Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:10]=12
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A sealed tube was charged with a solution of 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 1.0 mmol) in toluene (5 mL), pyridin-4-ylboronic acid (246 mg, 2.0 mmol, Lancaster), 0.5 mL of ethanol, and potassium phosphate (1.0 mL, 2 M solution, 2.0 mmol). Argon was bubbled through the mixture for 15 minutes, and the reaction mixture was treated with tetrakis(triphenylphosphine)Pd(0)(58) mg, 0.05 mmol, Strem). the tube was sealed and the mixture was heated at 95 ° C. for 18 with vigorous stirring. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture ws washed with sasturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with 2% MeOH in dichloromethane) to give the desired product (237 mg, 49%) as a thick brown oil. MS(ESI+) m/z 481.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.C(O)(C(F)(F)F)=O.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NNc1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 156.1 %

Procedure:
To a 0° C. solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0° C. for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96%). LC-ES/MS m/e 194.0 (M+1)
Reaction SMILES: FC(F)(F)C1C=C(NC(N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@@H]2CC3CCN2CC3)=O)C=C(C(F)(F)F)C=1.C=CC.[N+:43]([CH3:46])([O-:45])=[O:44].[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])/[CH:60]=[C:61](\[C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)/[C:62]([F:65])([F:64])[F:63])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]>O>[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])[CH2:60][C@@:61]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)([CH2:46][N+:43]([O-:45])=[O:44])[C:62]([F:64])([F:63])[F:65])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: COc1ccc2nccc([C@H](NC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]3CC4CCN3CC4)c2c1
Solvent: C=CC
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Alternatively, to a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(S)-(6-methoxy-4-quinolyl)-[(2S)-quinuclidin-2-yl]methyl]urea; prop-1-ene (09 mg, prepared according to the literature: Organic Letters 2007, 9, (14), 2621-2624) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 3 days at 50° C. then allowed to stand at room temperature for 2 days. Water was then added and the resulting mixture was extracted with diethyl ether and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.43 minutes (major enantiomer), 7.78 minutes (minor enantiomer) indicated that the reaction proceeded with 95% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[F:27])[CH3:14].[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].CCOC(C)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:16]([C:17]1[C:18]([F:27])=[CH:19][C:20]([C:21](=[O:23])[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:24][C:25]=1[F:26])[O:15][CH2:13][CH3:14])[CH3:32]
Reactant: CC(C)CN
Reactant: CCOC(=O)C(OCC)c1c(F)cc(C(=O)O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)c1c(F)cc(C(=O)NCC(C)C)cc1F
Reaction time: 3 h
Yield: 67.3 %

Procedure:
1,1′-Carbonyldiimidazole (88 mg) was dissolved in THF (1 ml) and a solution of (RS)-4-(ethoxy-ethoxycarbonyl-methyl)-3,5-difluoro-benzoic acid (156 mg) in THF (1 ml) was added. After 30 min stirring at rt isobutylamine (41 mg) was added and the mixture was stirred 3 h. AcOEt (20 ml) was added and the solution was washed with 1 N HCl (20 ml). The aqueous layer was extracted with two more portions AcOEt (20 ml), the the combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC (Hept/AcOET 3:1) afforded 125 mg (67%) of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid ethyl ester. White solid.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@H:7]([CH3:35])[NH:8][C@@H:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.C(OCC)C.C(OCC)(=O)C.[ClH:48]>>[ClH:48].[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:15][CH2:16]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reaction time: 4 h

Procedure:
In 20 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.7 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester, and the solution is allowed to stand at room temperature for 4 hours. 100 ml of ethyl ether is added to the reaction solution, and the colorless powder, which separates out, is collected by filtration to give 1.2 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:28])[CH2:7][N:8]2[CH2:12][CH2:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:9]2=[O:27])[CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39])[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:11][CH2:12][N:8]([CH2:7][C:6]([NH:5][CH:3]3[CH2:4][N:1]([CH2:33][C:32]4[CH:35]=[CH:36][C:37]([C:38]([F:39])([F:40])[F:41])=[C:30]([F:29])[CH:31]=4)[CH2:2]3)=[O:28])[C:9]2=[O:27])=[CH:18][CH:17]=1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CNC1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CN(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-azetidin-3-yl-2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]acetamide (0.083 g, 0.215 mmol; Example 239A) in dichloromethane (5 mL) was added 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.062 g, 0.323 mmol), sodium triacetoxyborohydride (0.088 g, 0.323 mmol) and a few drops of acetic acid. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution. The separated organic layer was dried over MgSO4, concentrated, and purified by silica gel flash chromatography eluting with 5-10% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.54 (t, J=7.6 Hz, 1H), 7.28-7.33 (m, 4H), 7.12-7.16 (m, 2H), 6.98-7.05 (m, 4H), 6.30-6.37 (m, 1H), 4.40-4.59 (m, 1H), 3.99 (s, 2H), 3.54-3.66 (m, 4H), 3.50 (t, J=6.5 Hz, 2H), 2.77 (t, J=6.4 Hz, 4H); MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: CC(C)(C)OC(=O)NCCNc1cccc[n+]1[O-]
Reaction time: 47 h
Yield: 89.3 %

Procedure:
A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOH/CHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1 H), 7.05-7.30 (m, 2 H), 6.68 (br d, J=8.6 Hz, 1 H), 6.50-6.65 (m, 1 H), 5.70-5.95 (m, 1 H), 3.35-3.60 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 254 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:31](=[O:33])[N:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:29][CH2:28][C:27]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[C:3]([N:37]2[CH2:36][CH2:35][CH:34]([N:30]3[CH2:29][CH2:28][C:27]4[CH:40]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=4[NH:32][C:31]3=[O:33])[CH2:39][CH2:38]2)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3Br)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.38 g (1.1 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.29 g (1.1 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.22 g (1.6 mmol) potassium carbonate and 3.0 mL NMP were combined and stirred for 10 h at 130° C. Then the reaction mixture was combined with water and the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: ClI
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.40 g, 1.44 mmol) in glacial acetic acid (4 ml) at room temperature was added a solution of iodine monochloride (0.28 g, 1.76 mmol) in glacial acetic acid (4 ml). Water (6 ml) was also added, and the reaction was stirred for 16 hours, after which another portion of iodine monochloride (0.4 g, 2.47 mmol) in glacial acetic acid (4 ml) was added. The reaction mixture was stirred for an additional hour at room temperature. The acidic mixture was basified with saturated NaHCO3 solution and extracted into dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (5% CH3OH in CH2CL2 with 0.1% NH4OH) to give 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as beige colored solid (0.536 g, 92%). M+H 400.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].C(O)C.[OH-].[K+].Cl>CCCCCC>[CH3:1][O:2][CH:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCCCCC(CC=CCCCCCCCC(=O)OCC)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CCCCCCC(CC=CCCCCCCCC(=O)O)OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
Next, to a 1-l flask equipped with a stirrer, 68.1 g (0.2 mol) of ethyl 12-methoxy-9-octadecenoate, 600 ml of ethanol and 45 g of a 50% aqueous solution of potassium hydroxide were charged, followed by stirring at 50° C. for 4 hours. To the reaction mixture so obtained, hexane was added, followed by neutralization with 3N hydrochloric acid and then washing with saturated saline. After concentration under reduced pressure, the residue was purified by chromatography on a silica gel column, whereby 58.3 g of the title compound (8-d) were obtained (yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(OP([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])(=O)OCC)C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[Br:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:19]=[CH:7]/[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOP(=O)(Cc1ccccc1Br)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Yield: 81.3 %

Procedure:
5-Chlorosalicylaldehyde (188 g, 1.2 mol) was added to a solution of (2-bromo-benzyl)-phosphonic acid diethyl ester (369 g, 1.2 mol) in tetrahydrofuran (1500 ml) under nitrogen. A solution of potassium tert-butoxide (300 g, 2.68 mol) in tetrahydrofuran (3000 ml) was added while keeping the temperature at 33° C. After completion of the reaction water (1800 ml) was added followed by 4N HCl (450 ml). The organic layer was washed with sodium carbonate solution (500 ml) and saturated NaCl solution. The organic layer was evaporated under reduced pressure at 50° C. to give trans-2-bromo-5′-chloro-2′-hydroxystilbene (301.9 g, 92%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11]C1C=CC(C=O)=CC=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1.CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][CH2:22][C:5]1[CH:27]=[CH:26][C:25]([CH2:29][OH:28])=[CH:2][CH:1]=1)=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)OCCc2ccc(CO)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (5 mmol) of the aldehyde obtained in Example 45, 50 ml of THF and 50 ml of methanol are introduced into a round-bottomed flask. 100 mg (2.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])nc1
Yield: 62.4 %

Procedure:
A solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methylphenyl)benzamide (8.35 g, 28.4 mmol), 5-bromo-2-nitropyridine (5.24 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6 mmol) in N,N-dimethylformamide (70 mL) was stirred at 60° C. for 4 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→60/40), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (6.70 g, 63%) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6]1[CH2:9][NH:8][CH2:7]1)[CH3:2].C1COCC1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(=O)(O)[O-].[Na+]>[CH2:19]([O:18][C:16]([N:8]1[CH2:9][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:7]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a stirring mixture of azetidin-3-yl-acetic acid ethyl ester (1.0 g, 6.98 mmol), in saturated aqueous sodium bicarbonate (5 mL) and THF (5 mL) at 0° C. was added carbobenzyloxy chloride (1.1 mL, 7.68 mmol) dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hrs, then extracted with ethyl acetate acetate (3×20 mL). The combined ethyl acetate layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane to give 0.30 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([O:23][CH3:24])[CH:10]=2)=[O:7])=[C:4]([N+:27]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:27][C:4]1[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:11]([O:23][CH3:24])[CH:10]=1)=[O:7]
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])ccc1OCCN1CCCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc(NC(=O)c2ccc(Cl)cc2N)ccc1OCCN1CCCC1
Yield: 97 %

Procedure:
To a solution of 4-chloro-N-{3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-nitrobenzamide (11.9 mmol, 5.0 g) in ethanol was added tin(II) chloride dihydrate (35.8 mmol, 8.1 g). The resulting mixture was heated to reflux for 4 h and then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and was washed with potassium sodium tartrate tetrahydrate solution repeatedly. The crude product was first extracted with 2N HCl, then made basic by adding NaOH with ice cooling. The combined basic aqueous solution was extracted with DCM. The organic extraction was washed with brine, dried and concentrated giving the product (4.5 g, 97%). 1H NMR (DMSO-D6): δ 1.67 (4H, m), 2.48 (4H, m), 2.81 (2H, t, J=5.8 Hz), 3.75 (3H, s), 4.10 (2H, t, J=5.8 Hz), 7.02 (1H, d, J=6.2 Hz), 7.10 (1H, d, J=8.6 Hz), 7.16 (1H, s), 7.62 (1H, d, J=8.6 Hz), 7.80 (1H, s), 8.17 (1H, d, 8.6 Hz), 8.35 (1H, s). LCMS m/z=390 (m+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C=O.C([O-])(=[O:15])C.[NH4+].O>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: C=O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Yield: 61.1 %

Procedure:
13.2 g of p-cyanobenzylamine, 12.0 g of paraformaldehyde, 46.0 g of ammonium acetate, 60 ml of water and 60 ml of acetic acid were mixed and reacted at 100° C. for 3 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and water in an amount equal to the amount of solvent distilled off was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 8.0 g (yield: 62%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=3[C:6]=2[N:18]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>N1C=CC=CC=1>[I:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:3][C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][C:6]=3[C:7]=2[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C1Cc2cnc(NC(=O)c3ccccc3)nc2-c2cc(I)ccc2N1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51) (69.7 mg, 0.20 mmol) was dissolved in pyridine (800 μL) and benzoyl chloride (23 mL, 0.20 mmol). The mixture was stirred at 110° C. for 1 h, then cooled to 22° C. Et2O was added and the product was filtered from the solution to give I-83 (37%): MS (FA) Rt=1.49 min, m/z=457 (M+H).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CO.C(OC(C)C)(C)C>>[C:1]([O:9][CH2:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCCCCCO
Solvent: CC(C)OC(C)C
Product: NCCCCCCOC(=O)c1ccccc1
Yield: 82 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 6-aminohexan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of the mole number of zinc atoms; in the following Examples, the amount will be similarly expressed in terms of the mole number of zinc atoms) and diisopropyl ether (5.0 ml) was heated to reflux for 18 hours, and as a result, 6-aminohexyl benzoate having an acylated hydroxyl group was obtained at a yield of 82% (the yield is based on the carboxylic acid ester. The same applies in the following). The yield of 6-benzoylaminohexyl benzoate in which an amino group and a hydroxyl group were both acylated, was 18%.