Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH2:8][CH2:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH2:1])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2CC2)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Dissolve methyltriphenylphosphonium bromide (20.26 g, 55.6 mmol) in THF (200 mL) and cool to −78° C. Add butyllithium (20.2 mL, 50.5 mmol) and stir at −78° C. for 15 minutes. Warm to ambient temperature and add a solution of tert-butyl 4-(cyclopropylcarbonyl)piperidine-1-carboxylate in THF (5 mL) dropwise. Stir the mixture overnight at ambient temperature. Quench with 50% saturated sodium bicarbonate solution, extract twice with diethyl ether and twice with EtOAc. Combine the organic extracts; wash with brine; dry over sodium sulphate; collect the filtrate; and concentrate under vacuum. Add a mixture of 1:1 diethyl ether:hexane (20 mL) and filter. Concentrate the filtrate under vacuum and purify via flash column chromatography to give the title compound (5.3 g, 83.5%). MS (m/z): 196 (M+1-tBu)
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][N:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3=[O:24])=[CH:5][CH:4]=1>C(OCC)(=O)C>[C:6]1([C:9]2[CH:10]=[CH:11][N:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3=[O:24])[C:7]2[C:8](=[CH:8][CH:3]=[CH:4][CH:5]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OC)cc3)ccn2c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(-c3cccc4ccccc34)ccn2c1=O
Yield: 51 %

Procedure:
Using the procedure as described in Example 17 (i.e., for compound 22) ethyl 8-(napthy-1-yl)-4-oxo-4H-quinolizine-3-carboxylate (23) was isolated in 51% yield by flash chromatography (ethyl acetate). M.p. 245-247° C. 1H NMR (δ, CDCl3): 1.48 (t, J=7 Hz, 3H), 4.48 (q, J=7 Hz, 2H), 6.73 (d, J=8 Hz, 1H), 7.40 (dd, J=2 Hz, J=8 Hz, 1H), 7.55-7.64 (m, 4H), 7.72 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.98-8.06 (m, 2H), 8.48 (d, J=8 Hz, 1H), 9.52 (d, J=8 Hz, 1H). MS: m/z 343.1213; required for C22H17NO3: 343.1208.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95 mg (0.35 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C([Li])CCC.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(F)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Nc1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
A solution of 3,4-difluoroaniline (10.0 mL, 1.0 mol) in tetrahydrofuran (200 mL) was cooled to −78° C., treated with n-butyllithium solution (44 mL of a 2.5 M hexanes solution, 1.1 mol), stirred at −78° C. for 1 h and then warmed to 0° C. for 30 min. The reaction mixture was cooled to −78° C. and 1-fluoro-2-nitrobenzene (9.5 mL, 0.9 mol) in tetrahydrofuran (10 mL) was slowly added and the reaction, after which the reaction was warmed to room temperature. The reaction mixture was evaporated to provide 3,4-difluoro-N-(2-nitrophenyl)aniline (22.76 g, 91%) as a brown solid. The crude product was taken on to the next step.
Reaction SMILES: O=[C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:10]=2[N:11]=1)=O.FC(F)(F)C([O-])=O.[NH4+:37]>O>[CH3:23][O:22][C:12]1[C:10]2[N:11]=[C:7]([C:5]3[NH:4][CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:37]=3)[S:8][C:9]=2[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=1
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccccc3)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4ccccc4)c[nH]3)nc12
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 0.18 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide and 0.57 g ammonium triflouroacetate was melted at 165° C. for 40 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:2 gave 0.07 g (41%) 4-methoxy-7-morpholin-4-yl-2-(4-phenyl-1H-imidazol-2-yl)-benzothiazole as yellow solid; M.p.: 226–233° C.; MS (ISP): m/e=393 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[N:28]2)=[CH:23][CH:22]=1.O>CN(C=O)C>[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[N:28]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.6 %

Procedure:
Triethylamine (8.9 mL, 64 mmol) and tert-butyl N-(3-aminopropyl)carbamate (30.95 g, 177.6 mmol) were added to a solution of 7-bromo-4-chloro-3-nitroquinoline (42.55 g, 148.0 mmol, U.S. patent application publication no. US 2004/0147543, Example 1, Parts A through D) in DMF (500 mL), and the reaction was stirred for four days at ambient temperature. The reaction mixture was poured into water (2 L), and a precipitate formed. The precipitate was isolated by filtration and dried in a vacuum oven overnight at 65° C. to provide 56.4 g of tert-butyl 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[NH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:15])[N:4]2[CH2:23][CH2:24][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c(Nc2ccccc2)ncc1Br
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cnc2n1CCN2c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-(phenylamino)pyrimidin-4(3H)-one (0.082 g, 0.308 mmol) in DMF (8 mL) was added K2CO3 (0.043 g, 0.308 mmol) and 1,2-dibromoethane (0.029 ml, 0.339 mmol). The reaction was stirred at 60° C. overnight, cooled to room temperature and then partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by trituration with Et2O/CH2Cl2. The resulting solid was washed with Et2O, and the filtrate discarded. The solid was then dissolved with CH2Cl2/MeOH, concentrated and dried under vacuum. The product was obtained (75 mg; 83%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (m, 2H), 7.42 (m, 2H), 7.15 (m, 1H), 4.18 (m, 4H). LRMS (ESI pos) m/e 292, 294 (M+, Br pattern).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: C1CCNCC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCCCC2)c1OCCC(C)c1ccc(F)cc1
Yield: 43 %

Procedure:
Example 8a (90 mg, 0.19 mmol) was reacted with piperidine (8.0 eq.) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica gel, DCM/MeOH 100:0, 49:1) to afford the title compound (40 mg, 43%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.95 (t, J=6.8 Hz, 2H), 3.83 (s, 3H), 3.00 (m, 1H), 2.59 (t, J=6.0 Hz, 3H), 2.50 (s, 3H), 2.45-2.35 (m, 4H), 2.18 (s, 3H), 2.05-1.98 (m, 2H), 1.61-1.54 (m, 4H), 1.46-1.42 (m, 2H), 1.24 (d, J=6.9 Hz, 3H). MS (ES+) m/z 492.3 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O-])=O>C(Cl)Cl.N1C=CC=CC=1>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.4 %

Procedure:
To a solution of pyridine (50 mL) and MsCl (15.86 g, 139.13 mmol) in DCM (150 mL) was added the solution of 4-nitrobenzenamine (16.0 g, 115.94 mmol) in pyridine (100 mL) at 0° C. The mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure. The residue was rinsed with water (200 mL×3) and dried under reduced pressure to afford the title compound as a yellow powder (23.20 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[O:8][CH:14]=1
Reactant: NC(=O)c1sccc1Cl
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2sccc2Cl)n1
Yield: 54 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-chloro-2-thienyl)oxazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: C1CNC1
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CCC2)ncn1

Procedure:
150 mg (0.5 mmol) of the compound from Example 23 and 63 mg (1 l mmol) of azetidine are suspended in 4 ml of ethanol and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solid is filtered off, washed twice with in each case 0.5 ml of ethanol and discarded. The mother liquor is combined with the wash solutions, and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is stirred under reflux in ethanol for 20 min and then filtered off while still hot. The solid obtained is dried under high vacuum.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:9][CH:8]([OH:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
1,1-Diphenyl-2,3-epoxy-propane prepared as described in Example 21, was further reacted with dimethylamine in ethanol by the procedure described in Example 8 to give 3-dimethylamino-1,1-diphenyl-propan-2-ol (90%) m p 72° - 73°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].Br[CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CC(O)C>CCOCC.CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([C:6]#[N:7])[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccc(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A solution of 3.37 g (22.2 mmol) of 3-Chlorobenzyl cyanide and 4.93 g (24.4 mmol) of 1,3-dibromopropane in 15 mL of ether was added dropwise into 1.17 g (48.8 mmol) of NaH in 60 mL of DMSO. The temperature was held between 25° and 350 by water bath cooling. The mixture was stirred at room temperature for 18 hours. The mixture was cooled in ice water and 3 mL of 2-propanol was added dropwise, followed by the addition of 50 mL of water. The mixture was extracted with hexane (3×100 mL), and the combined extracts were washed with water (3×75 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 3.0 g (71%) product as colorless oil. 1H NMR (CDCl3) δ 2.04-2.16 (m, 1H), 2.38-2.50 (m, 1H), 2.56-2.67 (m, 21), 2.79-2.89 (m, 2H), 7.29-7.36 (m, 3H), 7.41-7.43 (m, 1H). 13C NMR (CDCl3) 17.3, 34.8, 40.1, 124.2, 126.2, 128.4, 130.5, 135.2, 142.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(C)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) in methylene chloride (15 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.17 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 228) (151 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:33][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccccc2)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(CBr)cccc1-c1ccccc1
Yield: 92.6 %

Procedure:
A stirred solution of 2-chloro-3-methyl-[1,1'-biphenyl] (0.5 g, 0.0023 mole) in 8 ml of carbon tetrachloride was irradiated and heated to reflux with a 250 watt brooder lamp. A small amount of benzoyl peroxide was added and the reaction mixture refluxed for ten minutes. A second portion of benzoyl peroxide (total 0.01 g) was added, followed by N-bromosuccinimide (0.43 g, 0.0024 mole). The stirred reaction mixture was irradiated for 16 hours, then cooled, and then filtered. The filter cake was rinsed with carbon tetrachloride and the combined filtrates washed with aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 3-bromomethyl-2-chloro-[1,1'-biphenyl] (0.6 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH3:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:4]=2[N:3]=1>C(O)C.C(N)(C)C>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:5]2[N:6]([C@@H:7]3[O:13][C@H:12]([CH3:14])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:2]([NH:3][CH:4]([CH3:18])[CH3:5])=[N:3][C:4]=2[CH:18]=1
Reactant: COc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: CC(C)N
Product: COc1ccc2c(c1)nc(NC(C)C)n2[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 10.2 %

Procedure:
2-Chloro-5-methoxy-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (0.320 g, 1.1 mmol) was dissolved in ethanol (15 mL) and isopropylamine (5 mL). The resulting mixture was heated in a sealed tube for three days, after which time it was concentrated in vacuo. The resulting product was purified by flash chromatography (9:0.5:0.5 CH2Cl2:ethyl acetate:methanol) to yield the title compound (18 mg, 5%) as a 1.5:1 mix of regioisomers by 1H NMR; MS (ES): m/z 322 (M+1); 1H NMR (DMSO-d6) δ: 7.13 (d, J=8.5 Hz, 0.4H), 7.03 (d, J=8.5, 0.6H), 6.85 (d, J=2.4 Hz, 0.6H), 6.76 (d, J=2.4 Hz, 0.4H), 6.62 (dd, 0.4H), 6.50 (dd, 0.6H), 5.67 (t, 1H), 5.28-5.19 (m, 1.5H), 4.37 (m, 1H), 3.73 (s, 3H), 1.40 (m, 3H), 1.23 (d, 6H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14]CC)=[O:13])[N:4]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:22]=[C:3]12.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([OH:14])=[O:13])[N:4]2[CH:20]=[C:21]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:22]=[C:3]12
Reactant: CCOC(=O)c1cccc(Cc2c[nH]c(=O)c3cc(-c4ccncc4)cn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cc2c[nH]c(=O)c3cc(-c4ccncc4)cn23)c1
Temperature: 80 °C

Procedure:
To a suspension of EXAMPLE 4E (30 mg, 0.08 mmol) in tetrahydrofuran (5 mL) was added NaOH (32 mg, 0.8 mmol) in water (0.5 ml). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was neutralized with 1N aqueous HCl, and concentrated. The residue was separated by HPLC (0-100% gradient CH3CN in water containing 0.1% CF3CO2H to afford the title compound. MS (DCI/NH3) m/z 346 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 4.19 (s, 2H), 6.59 (d, J=5.55 Hz, 1H), 7.47 (t, J=7.54 Hz, 1H), 7.68 (d, J=7.54 Hz, 1H), 7.77 (d, J=1.59 Hz, 1H), 7.82 (d, J=7.93 Hz, 1H), 7.97 (s, 1H), 8.19 (d, J=6.74 Hz, 2H), 8.33 (d, J=1.59 Hz, 1H), 8.73 (d, J=6.35 Hz, 2H), 10.74 (d, J=5.55 Hz, 1H), 12.98 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:19]4[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=4)=[CH:14][C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([CH2:32][C:33]([OH:35])=[O:34])#[N:31]>C(#N)C.N1CCCCC1>[C:30]([C:32](=[CH:24][C:22]1[S:23][C:19]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[C:17](=[CH:18][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:8]=4)[CH2:16][C:15]=3[CH:14]=2)=[CH:20][CH:21]=1)[C:33]([OH:35])=[O:34])#[N:31]
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2
Reactant: N#CCC(=O)O
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=C(C#N)C(=O)O)s3)ccc1-2

Procedure:
As shown in Scheme 1, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11). Then, (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a). Finally, in acetonitrile, 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-cyano-3-[5-(7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (13a).