Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:12])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH2:23][CH2:24]Br)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[Mg].C1COCC1>CCOCC.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)OCc1ccccc1
Reactant: BrCCc1cccc2ccccc12
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Temperature: 4 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.BrCC=CC(OC(=O)C)CCCCC.C([O:32][CH:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])/[CH:34]=[CH:35]/[CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[C:38](=[O:40])[CH3:39])(=O)C>>[OH:32][CH:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:34]=[CH:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:38](=[O:40])[CH3:39]
Reactant: CCCCCC(/C=C/CN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCCC(C=CCBr)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCC(O)C=CCN(CCCCCCC(=O)O)C(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 2 except that, in Step B, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonene (Example H). The product of Step B is ethyl 7-[N-(4-acetoxy-(E)-2-nonenyl)acetamido]-heptanoate. The subsequent step yields 7-[N-(4-hydroxy-2-noneneyl)acetamido]heptanoic acid (C).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[S:16][C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:20][N:21]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.ClCl>[C:12]([C:7]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[S:16]([C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:20][N:21]=1)=[O:36])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1Sc1nnc(-c2ccccn2)o1
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1S(=O)c1nnc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a solution of 2-(2,6-ditertbutyl-4-hydroxyphenyl)thio-5-(2-pyridyl)-1,3,4-oxadiazole (1.25 g, 0.00325 mol) in CH2Cl2 (30 ml) at rt was added dropwise a solution of mCPBA (1.04 g, 0.0039 mol, 65% pure) in CH2 Cl2 (25 ml) over 30 min. The reaction was stirred at rt for an additional 1.5 h and treated with sat aq. Na2S2O3 (5 ml) and sat. aq. Na2CO3 (20 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×25 ml), dried (MgSO4) and the solvent evaporated in vacuo. Chromatography on silica gel using ethyl acetate/hexanes (1/1) as the eluant gave 2-(2,6-di-tertbutyl-4-hydroxyphenyl)sulfinyl-5-(2-pyridyl)-1,3,4-oxadiazole (98) as a white solid (0.900 g, 70%); m.p. 172.5°-173.0° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34]([OH:36])=[O:35])=[N:3]1.[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[CH2:42][CH2:43][CH2:44]O.OCCOC1C=CC(C=O)=CC=1C>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34]([O:36][CH2:44][CH2:43][CH2:42][CH:38]2[O:39][CH2:40][CH2:41][O:37]2)=[O:35])=[N:3]1
Reactant: Cn1nc(C(=O)O)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: OCCCC1OCCO1
Agent: Cc1cc(C=O)ccc1OCCO
Product: Cn1nc(C(=O)OCCCC2OCCO2)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1

Procedure:
The title compound was prepared as described in Example 1 Step 10 with 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)-1H-pyrazole-3-carboxylic acid and 3-(1,3-dioxolan-2-yl)propan-1-ol replacing 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-benzoic acid and 4-(2-hydroxyethoxy)-3-methylbenzaldehyde respectively.
Reaction SMILES: C([NH:11][C:12](=[N:45]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.[ClH:56]>[Pd].CC(O)=O>[ClH:56].[C:21]1([CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]([NH:18][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:45])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(R)-N-(1-phenylethyl)arginine amide (0.6 g; 0.8 mmol; from step (d) above), 10% Pd/C (w/w; 200 mg), HOAc (25 mL), overnight reaction time. The crude acetate salt was converted to the hydrochloride to give 0.4 g (99%) of title compound as a solid.
Reaction SMILES: C=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[O:14]=[O+][O-].CCOC(C)=O>C(Cl)Cl.CO>[O:14]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1
Reactant: O=[O+][O-]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(=O)C1
Yield: 70 %

Procedure:
To a solution of tert-butyl (3-methylidenecyclobutyl)carbamate (165 g, 0.91 mol) in CH2Cl2 (1000 mL) and MeOH (1000 mL) was bubbled O3 at −78° C. until the solution turned blue. TLC (petroleum ether:EtOAc=10:1) showed that the starting material was consumed completely. Nitrogen gas was then bubbled through the reaction to remove excess O3, and then the mixture was quenched with Me2S (200 mL) and stirred for an hour. The solution was concentrated to give a residue, which was washed with sat. NaHCO3 and water to yield the title compound (118 g, 70% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:18])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cc(F)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2cc(F)ccc2c1

Procedure:
6-Fluoro-2-naphthoic acid (228 mg, 1.2 mmol) was dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (0.1 mL), and in an ice bath oxalic chloride (228 mg, 1.8 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was moved to react at room temperature for 3 hours, and concentrated under reduce pressure to obtain a white solid, i.e. 6-fluoro-2-naphthoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]=[C:23]=[O:24])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:23]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=[C:2]3[CH3:1])=[O:24])=[CH:19][CH:20]=1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2c(C)n1
Temperature: 87.5 °C
Reaction time: 3 h

Procedure:
The product from Example 178A(375 mg, 2.2 mmol) in toluene (7 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.31 mL, 2.2 mmol). After stirring at 85-90° C. for 3 hours, the mixture was cooled to room temperature and filtered. The filter cake was treated with methanolic HCl to provide the title compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.17 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.45-7.60 (m, 4H), 7.32 (d, 2H, J=8.1 Hz), 7.06 (t, 1H, 5.7 Hz), 4.34 (d, 2H, 5.8 Hz), 2.84 (s, 3H), 2.75 (s, 3H); MS (ESI+) m/z 383/385 (M+H, 79Br/81Br).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=O)[NH:4][N:3]=1.Cl.[F:19][C:20]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][NH:22][CH2:21]1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([N:22]2[CH2:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=3)([F:19])[CH2:23]2)=[O:13])[NH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]nc(C)c1C
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CC(F)(c3ccc(C#N)cc3)C2)cc1-c1[nH]nc(C)c1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) were used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively. m/z (ES+) 389 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.45-12.26 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.65 (d, J=7.2 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.98-4.42 (m, 4H), 2.25 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([NH:12][CH:13]1[CH:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>[Pd].C(OCC)(=O)C.CO>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CNCCC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Ammonium formate (419 mg) and 10% Pd/C (84 mg) were added to an ethyl acetate/MeOH (4 ml/4 ml) solution containing benzyl 3-((tert-butoxycarbonyl)amino)-4-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (419 mg) obtained in the 1st step, followed by stirring at 60° C. for 1 hour. The reaction solution was cooled to room temperature and insoluble matter was removed through Celite. Filter cake was washed with ethyl acetate and water. Subsequently, the filtrate was mixed with wash liquid and sodium chloride was added to the mixture. The organic layers were separated and washed with saturated saline. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A white solid of tert-butyl (4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (280 mg) was thus obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][C@H:8]([NH2:12])[C:9](O)=[O:10])[C:4]([N+:13]([O-:15])=O)=[CH:3][CH:2]=1>CO.O.Cl.[Pt]>[NH2:12][C@H:8]1[CH2:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:13]([OH:15])[C:9]1=[O:10]
Reactant: N[C@@H](Cc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@H]1Cc2ccccc2N(O)C1=O
Reaction time: 1 h
Yield: 58.1 %

Procedure:
L-2-Nitrophenylalanine (C11) (419.6 mg, 2.0 mmol) was dissolved in methanol (23.8 mL) and water (240 μL). Concentrated aqueous HCl (2-4 drops) was added to aid solubility. Platinum on carbon (42 mg) was added and the reaction was hydrogenated on a Parr shaker at 10 psi for 1 hour, whereupon the reaction was filtered through Celite. The catalyst was washed with a 1 N solution of ammonium hydroxide in methanol and then with methanol. The filtrate was concentrated to provide a crude product, which was subsequently dry packed with a minimum amount of silica, using a methanol/dichloromethane solution to dissolve the material. Purification using silica gel chromatography (Gradient: 0% to 20% methanol (containing 1% ammonium hydroxide) in dichloromethane) provided Example 4 as a solid (207 mg, 58%). APCI m/z 179.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.88 (dd, J=14, 15 Hz, 1H), 3.09 (dd, J=15.3, 6.2 Hz, 1H), 3.67 (dd, J=13.6, 6.1 Hz, 1H,) 7.06 (ddd, J=7.2, 7.2, 1.7 Hz, 1H), 7.23 (br d, J=7.5 Hz, 1H), 7.27-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Yield: 36.9 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-benzimidazole-2-carboxamide (1.50 g, 2.78 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.42 g, 5.56 mmol,), sodium carbonate (1.17 g, 11.12 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) at 80° C. for 18 hours. Additional 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.90 mmol,), sodium carbonate (0.508 g, 4.80 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) was added and the mixture was heated for another 24 hours. Additional tetrakis triphenylphosphine palladium (0) (0.32 g, 0.27 mmol) was added and the mixture was heated for another 24 hours after which time all starting material was consumed. The solvent was removed in vacuo and the residue was triturated with water (30 mL) for 3 hours. The solid was collected by filtration and dried in vacuo. The crude product was suspended in acetone (60 mL) and water (8 mL) and reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.52 mmol) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solvent was removed an the residue was partitioned between dichloromethane (20 mL) and water (40 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (0.48 g, 31%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.19 (s, 1H), 9.64 (d, 1H), 8.52 (dd, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H), 7.75-7.82 (m, 2H), 7.47 (t, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.93 (dd, 1H), 4.25 (s, 3H), 4.04 (s, 3H), 1.86 (s, 3H); RP-HPLC (Conditions g) Rt 12.21 min.; MS: MH+ 468.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19](O)=[O:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:68])[C@@H:65]([OH:67])[CH3:66])[CH2:60][CH2:59]1>ClCCl>[OH:67][C@@H:65]([CH3:66])[C:64]([N:61]1[CH2:62][CH2:63][CH:58]([NH:57][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)[C:11]=3[NH:18][CH:17]=2)=[O:20])[CH2:59][CH2:60]1)=[O:68]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: C[C@H](O)C(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid from example A81 (43 mg; 0.12 mmol) in dichloromethane (2 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 mmol), triethylamine (0.24 mmol) and 1-hydroxybenzotriazole (0.12 mmol). The suspension is stirred for 20 min at ambient temperature and then (S)-1-(4-amino-piperidin-1-yl)-2-hydroxy-propan-1-one hydrochloride from example A190 (0.16 mmol) is added. The reaction mixture is stirred overnight at ambient temperature. The volatiles are evaporated and the crude is distributed between ethyl acetate and aqueous phosphate buffer (1M, pH=7). The organic phase is separated, washed with aqueous phosphate buffer and evaporated to dryness. The obtained crude product is purified by preparative HPLC yielding 38 mg of the title compound as white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K+].[Br-]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:24]2)=[O:3])=[CH:6][CH:7]=1
Reactant: c1ccc(CCCCN2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Cl)cc1)N1CCN(CCCCc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 86%. White crystals, m.p. 230-232° C.; 1H NMR (DMSO-d6): δ11.43 (br, 1H), 7.51-7.43 (d-like m, 2H), 7.33-7.15 (m, 7H), 4.33-3.95 (br, max at 4.21 and 4.10 ppm; 2H), 3.72-3.36 (br m, 4H), 3.22-2.96 (br, max at 3.10 ppm, 4H), 2.62 (t, J=7.54 Hz, 2H), 1.84-1.69 (m, 2H), 1.69-1.54 (m, 2H) ppm; IR (KBr): ν 1736, 1720 (C═O) cm−1.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:15])=[C:10]([CH3:14])[NH:11]2)=[C:7]([CH3:16])[CH:6]=1)(=O)C>Cl>[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:15])=[C:10]([CH3:14])[NH:11]2)=[C:7]([CH3:16])[CH:6]=1
Reactant: CC(=O)Nc1cc(C)c2c(C)c(C)[nH]c2c1
Agent: Cl
Product: Cc1[nH]c2cc(N)cc(C)c2c1C
Reaction time: 3 h
Yield: 118.4 %

Procedure:
A suspension of 3.67 g of 6-acetamido-2,3,4-trimethylindole in 15 ml of hydrochloric acid (12N) is brought to 100° C. for 3 hours. The mixture is cooled and the precipitate is drained and washed successively with 3 ml of hydrochloric acid (12N) and 20 ml of absolute ethanol. 3.5 g of a white precipitate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1C
Yield: 32.4 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.74 mmol) to give the title compound (0.055 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:44])([C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:28]>>[CH3:24][O:25][C:26](=[O:45])[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:34]=1)([CH3:44])[CH3:28]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COC(=O)C(C)(C)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)C(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.215 mmol) and 2-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionic acid methyl ester (Stage 229.1.1, 0.279 mmol) to give the title compound as a brown solid. (HPLC: tR 2.28 min (Method A); M+H=471 MS-ES)
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[F:22][C:23]([F:28])([F:27])[C:24](=[O:26])[CH3:25]>O1CCCC1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])([CH3:25])[C:16]#[C:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])=[CH:10][CH:11]=1
Reactant: C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of the 4-(1-pyrrolidinylsulfonyl)phenylacetylene (1.3 g) in anhydrous tetrahydrofuran (60 mL) cooled to -78° C. under a nitrogen atmosphere was added n-butyllithium (2.43 mL of a 2.5M solution in hexanes, 6.09 mmol). The anion was generated over a ten minute period at -78° C. To the anion was added a cooled (0° C.) solution of trifluoroacetone (644 mL) in anhydrous tetrahydrrofuran (10 mL) over a 20 second period. The reaction was stirred at -78° C. for five minutes before the ice bath was removed. After an additional five minutes, the reaction was quenched with 2N HCl (50 mL). The product was extracted into diethyl ether. The combined organic extracts were dried, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography (1:3 acetone: hexanes) followed by recrystallization (1:1 diethyl ether:hexanes) to yield the title compound as a white solid (1.38 g); mp 167.8°-168.7° C.; MS: m/z=348(M+1); NMR (CDCl3): 1.74 (s,3), 1.71-1.78 (m,4), 3.15 (s,1), 3.21-3.26.(m,4), 7.56-7.59 (m,2), 7.77-7.80 (m,2). Analysis for C15H16F3NO3S: Calculated: C, 51.87; H, 4.64; N, 4.03; Found: C, 51.80; H, 4.67; N, 3.88.