(2,4)eq, J=10.9 Hz], 7.58-7.75 (m, 5H, Ar--H); 13C NMR (DMSO-d6) ppm 17.57 (CH3), 27.39 [C(1,5)], 28.95 [C(9)], 48.88 [C(2,4)], 52.66[C(6,8)], 53.42 [CH(CH3)2 ], 126.90, 129.01, 132.36, 136.79 (Ar--C). Anal. Calcd. for C16H24N2O2S: C, 62.31; H, 7.85. Found: C, 62.48; H, 7.69.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15]([NH2:17])=O)[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15](=[S:19])[NH2:17])[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(n1)C(C(N)=O)CCC2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CC(C)(C)c1ccc2c(n1)C(C(N)=S)CCC2

Procedure:
The title compound was prepared from 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (4 g.) and P2S5 (3 g.) as described in Example 8 and was isolated as creamy needles after recrystallisation from n-hexane m.p. 126° C (650 mgs.). Found: C, 68.18; H, 8.25; N, 11.14%. C14H20N2S requires C, 67.70; H, 8.12; N, 11.23%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([NH2:20])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: [BH3-]C#N
Reactant: COc1c(F)cc(C(C)=O)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1c(F)cc(C(C)N)cc1F
Yield: 40.6 %

Procedure:
Slurry 3′,5′-difluoro-4′-methoxyacetophenone (1.0 g, 5.0 mmol), ammonium acetate (4.14 g, 50 mmol) and sodium cyanoborohydride (630 mg, 20 mmol) in anhydrous methanol (35 mL) and stir for 18 h at ambient temperature. Acidify with 1N aqueous HCl (5 mL), dilute, extract with ethyl ether (3×150 mL), basify aqueous with 1N aqueous NaOH, extract with DCM (3×50 mL), wash the organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by SCX chromatography to give crude the title compound as a yellow oil (380 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:19](OCC)[CH2:20][NH2:21])C.CCN=C=NCCCN(C)C.Cl>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH:19]=[CH:20][NH:21][C:13](=[O:15])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(CN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (10.5 g) and 2,2-diethoxyethylamine (7.33 g) in acetonitrile (50 ml) was added WSC hydrochloride (10.5 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and dilute hydrochloric acid. The organic layer was separated, washed with saturated and saturated brine, dried (MgSO4) and concentrated. To the residue were added p-toluenesulfonic acid (951 mg) and toluene (150 ml), and the mixture was refluxed for 30 minutes. The mixture was cooled, and to the reaction solution was added ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. The resulting crystals were filtered, washed with ether and dried to give colorless crystals of the title compound (7.37 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].I[CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[F:28][C:23]([F:29])([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 31.1 %

Procedure:
Using 0.30 g of (4-(trifluoromethoxy)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.06 g of sodium hydride (60% in oil), and 0.38 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(3,3,4,4,4-pentafluorobutyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (10)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:14](=O)[CH2:15]Br>>[CH3:10][C:11]1[CH:12]=[C:13]([C:14]2[N:1]=[C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]3[CH:15]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(C(=O)CBr)cc1C
Reactant: COc1ccnc(N)c1
Product: COc1ccn2cc(-c3ccc(C)c(C)c3)nc2c1

Procedure:
The title compound, pale yellow solid, m.p. 175° C. and MS: m/e=252.2 (M+), was prepared in accordance with the general method of example 1 from 2-amino-4-methoxy-pyridine and 3,4-dimethyl-phenacylbromide.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:20])[C:10]([C:15]([O:17]CC)=[O:16])=[CH:11][NH:12]3)=[C:7]([CH3:21])[C:6]=2[F:22])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:20])[C:10]([C:15]([OH:17])=[O:16])=[CH:11][NH:12]3)=[C:7]([CH3:21])[C:6]=2[F:22])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCC3)c(F)c(C)c2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(F)c(N2CCC2)nc2[nH]cc(C(=O)O)c(=O)c12
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of Example 5B (0.58 mmol) in THF (10 mL) was treated with 1M LiOH (30 mL), stirred for 12 hours, heated at 70° C. for 8 hours then cooled, stirred at ambient temperature for 2 days, heated at 70° C. for 8 hours then cooled, treated with 10% citric acid, and filtered.
Reaction SMILES: C(OC(N[C@@H](C(O)=O)CO)=O)(C)(C)C.[ClH:15].[NH2:16][C@@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:18]1.C(OC(N[C@H](C(O)=O)CO)=O)(C)(C)C>>[ClH:15].[NH2:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:18]1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Product: N[C@@H]1COc2ccccc2NC1=O

Procedure:
(R)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt was prepared from N-t-butyloxycarbonyl-D-serine by the procedures described in Itoh, et al., Chem. Pharm. Bull. 1986, 34, 1128–1147 for the preparation of (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt from N-t-butyloxycarbonyl-L-serine.
Reaction SMILES: [Mg].II.[CH2:4]1[O:15][CH:7]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[O:6][CH2:5]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:27][O:26][C:24]1[CH:23]=[C:20]([CH:19]=[C:18]([O:17][CH3:16])[CH:25]=1)[CH:21]([OH:22])[C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[O:15][CH2:4][CH2:5][O:6]2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc(C3OCCO3)cc2)c1
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a suspension of magnesium (0.9 g, 37 millimol) in tetrahydorfuran (30 ml) was added a small amount of iodine, and thereto was added a solution of p-bromobenzaldehyde ethylene acetal (8.0 g, 33 millimol) in tetrahydorfuran (10 ml) under nitrogen atmosphere. After a while, heat was generated, and magnesium was dissolved. After stirring for 1.5 hours as it was, the mixture was cooled with ice, and thereto was added at a breath 3,5-dimethoxybenzaldehyde (5 g, 30 millimol). After stirring for 2 hours as it was, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (8.8 g, 27.7 millimol, 92%).
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[S:29][C:30]([CH:33]=[O:34])=[CH:31][N:32]=1)=[O:22])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[S:29][C:30]([CH2:33][OH:34])=[CH:31][N:32]=1)=[O:22])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1c1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1c1ncc(CO)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 81 (6.4 mg, 0.012 mmol), EtOH/H2O (4:1) (3 mL), sodium borohydride (4.2 mg, 0.111 mmol) and stirring at room temp for 2 h, the title compound is isolated (quantitative yield) that is used crude in the next step. LC/MS (Condition A): ret, T=1.54 min, (2M+Na) 1087.51.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][O:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][O:31][CH2:30][CH2:29][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1cc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of tert-butyl 2-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate (400 mg, 1.39 mmol, prepared according to example 7, steps 1-2) and potassium carbonate (423 mg, 3.06 mmol) in DMF (4 mL) was stirred for 30 min at RT. After cooling to 0-5° C., 1-bromo-2-methoxyethane (157 μL, 1.67 mmol) was added. The ice bath was removed after 5 min and the reaction mixture was stirred at RT for 16 h. Another two equivalents of both potassium carbonate (618 mg, 4.45 mmol) and 1-bromo-2-methoxyethane (262 μL, 2.78 mmol) were added at RT and the reaction mixture was heated to 60° C. and stirred for 20 h. The reaction mixture was poured into ethyl acetate (50 mL) and the organic phase was washed with water (3×20 mL) and brine (25 mL). The aqueous layers were back-extracted with ethyl acetate (50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless solid (359 mg, 1.04 mmol, 74.7%). MS: M=346.2 (M+H)+
Reaction SMILES: C[Si](C)(C)[O:3][C:4](O)(O)[CH2:5][CH2:6]O[Si](C)(C)C.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][C:22](=[O:27])[CH2:21][CH2:20]2.C(OCC)C>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH2:4]1[O:3][C:22]2([CH2:21][CH2:20][C:19]3[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=3)[CH2:23]2)[O:27][CH:5]1[CH3:6]
Reactant: C[Si](C)(C)OCCC(O)(O)O[Si](C)(C)C
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1COC2(CCc3cc(Br)ccc3C2)O1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
1,3-bis-trimethylsilyloxy propandiol (38.5 grams, 175 mmol, prepared from 1,3-propanediol, triethylamine, and chlorotrimethyl silane in tetrahydrofuran) was slowly added to a stirring solution of trimethylsilyl trifluoromethanesulfonate (0.5 mL, 2.6 mmol) in methylene chloride (100 mL, -70° C.), while keeping the reaction temperature between -70° and -60° C. The solution was allowed to stir for 10 minutes at -70° C. A solution of 6-bromo-2-tetralone (35.5 grams, 158 mmol) in methylene chloride (100 mL) was slowly added over a 10 minute period. The resulting reaction mixture was allowed to warm slowly to 15° C. over 15 hours, after which time thin layer chromatography (55:45 diethyl ether:hexanes) and high pressure liquid chromatography showed complete consumption of the starting tetralone. The reaction was quenched with saturated sodium bicarbonate (200 mL) and the layers were separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride solution was washed with brine (200 mL), dried with sodium sulfate, and concentrated at reduced pressure to a gold colored residue. This was filtered through 300 grams of silica gel and eluted with 3:1 hexanes/ethyl acetate. The filtrate was concentrated at reduced pressure and the product recrystallized from hexanes to obtain 33.5 grams (75% yield) of 6-bromo-2-tetralone propylene ketal as white crystals (NMR, MS). Calculated for C13H15O2Br: C, 55.14; H, 5.34. Found C, 55.05; H, 5.52.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:20]=[C:19]([OH:21])[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1>CS(C)=O>[F:7][C:8]1[CH:20]=[C:19]([O:21][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:11]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2ccc([N+](=O)[O-])nc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Potassium carbonate (0.220 g, 1.59 mmol) was added to a stirred solution of 2,5-difluoro-4-hydroxy-N-(methylsulfonyl)benzamide (Preparation 34, 0.200 g, 0.796 mmol) and 5-bromo-2-nitropyridine (0.170 g, 0.836 mmol) in DMSO (2.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then at 60° C. for 24 hours. The reaction mixture was partitioned between EtOAc and 2M aqueous HCl ensuring the water layer was acidic. The organic layer was separated and washed further with citric acid, water and brine, then dried over magnesium sulfate, filtered, evaporated in vacuo and triturated in diethyl ether to yield the title compound (0.180 g, 60%):
Reaction SMILES: C([O:8][C:9]1[C:30]([O:31][CH3:32])=[CH:29][C:12]2[N:13]=[N:14][C:15]3[C:20]([C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:16]=31)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[C:30]([O:31][CH3:32])=[CH:29][C:12]2[N:13]=[N:14][C:15]3[C:20]([C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:16]=31
Reactant: COc1cc2ccc3c4cc(OCc5ccccc5)c(OC)cc4nnc3c2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2nnc3c4cc(OC)c(OC)cc4ccc3c2cc1O
Yield: 76 %

Procedure:
9-Benzyloxy-2,3,8-trimethoxydibenzo[c,h]cinnoline, 42, (5 mg, 0.012 mmol) was hydrogenated overnight in ethyl acetate (25 mL) at 26 lb./sq. in. using 10% palladium on carbon (1.5 mg). The solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 mL×3). Concentration of the ethyl acetate solution in vacuo gave the crude product. Chromatography using a 50:45:5 mixture of hexanes:ethyl acetate:methanol as eluting solvent gave compound 34 (3 mg) in 76% yield; 1H NMR (DMSO-d6) δ4.00 (3H, s), 4.10 (3H, s), 4.12 (3H, s), 7.66 (1H, s), 8.02 (2H, s), 8.21 (1H, d, J=8.4), 8.38 (1H, d, J=8.9), 8.96 (1H, s); 13C NMR δ55.9, 56.4, 103.1, 103.8, 108.5, 109.1, 117.4, 117.8, 118.0, 125.7, 128.1, 131.3, 140.4, 143.8, 150.5, 150.7, 151.3, 152.4; HRMS (EI) calcd for C19H16N2O4 m/z 336.111; found: 336.1109.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)[CH:22]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3cc(F)cc(-c4ccccc4C#N)c3)cnc2c1F
Yield: 51 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in WO 02/074773) as described in Example 1 to give 3′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as an off-white solid (200 mg, 51%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.13 (1H, s), 7.24 (1H, s), 7.27-7.29 (1H, m), 7.34-7.37 (1H, m), 7.51-7.58 (3H, m), 7.69-7.73 (1H, m), 7.76 (1H, s), 7.84 (1H, dd, J 8 and 1), 8.39 (1H, d, J 7); m/z (ES+) 390 [MH+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])=[O:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:11][CH2:10][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH2:6][CH2:7][O:8][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: O=C(N(CCO)CCO)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide (2.01 g, 10 mmol) of in THF (12 mL) was cooled to ice bath temperature. Triethylamine (20.1 mol, 2.3 g=1.56 mol) was added between 5-10° C. Methanesulphonyl chloride was then added to the reaction mixture at a temperature between 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. and then allowed to warm to ambient temperature overnight. The resulting precipitated solids were filtered off and the reaction flask was rinsed with THF (2×10 mL portions), then filtered. The filtrate was concentrated to yield the title compound as a clear thick oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25](O)=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.ClC(OCC(C)C)=O.[N+:76](=[CH2:78])=[N-:77]>>[C:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:25](=[O:26])[CH:78]=[N+:76]=[N-:77])=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)C=[N+]=[N-])cc1

Procedure:
In a manner analogous to that described in Example 19(i), N-(benzyloxycarbonyl)-3-(4-tert.butoxyphenyl)-L-alanine (prepared from 7.45 g of the dicyclohexylammonium salt) was treated with isobutyl chloroformate followed by reaction with diazomethane to give 3.58 g of benzyl [2-(4-tert.butoxyphenyl)-1(S)-(2-diazoacetyl)ethyl]carbamate as a yellow solid of melting point 80°-82° C.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([OH:27])=O)=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:34][NH:35][C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([N:41]3[CH2:42][CH2:43][CH:38]([C:36]([NH:35][CH3:34])=[O:37])[CH2:39][CH2:40]3)=[O:27])=[C:17]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CNC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Product: CNC(=O)C1CCN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
2-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (35 mg) was reacted with N-methylpiperidine-4-carboxamide via General Procedure F followed by Boc deprotection via General Procedure E and purified via reverse phase HPLC to give 10.3 mg 122 as a white solid. MS (Q1) 481.2 (M)+.