Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:10]=2)=[CH:7][C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]1=2.[Cl:30]C1N=C(C2SC3C(Cl)=CC=CC=3C=2)C=CN=1.NCCCN1CCN(C)CC1>>[Cl:30][C:29]1[C:5]2[S:4][C:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[N:10]=3)=[CH:7][C:6]=2[CH:26]=[CH:27][CH:28]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: Clc1nccc(-c2cc3cccc(Cl)c3s2)n1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: CN1CCN(CCCNc2nccc(-c3cc4cccc(Cl)c4s3)n2)CC1

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2-chloro-4-(7-chlorobenzo[b]thiophen-2-yl)pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 402 (35Cl) and 404 (37Cl) [M+H].
Reaction SMILES: C([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH2:17][N:18]2[C:24](=[O:25])[CH:23]([NH:26][C:27](=[O:37])[C:28]3[CH:33]=[C:32]([Cl:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=3)[CH2:22][CH2:21][C:20](=[O:38])[N:19]2[CH2:39][CH2:40][CH3:41])=[O:16])[CH2:12][C:11](=[O:42])[O:10]1)C1C=CC=CC=1.[CH2:43]([N:50]1[C:56](=[O:57])[CH2:55][CH2:54][CH:53]([NH:58][C:59]([C:61]2[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:64]=[CH:63][N:62]=2)=[O:60])[C:52](=[O:71])[N:51]1[CH2:72][C:73]([NH:75][CH:76]([CH:81]=[O:82])[CH2:77][C:78]([OH:80])=[O:79])=[O:74])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[Cl:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([Cl:34])[C:31]=1[OH:35])[C:27]([NH:26][CH:23]1[C:24](=[O:25])[N:18]([CH2:17][C:15]([NH:14][CH:13]([CH:9]=[O:8])[CH2:12][C:11]([OH:42])=[O:10])=[O:16])[N:19]([CH2:39][CH2:40][CH3:41])[C:20](=[O:38])[CH2:21][CH2:22]1)=[O:37].[CH2:43]([N:50]1[C:56](=[O:57])[CH2:55][CH2:54][CH:53]([NH:58][C:59]([C:61]2[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:64]=[CH:63][N:62]=2)=[O:60])[C:52](=[O:71])[N:51]1[CH2:72][C:73]([NH:75][CH:76]([CH:81]=[O:82])[CH2:77][C:78]([OH:80])=[O:79])=[O:74])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CCCN1C(=O)CCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: O=CC(CC(=O)O)NC(=O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Product: CCCN1C(=O)CCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC(C=O)CC(=O)O

Procedure:
3-{2-[6-(3,5-Dichloro-4-hydroxy-benzoylamino)-3,7-dioxo-2-propyl-[1,2]diazepan-1-yl]-acetylamino}-4-oxo-butyric acid (11c) was prepared from N-{2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-3,7-dioxo-1-propyl-[1,2]diazepan-4-yl}-3,5-dichloro-4-hydroxy-benzamide (10d, diastereomers) (30 mg, 0.05 mmol) by the method used to prepare 11a to afford 19 mg (74% yield) of the title compound. 1H-NMR (500 MHz, CDCl3/CD3OD=0.5 mL/3 drops) δ 0.90-0.95 (t, 3H), 1.60-1.70 (m, 2H), 2.00-2.10 (m, 1H), 2.25-2.36 (m, 1H), 2.48-2.82 (m, 3H), 2.98-3.10 (m, 1H), 3.20-3.35 (m, 1H), 3.90-4.50 (m, 4H), 4.95-5.08 (m, 1H), 7.62-7.72 (m, 2H). Analytical HPLC: 5.40 min. LC-MS (ES+): m/e=531, 533 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (364.5 mg, 1.5 mmol) and 3-chloroaniline (191 mg, 1.5 mmol) were dissolved in DCM (10 ml). To this solution was added sodium triacetoxyborohydride (413 mg, 1.95 mmol) and acetic acid (0.085 ml, 1.5 mmol), and the reaction stirred at room temperature overnight. The reaction mixture was washed with 2N NaOH (5 ml), saturated brine (5 ml), dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica eluting with DCM to give the title compound as a colourless oil (215 mg, 40%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([C:16](=O)[NH2:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=1)(=O)[NH2:2].S(Cl)(Cl)=O>N1C=CC=CC=1.C(Cl)Cl>[C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:6]2[CH:5]=[C:4]([C:1]#[N:2])[CH:9]=[CH:8][N:7]=2)[CH:15]=1)#[N:17]
Reactant: NC(=O)c1ccnc(-c2cc(C(N)=O)ccn2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1ccnc(-c2cc(C#N)ccn2)c1
Reaction time: 16 h

Procedure:
A suspension of 4.73 g (0.0195 mol) of 4,4'-dicarbamoyl-2,2'-bipyridine [J. Am. Chem. Soc. 80. 2745 (1958)] and 5.67 g (0.0476 mol) of thionyl chloride in 30 ml of pyridine is stirred for 16 hours at 100° . After cooling, the reaction mixture is diluted with 100 ml of methylene chloride, filtered and concentrated to dryness by evaporation. The residue is then chromatographed with methylene chloride over silica gel. In this manner, 4,4'-dicyano-2,2'-bipyridine is obtained in the form of white crystals having a melting point of 238°-240°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([NH:14][C:15]2[C:16]3[CH:29]=[C:28]([C:30]([NH:32][N:33]([CH3:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[S:27][C:17]=3[N:18](C(OC(C)(C)C)=O)[N:19]=2)=[O:13])=[CH:10][CH:9]=1>CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[C:16]3[CH:29]=[C:28]([C:30]([NH:32][N:33]([CH3:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[S:27][C:17]=3[NH:18][N:19]=2)=[O:13])=[CH:41][CH:42]=1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(Br)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(Br)cc3)n[nH]c2s1)c1ccccc1
Yield: 54.7 %

Procedure:
14.5 mg (105 μmol) of potassium carbonate are added to a solution of 0.04 g (70 μmol) of tert-butyl 3-(4-bromobenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 3 mL of methanol in a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 180° C. for 3 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 35° C. The residue is taken up in dichloromethane, and then in a mixture of 1 mL of methanol, 4 mL of water and 10 mL of ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with 3 mL of water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 35° C. The residue is taken up in diisopropyl ether, filtered on a sinter funnel, suction-filtered and then dried in an oven under vacuum (0.01 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a column of 15 g of silica gel (0.015-0.040 mm), eluting with a dichloromethane/methanol mixture (99/1 by volume, then 98/2 and finally 97/3) at a flow rate of 20 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 18 mg of 4-bromo-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a pale yellow solid melting at 172° C. LC-MS-DAD-ELSD: 468(−)/ . . . =(M−H)(−)/ . . . ; 470(+)/ . . . =(M+H)(+)/ . . . (1 Br present).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>C1COCC1>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:10]1([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of N-Boc-3-azetidinone (0.45 g, 2.64 mmol) in THF (5 mL) was slowly added a 0.5 M solution of 2-tert-butoxy-2-oxoethyl-zinc chloride in Et2O (10 mL, 5.0 mmol), and the reaction mixture was stirred for 5 h. The reaction was then quenched with sat. aq. NH4Cl (10 mL), and the aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with 5% aq. NaHCO3 (2×10 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl-2-(N-Boc-3-hydroxy-azetidin-3-yl)-acetate (MS m/e [M+H]+ calcd 288.2, found 287.7).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+]>CN(C=O)C>[CH3:15][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]1=2
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCCN2
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (192 mg, 1.0 mmol) in DMF (10 mL) was treated with potassium carbonate (345 mg, 2.5 eq), and iodomethane (0.08 mL, 1.25 eq) and stirred at room temperature for 30 min. Sodium hydride was added (1.5 eq) and the mixture stirred for 30 min, quenched with water and extracted with ether. The organic layers washed with brine and dried (MgSO4), filtered and concentrated to give 1-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (206 mg, 100%) as a yellow solid. MP: 52-54° C.; 1H-NMR (CDCl3) δ 7.97 (s, 1H), 7.89 (dd, J=2.6, 8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.42 (br s, 1H), 2.88-2.84 (m, 2H), 1.89-1.78 (m, 4H); LC/MS (ESI+): 207.04 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:34]#[N:35])=[CH:29][C:30]([F:33])=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:36][CH2:37][CH3:38])[N:15]4[N:39]=[C:40]([CH3:42])[N:41]=[C:14]34)[CH2:9][CH2:8]2)[O:3]1.[C:43]([BH3-])#N.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C[Mg]Br.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C.O1CCCC1>[F:33][C:30]1[CH:29]=[C:28]([C:34]#[N:35])[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[C:18](=[O:19])[N:13]([C@H:10]4[CH2:11][CH2:12][C@H:4]([O:5][CH:6]([CH3:7])[C:2]([OH:3])([CH3:1])[CH3:43])[CH2:8][CH2:9]4)[C:14]4[N:15]([N:39]=[C:40]([CH3:42])[N:41]=4)[C:16]=3[CH2:36][CH2:37][CH3:38])=[CH:22][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2nc(C)nn12
Reactant: [BH3-]C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Mg]Br
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 40 h

Procedure:
A mixture of 4′-{[4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile (1.3 g), sodium cyanoborohydride (0.71 g), boron trifluoride-diethyl ether complex (1.4 mL) and tetrahydrofuran (30 mL) was stirred at 40° C. for 40 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in acetonitrile (20 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.96 g) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.65 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 18%).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C=O)C>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-phenyl-1-propanol (0.545 g, 3.19 mmol, 99% ee, Aldrich Chemical Co.), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.748 g, 3.04 mmol), potassium carbonate (0.420 g, 3.04 mmol), sodium iodide (0.684 g, 4.56 mmol) and DMF (6.0 mL) at room temperature. After stirring at 100° C. for 3 hrs, TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature and poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (1:1=hexane: ethyl acetate with 1% isopropylamine) to afford the desired product (1.09 g, 94% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.46–7.35 (m, 6H), 7.27 (m, 2H), 6.98 (apparent d, 1H, J=7.6 Hz), 5.02 (apparent dd, 1H, J=4.4, 8.1 Hz), 3.18 (apparent dd, 2H, J=2.5, 12.5 Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.30–2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 381.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[CH:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[C:12]=2[Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccc(F)cc2)nc2n1CCC2
Temperature: -30 °C

Procedure:
To a -78° C. solution of 2-(4-fluorophenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole (2.0 g, 0.010 mole) in 60 ml of tetrahydrofuran (THF) is added 4.0 ml of 2.5M n-butyllithium. The solution is warmed to -30° C. for 20 minutes and then tributyltin chloride (3.3 g, 0.01 mole) in THF is added. The reaction is allowed to warm gradually to 20° C. and then is quenched with saturated ammonium chloride. Further workup and purification on silica as described in Example 6b yields the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.C([O-])(=O)C.[K+].Br[C:44]1[CH:45]=[C:46]([S:50]([NH:53][CH2:54][CH2:55][O:56][CH3:57])(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:44]2[CH:45]=[C:46]([S:50]([NH:53][CH2:54][CH2:55][O:56][CH3:57])(=[O:51])=[O:52])[CH:47]=[CH:48][CH:49]=2)=[N:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Reactant: Nc1ncc(Br)nc1C(=O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCNS(=O)(=O)c1cccc(-c2cnc(N)c(C(=O)c3cccnc3)n2)c1

Procedure:
A suspension of (3-Amino-6-bromo-pyrazin-2-yl)-pyridin-3-yl-methanone (Intermediate AA) (0.05 g, 0.18 mmol), bis(pinacolato)diboron (0.05 g, 0.19 mmol), Pd(dppf)Cl2.DCM (0.015 g, 0.018 mmol) and potassium acetate (0.03 g, 0.27 mmol) in DME (4 ml) is heated at reflux for 4 hours. Pd(dppf)Cl2.DCM (7 mg, 0.009 mmol), 3-Bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (Intermediate DD) (0.05 g, 0.18 mmol), 2M Na2CO3 (1 ml) and DME (3 ml) are added to the suspension, which is heated at reflux for a further 1 hour. After cooling, the reaction mixture is diluted with EtOAc, washed with water, dried (MgSO4) and filtered through a short pad of Celite® (filter material). The solvent is removed in vacuo, and the residue purified by flash column chromatography (SiO2, iso-hexane/EtOAc) to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-6) δ 9.16 (2H, m), 8.86 (1H, dd), 8.43 (1H, dt), 8.37 (1H, m), 8.23 (3H, m), 7.85 (1H, m), 7.77 (1H, m), 7.66 (1H, ddd), 3.38 (2H, t), 3.22 (3H, s), 3.01 (2H, m). MS m/z 414.01 [M+H]+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:10].[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(N)=O)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Yield: 737.7 %

Procedure:
The compound of Example 109 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:10]1[CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCOC1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a suspension of 4 g of 5-n-butyloxy-pyrrolidin-2-one, 1.79 g of potassium hydroxide hydrated to 85%, and 0.4 g of n-tetrabutylammonium bromide in 80 cm' of tetrahydrofuran, there is added a solution of 4.35 g of benzyl bromide, without exceeding 30° C. After agitating for 1 hour at ambient temperature, the insoluble matter is filtered off and the solvent is evaporated. The residue (4.7 g) is distilled at 230° C. under 0.05 mbar, then the distillate is chromatographed on silica (eluent: ethyl acetate--n-hexane, 1--1). 3.5 g of the expected product is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][CH:69]=1)[C:53]([NH:55][C:56]1[CH:65]=[C:64]2[C:59]([CH2:60][CH2:61][N:62]([CH3:66])[CH2:63]2)=[CH:58][CH:57]=1)=[O:54]>CN(C=O)C>[CH3:66][N:62]1[CH2:61][CH2:60][C:59]2[C:64](=[CH:65][C:56]([NH:55][C:53]([C:52]3[CH:51]=[C:50]([CH:69]=[CH:68][CH:67]=3)[CH2:49][NH:48][C:12]([C:10]3[S:11][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)=[O:14])=[O:54])=[CH:57][CH:58]=2)[CH2:63]1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: O=C(O)c1ccc(-c2cccnc2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccnc5)s4)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 5-pyridin-3-yl-thiophene-2-carboxylic acid (31 mg, 0.15 mmol) in DMF (1 mL) add Hunig's Base (0.10 mL, 0.54 mmol) and TBTU (52 mg, 0.16 mmol) and stir at rt for 20 min. To this add 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (50 mg, 0.1 mmol) and stir the solution for 18 h at rt. Concentrate the solution and purify the residue by prep-HPLC (10% to 90%, CH3CN/H2O) to provide the desired product 5-pyridin-3-yl-thiophene-2-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (62 mg, 0.087 mmol). MS, electrospray 483.8 (M+H), rt 0.88 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O>>[CH3:20][C:6]1[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:13]2[C:8]([CH:7]=1)=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2
Reactant: Oc1ccccn1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)COc1ccccn1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and 2-pyridinol: MS (ES) m/z 360 (M+1).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:38])=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: Anal. Calcd for C32H37FN2O3+0.07CHCl3: C, 73.4; H, 7.12; N, 5.34. Found: C, 73.4; H, 6.96; N, 5.14; ESMS m/e: 517.1 (M+H)+.