Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=2)[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COc1ccc(OC(F)(F)F)cc1)Cn1cc([N+](=O)[O-])nc1Br
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cn(CC(CO)COc2ccc(OC(F)(F)F)cc2)c(Br)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
Silyl ether 172 (3.42 g, 6.17 mmol) was treated with a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (31 mL), and the mixture was stirred at room temperature for 12 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (6.6 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-30% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40-50% EtOAc/petroleum ether gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-{[4-(trifluoromethoxy)phenoxy]methyl}-1-propanol (174) (2.48 g, 91%) as a white solid: mp (CH2Cl2/pentane) 97-99° C.; 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.17 (br d, J=8.5 Hz, 2H), 6.88 (dt, J=9.1, 3.0 Hz, 2H), 4.34 (dd, J=14.4, 7.4 Hz, 1H), 4.31 (dd, J=14.4, 7.1 Hz, 1H), 4.06 (dd, J=9.6, 5.7 Hz, 1H), 4.03 (dd, J=9.6, 4.8 Hz, 1H), 3.88 (dt, J=10.8, 4.4 Hz, 1H), 3.76 (dt, J=10.8, 4.9 Hz, 1H), 2.54 (m, 1H), 1.72 (t, J=4.4 Hz, 1H); HRFABMS calcd for C14H14BrF3N3O5 m/z [M+H]+ 442.0049, 440.0069. found 442.0053, 440.0063.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:22])=[CH:29][CH:30]=1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccc(Cl)cc1
Product: CC(C(=O)NCc1ccc(Cl)cc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=462.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(4-chloro-benzyl)-malonamic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[N+](=O)[O-]
Reactant: CCCCc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
A mixture of 4-n-butylbenzaldehyde (5 g, 30.8 mmol), nitromethane (3.31 mL, 61.6 mmol), ammonium acetate (3.56 g, 46.2 mmol) and acetic acid (50 mL) was stirred for 5 hours at 100° C. The mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.7 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:15](=[O:17])[NH:13][C:4]=2[CH:3]=1
Reactant: CCCCNc1ccc(Br)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCCCn1c(=O)[nH]c2cc(Br)ccc21

Procedure:
A mixture of Example 166B (1.36 g, 5.59 mmol) and triphosgene (582 mg, 1.96 mmol) in dioxane was heated to reflux for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[O:23][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Reaction time: 16 h
Yield: 60 %

Procedure:
Cool 13β-butyl-17β-hydroxy-gon-4-en-3-one (0.10 g.) in pyridine (0.3 cc.) to -20° and add 3-phenylpropionyl chloride (0.10 g.) in benzene (0.3 cc.). Stir the mixture at -10° for 16 hours, add ice-cold water, ether (15 cc.) and benzene (15 cc.). Separate the organic layers and wash in turn with 2N sodium hydroxide solution, water and brine, and dry. Evaporate the solvent to an uncrystallizable gum, and take up in a little benzene and filter through neutral alumina (5 g.), then wash with more benzene. Evaporate the resulting benzene solution to obtain the title compound as a gum (0.085 g.); infrared absorption peaks at 5.78, 5.99, 13.3, 14.3 μ, with no absorption due to hydroxyl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:12]([C:15]1[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[CH2:6][CH2:5]2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Fc1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(F)ccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 5-fluoroindoline from above, 5-chlorosulfonyl-2-oxindole (6.1 g, 1.2 equivalent) and pyridine (7.1 mL) in dichloromethane (40 mL) was stirred at room temperature overnight. The reaction was concentrated and the residue was recrystallized from methanol to give 5 g (68% yield) of 5-(5-fluoro-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink-colored solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.75 (br s, 1H, NH), 7.60 (m, 2H), 7.60 (dd, 1H), 7.02 (m, 2H), 6.90 (d, 1H), 3.89 (t, 2H, CH2), 3.52 (s, 2H, CH2), 2.87 (t, 2H, CH2). MS 331 [M+−1].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[O:6][CH:7]([CH2:10][OH:11])[CH2:8][OH:9].[C:12](O[K])([CH3:15])([CH3:14])C.C1(C)C=CC(S(O[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:45]([O:11][CH2:10][CH:7]([CH2:8][O:9][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]/[CH:34]=[CH:33]\[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:14][CH2:12][CH3:15])[O:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]/[CH:37]=[CH:36]\[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)O[K]
Reactant: OCC(CO)OC1CCCO1
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)OC1CCCO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
In 30 ml of xylene was dissolved 854 mg (5.3 mmol) of 2-O-tetrahydrofuranylglycerol. To this was added 1.78 g (15.9 mmol) of t-butoxypotassium under argon gas and the mixture was stirred for 5 minutes. Then, 10 ml of a solution of 6.71 g (15.9 mmol) oleyl p-toluenesulfonate in xylene was added dropwise and the mixture was stirred under reduced pressure (20-30 mmHg) at ambient temperature for 30 minutes and further at 50° C. for 1 hour. This reaction mixture was poured in ice-water and extracted with ether, and the extract was washed with water, dried, and concentrated. The residue was purified by column chromatography (silica gel/chloroform) to provide 628 mg (18%) of 1,3-O-dioleyl-2-O-tetrahydrofuranylglycerol as yellow oil. (5) In 30 ml of tetrahydrofuran was dissolved 628 mg (0.95 mmol) of 1,3-O-dioleyl-2-O-tetrahydrofuranylglycerol followed by addition of 5 ml of diluted (10%) hydrochloric acid, and the mixture was stirred overnight. The reaction mixture was then diluted with water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ether. The extract was dried and concentrated and the residue was subjected to column chromatography (silica gel/n-hexane-ethyl acetate) to provide 321 mg (57%) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]#[N:5])(=[O:17])[CH3:16]
Reactant: COC(=O)c1ccc(O)c(C=NO)c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(OC(C)=O)c(C#N)c1

Procedure:
70.3 g (0.36 mol) of the compound from Example XXXVII are stirred under reflux in 0.5 l of acetic anhydride for 1.5 hours. The mixture is concentrated to dryness, the residue is dissolved in methylene chloride and the title compound is crystallised out by addition of petroleum ether.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH2:11]([O:13][N:14]=[CH:15][CH3:16])[CH3:12].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:11]([O:13][N:14]1[CH:15]([CH3:16])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:12]
Reactant: C=C(C)C1CCCCC1=O
Reactant: CC=NOCC
Agent: CCON1C(=O)CCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), acetaldehyde O-ethyl oxime (0.67 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.14 g, 80% yield).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1([CH3:32])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[I:31])=O)[CH:8]=[CH:7][C:6]1=2.[Br-].[CH3:34]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[O:20][CH:19]=[C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]([CH3:4])([CH3:32])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:10]=1)[CH3:34])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(I)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30% sodium methoxide solution (2.67 g, 14.83 mmol) is added over 8 hours to a mixture of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)methoxy]-3-iodobenzoate (7.50 g, 14.8 mmol) and methyltriphenylphosphine bromide (7.30 g, 20.42 mmol) in THF (80 ml). The mixture is stirred for 18 hours at room temperature. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. This is extracted with 90 ml of ethyl ether and 90 ml of water. After separation of the phases by settling, the organic phase is washed twice with 90 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (70% CH2Cl2, 30% heptane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.Br[C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(Br)C(=O)O
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C

Procedure:
A mixture of 5.4 g (0.02 mole) of 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol, and 5.1 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid was heated for two hours to 90°-130° C. Subsequently the mixture was taken up in chloroform/methanol (8:2) and chromatographed on silicagel. The evaporation residue of the eluate was stirred with cyclohexane and suction filtered.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1(C)C=C(C)C=C(C)C=1.P(=O)(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: O=P(O)(O)O
Solvent: Cc1cc(C)cc(C)c1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
83.5 g (0.50 mol) of 4-nitrobenzoic acid, 30.0 g (0.50 mol) of urea and 1 g of phosphoric acid are heated in 250 ml of mesitylene with stirring at from 160° to 162° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and is washed with 25 ml of mesitylene. The filter cake is introduced into 250 ml of water and the mixture is adjusted to a pH of 12 with aqueous sodium hydroxide solution and subjected to steam distillation. Subsequently the solid is filtered off with suction and is dried at 100° C. 52.0 g of 4-nitrobenzamide are obtained having a melting point of from 193° to 195° C. This corresponds to a yield of 62.7% of theory.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:18]O>>[OH:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:18])=[O:10]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a methanol solution (15 mL) at 0° C. was dropwise added thionyl chloride (6.4 mL, 0.088 mol). After 15 minutes, 3-hydroxy-2-nitrobenzoic acid (4 g, 0.022 mol) was added and the resulting mixture was stirred at room temperature for 72 hours. Volatile was removed under vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and saturated sodium chloride, and was dried over sodium sulfate. After concentration, the crude product was recrystallized from dichloromethane and hexane to gave 4.5 g of methyl 3-hydroxy-2-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[N:19]=[CH:4]/[C:3]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: NNc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(Cl)c1/C=N/Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 31.4 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde (1.0 g, 6.32 mmol) in ethanol was added (4-bromophenyl)hydrazine (1.7 g, 7.59 mmol) and aq. solution of NaHCO3 (0.637 g, 4.59 mmol). The reaction mixture was stirred at RT for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on silica gel, eluting with 4.6% EA: pet. ether to afford 0.650 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.98 (d, J=7.8 Hz, 2H), 7.23-7.40 (m, 5H), 8.07 (s, 1H), 10.87 (br s, 1H). MS (m/z): 329.17 (M+H)+.
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=[CH:38][C:35]=1[CH:36]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([O:42][CH3:43])[C:34]=3[O:33][CH3:32])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:22][CH2:21][CH2:20][C:19]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
Add 3-methoxyphenylmagnesium bromide (1.0 M in tetrahydrofuran, 91.0 mL, 91.0 mmol) dropwise to 1-(tert-butoxycarbonyl)-2-pyrrolidinone (11.9 mL, 70.0 mmol) in tetrahydrofuran (230 mL) at −40° C. After stirring at −40° C. for one hour, warm to 0° C. for 2 h before quenching with 2 M hydrochloric acid (70 mL). Dilute with methylene chloride (250 mL), separate the layers, and extract the aqueous layer with methylene chloride (2×200 mL). Dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (23.20 g, >100%). MS (APCI+): 194 [C16H23NO4—C5H8O2+H]+; 1H NMR (300 MHz, CDCl3): δ 7.55-7.47 (m, 2H), 7.39-7.33 (m, 1H), 7.12-7.08 (m, 1H), 4.66 (bs, 1H), 3.85 (s, 3H), 3.29-3.18 (m, 2H), 3.01 (t, J=7.1 Hz, 2H), 1.93 (quintet, J=7.0 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:14])=[O:13]
Reactant: NCCCCc1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCCCc3ccccc3)cc2c1=O
Yield: 19 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 4-phenyl-butylamine according to the GPA but purified, due to low solubility, by preparative TLC (eluent: hexane/ethyl acetate/acetic acid, 3/7/0.1) affording 5.4 mg (19%) of a red powder. Rt=5.93 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[N:44]=[N:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CCc1ccc(-c2cc(C)c(Cl)c(C)c2)nn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: CCc1ccc(-c2cc(C)c(-c3ccc(F)c4c3CC[C@H]4Oc3ccc4c(c3)OC[C@H]4CC(=O)OC)c(C)c2)nn1

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-chloro-3,5-dimethyl-phenyl)-6-ethyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.14 min; Mass spectrum (ESI+): m/z=553 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[C:34]([C:35]([NH2:37])=[O:36])=[C:33]([C:38]([NH2:40])=[O:39])[N:32]=[CH:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]([C:35]([NH2:37])=[O:36])=[C:33]([C:38]([NH2:40])=[O:39])[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: NC(=O)c1nc[nH]c1C(N)=O
Product: NC(=O)c1ncn(CCCc2ccc(OCc3coc(/C=C/c4ccccc4)n3)cc2)c1C(N)=O
Yield: 44 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with 4,5-imidazoledicarboxamide to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxamide. The yield was 44%. Recrystallization from ethyl acetate gave colorless prisms, mp 194-195° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(O)[O-:57].[Na+]>O.O1CCCC1>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:57]
Reactant: O=S([O-])O
Reactant: CSc1ccc(-n2cnnn2)cc1C(=O)O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.50 g, 2.0 mmol), pyridine (20 mL) and water (20 mL). Cool in an ice bath. Add phenyltrimethylammonium tribromide (0.75 g, 2 mmol) and tetrahydrofuran (20 mL). Warm to ambient temperature. After 1 hour, add a solution of sodium bisulfite (1 g) in water (1 mL). Extract the reaction mixture with ethyl acetate and then dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. the title compound. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate to give methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate.