Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=3)[CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([N:38]4[CH2:39][CH2:40][CH2:41][CH:36]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[CH2:37]4)=[CH:43][CH:44]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(N2CCCC(N3CCOCC3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(N5CCOCC5)C4)cc3)nn12
Yield: 36.3 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.0003480 mol), N,N-Diisopropylethylamine (0.0909 mL, 0.000522 mol) and 4-(3-Morpholin-4-yl-piperidin-1-yl)-phenylamine (0.182 g, 0.000696 mol) were dissolved in 1-Methoxy-2-propanol (0.99 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 61.16 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(3-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=486.3. 1H NMR (400 MHz, DMSO, d6) δ 9.20 (m, 1H), 8.92 (s, 1H), 7.84 (dd, 1H, J=1.67, 5.97 Hz), 7.61 (d, 2H, J=9.00 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.00 Hz), 7.15 (m, 1H), 6.91 (m, 4H), 4.33 (m, 2H), 3.77 (s, 3H), 3.74 (m, 2H), 3.42 (m, 3H), 2.90 (m, 2H), 2.67 (m, 2H), 2.13 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (96.5 mg, 76%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][OH:9].C(N(CC)CC)C.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:20]([O:9][CH2:8][CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: OCC=Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC=Cc1cccs1

Procedure:
1.50 g (10.7 mmol) of 3-(thiophene-2-yl)-2-propene-1-ol, 0.5 ml (3.59 mmol) of triethylamine and 1.0 ml (13.0 mmol) of diketene were heated to 70° C. under stirring in 30 ml of toluene for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture at room temperature. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C=O)C>[CH2:26]([N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:13]1=[O:18])[CH3:27]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cccc(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
350 mg (1.42 mmol) of the product from example 55A are suspended in 3.5 ml of DMF. To this are added 393 mg (2.84 mmol) of potassium carbonate and 266 mg (1.71 mmol) of iodoethane, and the mixture is left to stir at RT for 3 h. Then it is admixed with water and extracted with dichloromethane. The organic solution is dried over sodium sulfate, concentrated and purified by preparative HPLC. This affords 224 mg (57% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)=O.C=O>>[CH3:21][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCCCNCCCc2ccccc2)cc1
Reactant: O=CO
Agent: C=O
Product: CN(CCCCc1ccccc1)CCCc1ccccc1

Procedure:
Phenylbutyric acid chloride and 3-phenylpropylamine were reacted to form the amide which next was reduced with diborane to give N-(3-phenylpropyl)-4-phenylbutylamine. The amine was methylated with formic acid/formaldehyde to form the starting material, N-methyl-N-(3-phenylpropyl)-4-phenylbutylamine. 5.3 Grams of N-methyl-N-(3-phenylpropyl)phenylbutylamine was dissolved in 150 ml. of diethyl ether in a 300 ml. round bottom flask. Methyl bromide gas was bubbled through the mixture until it was saturated. The mixture was stirred at room temperature for 3 days. The solid material which had formed was collected by filtration and crystallized from 100 ml. methyl ethyl ketone and ethyl acetate to yield 5.08 g. of N,N-dimethyl-N-phenylpropyl-phenylbutylammonium bromide. M.P. 81°-83° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:26])[CH:18]([CH3:25])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>C1COCC1.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:26])[C:18]([CH3:31])([CH3:25])[C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:11][C:10]=1[O:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1cc(/C=C/C(=O)C(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C/C(=O)C(C)(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.8 %

Procedure:
To a stirring solution of (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,6,6-trimethylhept-1-ene-3,5-dione (540 mg, 1.33 mmol) in THF (10 ml) under N2 was added sodium hydride (64 mg (of 60%), 1.60 mmol) and stirred for a further 45 min at room temperature. A solution of methyl iodide (0.1 ml, 1.60 mmol) in THF (1 ml) was added and the mixture heated at reflux for 5 h. Water (25 ml) was added to the cooled mixture followed by DCM (25 ml). The organic layer was separated, washed with water (25 ml), dried (MgSO4(anh)), filtered and concentrated. The residue was purified by column chromatography on silica using dichloromethane as eluent to give (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,4,6,6-tetramethylhept-1-ene-3,5-dione (266 mg, 48%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 0.17 (6H, s, Si(CH3)2), 0.99 (9H, s, SiC(CH3)3), 1.18 (9H, s, C(CH3)3), 1.41 (6H, s, 2×C(CH3)), 3.83 (3H, s, OCH3), 6.54 (1H, d, J=15.6 Hz, vinyl CH), 6.84 (1H, d, J=8.0 Hz, ArH), 6.98 (1H, d, J=2.0 Hz, ArH), 7.06 (1H, dd, J=8.0, 2.0 Hz, ArH), 7.66 (1H, d, J=15.6 Hz, vinyl CH) ppm.
Reaction SMILES: COC[N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1.O.Cl.[O-]CC.[Na+]>C(O)(=O)C>[NH:14]1[C:10]([CH2:9][C:5]2[NH:6][CH:7]=[CH:8][N:4]=2)=[N:11][N:12]=[N:13]1
Reactant: COCn1ccnc1Cc1nnn[nH]1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1c[nH]c(Cc2nnn[nH]2)n1

Procedure:
8.14 g (41.9 mmol) of 1-methoxymethyl-2-(5-tetrazolylmethyl)-imidazole are refluxed in a mixture of 85 ml glacial acetic acid, 8.5 ml of water and 8.5 ml of conc. hydrochloric acid for 24 hours. The mixture is then concentrated in vacuo and the residue rapidly dried to a far extent in a high vacuum over potassium hydroxide and conc. sulphuric acid. The acid addition salt obtained is decomposed with the stoichiometric quantity of sodium ethoxide in an ethanolic solution. After removal of the sodium chloride precipitated, the solvent is distilled off and the residue recrystallised from methanol at boiling heat with the addition of a little ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]1[CH2:12][CH2:11]1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:14](OCC#N)=[O:15]>ClCCl>[C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]1[CH2:12][CH2:11]1)[NH:8][CH:14]=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCOC=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CC1CC1)NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10 g (54 mmol) of (S)-β-cyclopropylalanine tert-butyl ester and 4.7 g (55.2 mmol) of cyanomethyl formate in 100 mL of dichloromethane was stirred at room temperature overnight. The residue obtained after removal of the solvent in vacuo was distilled in vacuo. Yield: 8.8 g (76%). Boiling point 120° C./40 Pa (0.3 torr).
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])=[O:5])[CH3:2].[NH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:26]1=[O:37]>>[CH2:1]([O:3][P:4]([NH:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:26]1=[O:37])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)CCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CN1CCC[C@H](N)C1=O
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)C1=O

Procedure:
Ethoxy(6-phthalimidohexyl)phosphinyl chloride and (S)-3-amino-2-oxopiperidineacetic acid, ethyl ester are reacted according to the procedure of Example 1(g) to give (S)-3-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(-c2cccs2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-(2-thienyl)benzonitrile (0.086 g, 0.464 mmol) was dissolved in dry tetrahydrofuran (1.6 ml) before lithium aluminum hydride (0.46 ml, 0.464 mmol, 1 M in THF) was added dropwise. The reaction was allowed to stir at room temperature overnight. TLC (5% methanol in dichloromethane) still showed starting material remaining. Another 1 eq of LAH was added. After an additional hour, the reaction was quenched by the Fieser and Fieser method using wager (17.46 μl), aqueous sodium hydroxide solution (17.46 μl, 15% soln.), and water (52.37 μl) added sequentially to the reaction. The reaction was then diluted with diethyl ether and water and extracted twice with diethyl ether before drying over sodium sulfate and concentrating in vacuo. The residue was carried on crude without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)O)[CH:7]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:11])[CH:13]=[CH:14][CH:10]2[OH:19])[CH:7]=1
Reactant: CC(C)=O
Reactant: CCc1ccc(Br)cc1C(O)c1ccco1
Solvent: O
Product: CCc1ccc(Br)cc1C1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 44 h

Procedure:
A solution of (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.73 g, 145 mmol) in acetone (1150 ml) and water (170 ml) is heated to 55° C. and 30 drops of polyphosphoric acid are added. The mixture is stirred at 55° C. for 44 hours, then cooled to room temperature. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (500 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(5-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone (33.67 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 378) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.090g 21%). mp 180-183° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.49 (m, 5H), 7.36 (m, 2H), 7.53 (m, 2H), 7.62-7.73 (m, 4H), 7.98 (m, 3H). MS (DCI/NH3) m/z 416 (M+H)+, 433 (M+NH4)+. Anal. calc. for C21H22FN3O3S: C, 60.71; H, 5.34; N, 10.11. Found: C, 60.37, H, 5.36, N, 9.84.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:21]1([S:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2)cc1)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g), phenylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from methanol/diethyl ether to give 1-(4-phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) as colorless prisms, m.p. 178-182.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Reactant: FCc1cccc(Br)n1
Product: O=[N+]([O-])c1cccc2nn(CCC#Cc3cccc(CF)n3)nc12

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (92 mg, 0.48 mmol) and 2-but-3-ynyl nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol, Example, 160(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 59 mg (0.18 mmol, 42%) of 2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)+nitro-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O.C(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCc1ccc(O)cc1
Yield: 49.1 %

Procedure:
4-hydroxyphenylacetaldehyde (15) was synthesized as described in Heterocycles, 2000, 53, 777-784. 4-Hydroxyphenethyl alcohol (Compound 14, 1.0 g, 7.3 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). With stirring, TEA (2.2 mL, 16 mmol, Aldrich) was added slowly. Pyridine-sulfur trioxide (SO3.py) complex (2.5 g, 16 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (9 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (5:1, then 2:1) yielded 488 mg (49%) of 4-hydroxyphenylacetaldehyde (5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([NH:21][CH3:22])[C:16]([N+:23]([O-])=O)=[CH:15][CH:14]=1>>[NH2:23][C:16]1[C:17]([NH:21][CH3:22])=[C:18]([C:19]#[N:20])[C:13]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Product: CNc1c(N)ccc(-c2ccc(Cl)cc2Cl)c1C#N
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from 2,4-dichloro-phenylboronic acid and 6-chloro-2-methylamino-3-nitro-benzonitrile according to the procedure for Example 1A. 1H NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), 7.24-7.31 (m, 2H), 6.89 (d, 1H, J=8.4 Hz), 6.78 (d, 1H, J=8.0 Hz), 3.67 (br s, 3H), 2.97 (s, 3H). MS (ES) [m+H] calc'd for C14H11N3Cl2, 292, 294; found 292, 294.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].FC1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1>>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2F)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 2-fluoroaniline using a method similar to that described for D3 in Description 3.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C@@H:19](C(O)=O)CC1C=CC=CC=1>CO>[CH3:19][O:16][C:15](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:6]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Yield: 12.6 %

Procedure:
5.8 ml of 95% sulfuric acid was added to 33 ml of methanol and heat-refluxed. Subsequently, methanol was removed under reduced pressure and water was added to provide 15 ml of CH3SO4H solution. 2.7 g L-Phe and 0.3 g (D-Phe/L-Phe=11.1%) D-Phe were added thereto and dissolved by heat, following which was then cooled with ice. The separated crystals were isolated by suction filtration and washed with a small amount of cold water. Yield, 3.73 g. The results of HPLC analysis using an optically active column revealed that the crystals contained 1.66 g L-Phe and 0.049 g (D-Phe/L-Phe=2.9%) D-Phe. In addition, 41 mg of L-phenylalanine methyl ester was also produced as a result of esterification of L-Phe with the methanol remaining in the CH3SO4H solution.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(F)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(F)cc1
Yield: 74 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-fluorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-fluorobenzyl ester of melting point 168° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:41]=2)[C:36](=[O:56])[N:35]1[CH2:57][C:58](O)=[O:59]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:58](=[O:59])[CH2:57][N:35]1[C:36](=[O:56])[C:37]2[C:42](=[CH:41][CH:40]=[C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]3)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:38]=2)[C:34]1=[O:33]
Reactant: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 96 h
Yield: 52.1 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (188 mg, 0.449 mmol), DMAP (110 mg, 0.897 mmol) and EDC (129 mg, 0.673 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetic acid hydrochloride (200 mg, 0.449 mmol) was added portion wise over 5 hours, and the resulting mixture was stirred at room and for 96 hours. The solvent was removed and the crude was purified by silica gel chromatography (EtOAc/DCM 2/1 then DCM/MeOH 100/3). The resulting white solid was triturated with EtOH and recovered by filtration affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (190 mg, 0.234 mmol, 52.2% yield, LC-MS purity (BPI): 98.3%, MS/ESI+ 811.21 [MH]+, [αD]=+28.12, c=0.653 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.97 (d, 1H), 7.95 (d, 1H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.91-4.04 (m, 2H), 3.88 (t, 2H), 3.38 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 2.35 (t, 2H), 2.17-2.31 (m, 4H), 1.03-1.53 (m, 7H), 0.49-0.68 (m, 2H), 0.28-0.46 (m, 2H).