Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[Br-].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]2)#[N:8].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=O)[C:58]([O:60][CH3:61])=[O:59])=[CH:53][CH:52]=2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1CCN2C(=NCCC2)CC1>CO>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([O:50][C:51]2[CH:52]=[CH:53][C:54]([CH:57]([CH2:18][C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([C:7]#[N:8])=[CH:17][CH:16]=4)[C:58]([O:60][CH3:61])=[O:59])=[CH:55][CH:56]=2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: N#Cc1ccc2[nH]c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc2cc(C#N)ccc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol were dissolved 5.0 g of (5-cyano-2-indolyl)methyltriphenylphosphonium bromide and 3.6 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. With stirring at room temperature, 1.07 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the thus prepared solution, and the mixture was stirred at the same temperature for 2 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an eluant, thereby obtaining methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-indolyl)acrylate as a mixture of E and Z forms. The thus obtained compound was dissolved in a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol, and the resulting solution was mixed with 5.0 g of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an eluant. In this way, 3.5 g of the title compound was obtained in a viscous and oily form.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(Nc2c(C#N)cnc3sc(CCCCO)cc23)cc(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3sc(CCCCBr)cc23)cc(OC)c1OC

Procedure:
To a solution of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464 mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine (314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by flash column chromatography eluting with a gradient of 9:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate to provide crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile. The crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile is heated 70° C. in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67 mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a yellow oil; 1H NMR (DMSO-d6) δ 1.49 (quintet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J=7 Hz, 2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H), 9.46 (s, 1H); MS 483.5 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([OH:42])=O)[CH:36]=1.[NH2:43][C@H:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=2)[CH2:46][CH2:45]1>ClCCl>[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([NH:43][C@H:44]2[C:52]3[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=3)[CH2:46][CH2:45]2)=[O:42])[CH:36]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: Cc1cc(C(=O)O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(C)on1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
HATU (4.4 g, 11.7 mmol, 1.5 eq) and DIPEA (3.0 ml, 15.6 mmol, 2 eq) were added to an ice-cooled solution of 5-methylisoxazole-3-carboxylic acid (990 mg, 7.8 mmol, 1 eq) in dichloromethane (80 ml), and stirring was carried out for 30 min. (R)-Methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (7.8 mmol, 1 eq) was dissolved in dichloromethane (20 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (250 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloro-methane), the desired product was obtained in the form of a yellowish solid. Yield: 68% (1.6 g, 5.3 mmol).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH2:10][OH:11])C)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:6][NH:7][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH2:10][OH:11]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CO)Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H](CO)Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 3 h

Procedure:
To the alcohol from step 1 (26 mg) was added 4.0 M HCl in dioxane (0.5 mL). After 3 h, the dioxane was removed to give 22 mg of product. 1H NMR (400 MHz, DMSO-d6) δ 2.57-2.63 (m, 3H), 2.80 (dd, J=13.6, 10.4 Hz, 1H), 3.02 (dd, J=13.6, 4.8 Hz, 1H), 3.23-3.43 (m, 2H), 3.55-3.62 (m, 1H), 5.43 (br s, 1H), 6.96-7.16 (m, 9H), 7.28-7.43 (m, 4H), 8.70 (br s, 1H), 8.91 (br s, 1H); LCMS; 100%, ESI+, Calcd: 349.43 m/z. Found 350.9 (M+1) m/z.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[Br:12][C:13]1[C:14]([Cl:20])=[C:15](F)[CH:16]=[CH:17][CH:18]=1>>[ClH:20].[Br:12][C:13]1[C:14]([Cl:20])=[C:15]([O:11][CH:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: OC1CNCCc2sccc21
Reactant: Fc1cccc(Br)c1Cl
Product: Cl
Product: Clc1c(Br)cccc1OC1CNCCc2sccc21

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 29) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]4[CH:32]=N[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12]C(F)(F)F)[CH:11]=2)=[CH:3][CH:2]=1.CN1C=C(C2C=CN=CC=2)C(C2C=CC(O)=CC=2)=N1.[Cl:54][C:55]1C2C(=CC=CC=2)N=C(CO)C=1>>[Cl:54][C:55]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17]([C:8]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:11][N:10]([CH3:12])[N:9]=3)=[CH:34][CH:33]=2)[CH:32]=1
Reactant: OCc1cc(Cl)c2ccccc2n1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and (4-Chloro-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.6 Hz, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.73 (m, 2H), 7.60 (t, J=7.1 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=9.1, Hz, 2H), 7.12 (d, J=6.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 3.90 (s, 3H); MS: (M+H m/z=427.1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl.NO.C(=O)([O-])[O-:14].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:9])=[O:14])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(N)nc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(N)nc1
Yield: 24.1 %

Procedure:
A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-7] (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 ml) and ethanol (21 ml) was heated under reflux conditions for 6 h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (4×100 ml). The combined organic layers were washed with brine (150 ml), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH4OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22%) as an off-white solid. MS (EI) 152.1 [(M)+]; mp 300° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClC(Cl)(Cl)Cl>[Cl:20][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[CH2:19][Br:1]
Reactant: Cc1ccc(C(C)(C)C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(Cl)c1

Procedure:
1.75 g (9.85 mmol) of N-bromosuccinimide and 10.8 mg (0.006 mmol) of 2,2′-azobis-2-methylpropanenitrile are added to a solution of 2 g (10.95 mmol) of 4-tert-butyl-2-chloro-1-methylbenzene in 10 ml of tetrachloromethane, and the mixtures is stirred under reflux for 4 hours. After cooling, the mixture is concentrated. The residue is purified by flash chromatography on silica gel (mobile phase, cyclohexane). 2.1 g (38% of theory) of the title compound are obtained with a purity of 52%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Yield: 90.8 %

Procedure:
A solution of (S)-2-[3-(2-Benzenesulfonylphenyl)ureido]-3-(4-nitrophenyl) propionic acid methyl ester (3.64 g, 7.53 mmol) in ethanol (70 ml) was hydrogenated in the presence of a catalytic amount of Raney-Ni®. The catalyst was removed by filtration through Celite® and the solvent was eliminated under reduced pressure. The crude product was dissolved in dichloromethane (100 ml) and washed with saturated aqueous NaHCO3 (3×50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to yield the title compound (3.1 g, 91%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH:22]=[O:23].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][OH:23]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-formyl-4-oxoazetidin-3-yl)carbamate (218 g, 0.546 mol) in a mixture of DCM:MeOH (4:1, 2.25 L) at 0° C. was added sodium borohydride (41.3 g, 1.09 mol), portion-wise. The resulting mixture was stirred at 0° C. for 2 h, whereupon it was quenched with cold water (1 L) for 30 min and the layers were separated. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (208 g, 95%) as an off white solid. LCMS: m/z=401.2 (M+1); 1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.21-7.18 (m, 1H), 6.46-6.49 (m, 2H), 5.82 (bd, J=9.6 Hz, 1H), 5.18-5.08 (m, 3H), 4.45 (d, J=14.4 Hz, 1H), 4.28 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.76-3.72 (m, 1H), 3.63-3.52 (m, 2H), 1.87 (dd, J=9.6, 4.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCOc1cccc(-c2ccnc(Cl)n2)c1
Product: CCCCOc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 46 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 364. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.7 (d, 2H) 5.49 (br s, 1H) 4.0 (t, 2H) 3.7 (d, 2H) 2.85 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[CH:10]=1
Reactant: COCCn1c(C)nc2cc(C(=O)OC)cc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: CO
Product: COCCn1c(C)nc2cc(C(=O)OC)cc(O)c21
Reaction time: 5 h
Yield: 92.4 %

Procedure:
A mixture of methyl 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylate (9.21 g, 26.0 mmol, Step 6) and 10% palladium on carbon (500 mg) in methanol (150 mL) was stirred under hydrogen gas (4 atm) for 5 hours. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was suspended in diisopropyl ether (150 mL), and the precipitate was collected by filtration to afford the title compound as a gray solid (6.35 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22](=[N:41][OH:42])[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:42][N:41]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)=[CH:10][C:9]=1[C:17]([F:18])([F:20])[F:19]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CC(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 24 (168 mg; 0.6 mmol) and Intermediate 5 (174 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification with MD-Autoprep afforded the title compound as a yellow oil. LC/MS (method B): 550.1 (M+H)+. HPLC (Method A) Rt 4.95 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH:15]([C:22](=[O:38])[N:23]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])(=[O:13])=[O:12].[OH-].[Na+]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH:15]([C:22](=[O:38])[N:23]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:13])=[O:12]
Reactant: CCCCCN(CC(=O)N1CCCCC1)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(CC(=O)N1CCCCC1)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
To a solution of methyl 5-(2-naphthylsulfonyl)-4-(N-pentyl-N-piperidinocarbonylmethylcarbamoyl)pentanoate (0.18 g) in methanol (3 ml) was added a 1N sodium hydroxide solution (0.32 ml). After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was recrystallized from isopropyl ether to give 0.08 g of 5-(2-naphthylsulfonyl)-4-(N-pentyl-N-piperidinocarbonylmethylcarbamoyl)pentanoic acid.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CO>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16]
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: O
Solvent: CO
Product: CC(C(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 50 °C
Yield: 80 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is dissolved in 50 ml. of methanol and 5 ml. of N-hydrochloric acid is added. The mixture is heated to 50°C. for 30 minutes then cooled and added to water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 80% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide which is recrystallized from methanol, m.p. 158°-159°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[O:53][C:52]([C:54](O)=[O:55])=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:52]2[O:53][C:49]([CH3:48])=[CH:50][CH:51]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1ccc(C(=O)O)o1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)o1
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methyl-2-furoic acid as starting materials in 46% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[CH3:10].N#N.[CH3:13][CH2:14][OH:15].[Li][CH:17](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:9][C:4]1[C:3]([CH3:10])=[C:2]([CH2:13][C@H:14]([OH:15])[CH3:17])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CCO
Reactant: Cc1c(Br)ccc(F)c1F
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1c(C[C@@H](C)O)ccc(F)c1F
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of 1-bromo-3,4-difluoro-2-methylbenzene (4.14 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7) to give (2R)-1-(3,4-difluoro-2-methylphenyl)propan-2-ol (2.64 g, 71%) as pale oil. 1H NMR (300 MHz, CDCl3): δ 6.85-7.26 (m, 2H), 3.98 (m, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.45 (d, J=3.75 Hz, 1H), 1.26 (d, J=6.21 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[N:6]=1.[CH:14]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][C:2]2[O:3][CH:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:7])[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1=NC(=O)C(c2ccccc2)O1
Reactant: NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)OC1c1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-phenyl-1,3-oxazol-4(5H)-one and cycloheptylamine according to Method G+H.