Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O>>[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:17]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Yield: 69.7 %

Procedure:
3-Nitrophenyl-guanidine nitrate (28 g, 0.12 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (16.9 g, 0.09 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (18.4 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH2:12]=O.[ClH:14]>>[ClH:14].[S:1]1[C:2]2[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: C=O
Reactant: N[C@H](Cc1cccs1)C(=O)O
Agent: Cl
Product: O=C(O)[C@H]1Cc2sccc2CN1
Temperature: 110 °C

Procedure:
A mixture containing 87 mmol of β-2-thienyl-D-alanine, 11 ml of formaldehyde at 40% in aqueous medium, and 88 ml of 1N hydrochloric acid is heated for 2 h 30 min at 110° C., with stirring, and then at 60° C. overnight. After evaporation, the residue is taken up in ethanol and then evaporated and the expected product is recovered in the form of a solid in diethyl ether.
Reaction SMILES: Cl.Cl.[Cl:3]C1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.Cl.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C:36]=4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1>>[ClH:3].[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C@@H:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C@@H:36]4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Reactant: Clc1cccc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Agent: Cl
Product: Clc1cccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole dihydrochloride the title compound was prepared: 1H NMR (DMSO-d6) δ 1.35, 1.55, 2.10, 2.71, 3.05, 3.28, 3.97, 4.20, 6.65, 7.12, 7.4-7.5, 8.8. HRMS (FAB) calcd for C18H21ClN12 (MH+) 299.1315, found 299.1306.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([N:34]2[C:38]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=[N:37][NH:36][C:35]2=[O:48])=[CH:25]1.[Br:49]C(Br)(Br)Br>C1COCC1>[Br:49][CH2:21][CH2:22][CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([N:34]2[C:38]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=[N:37][NH:36][C:35]2=[O:48])=[CH:25]1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1[nH]nc(-c2c[nH]c3ccccc23)n1-c1cn(CCCO)c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2c[nH]c3ccccc23)n1-c1cn(CCCBr)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Triphenylphosphine (0.168, 0.64 mmol) was added to a mixture of 4-[1-(3-hydroxy-propyl)-5-fluoro-indol-3-yl]-5-(1-H-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one (0.23 g 0.59 mmol), synthesised in accordance to the procedure for Example 1, triphenylphosphine (0.168 g, 0.64 mmol) and tetrabromomethane (0.218 g, 0.66 mmol) in dry THF (15 ml). The resulting mixture was stirred at ambient temperature. After 16 h the LCMS showed that some starting material still was left. Additional tetrabromomethane (0.198 g, 0,60 mmol) and triphenylphosphine (0.158 g, 0.60 mmol) were added and the solution was allowed to proceed for 20 h more at ambient temperature. Evaporation and silica gel chromatography (dichloromethane/methanol, gradient to 100/5) afforded 0.165 g (57%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11](OCC)=[O:12])[C:6](OCC)=[O:7])=[CH2:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C1CCCCC1.C(OCC)(=O)C>[OH:7][CH2:6][C:4]1([CH2:11][OH:12])[CH2:5][CH:3]1[CH:1]=[CH2:2]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CC1CC1(CO)CO
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 23 g (0.108 mole) of diethyl 2-vinylcyclopropane-1,1-dicarboxylate in 90 ml of dry THF (tetrahydrofuran) was added dropwise to 196 ml of 1M LAH (lithium aluminum hydride) which was stirred and heated at 68°. The addition required 30 minutes and heating and stirring were continued for 2 hours. TLC in cyclohexane-ethyl acetate (1:1) and CHCl3MeOH (9:1) showed that the reaction was complete. The reaction was cooled to 0° and a total of 200 ml of water was continuously added. After being stirred for 15 minutes, the mixture was filtered and the solid was washed with THF. The combined filtrates were concentrated to yield 12.9 g (93%) of the title compound, RfCHCl3 -MeOH (9:1) 0.45.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[OH:10][C:6]1[N:5]=[C:4]([CH3:11])[CH:3]=[C:2]([O:13][CH3:12])[C:7]=1[C:8]#[N:9]
Reactant: C[O-]
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(O)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (337 mg, 2.0 mmol), sodium methanolate (540 mg, 10.0 mmol), methanol (15 mL), and magnetic stirrer. The pressure vessel was sealed, and it was stirred at 100° C. for 16 hours. After being cooled to room temperature, the vessel was opened, and the reaction solution was transferred to an eggplant-shaped bottle. The solvent was removed by rotary evaporation. To the residue was added water (10 mL) and ethyl acetate (50 mL). The layers were separated. The organic phase was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 2-hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 21%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][C:23]1([CH3:41])[O:27][C@@H:26]([CH2:28]OS(C2C=C(Cl)C=CC=2Cl)(=O)=O)[CH2:25][O:24]1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][C@H:26]2[CH2:25][O:24][C:23]([CH3:41])([CH3:22])[O:27]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC[C@H](COS(=O)(=O)c2cc(Cl)ccc2Cl)O1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.4 g, 5.24 mmol) in dry N,N-dimethylformamide (25 mL) at 0° C. under an atmosphere of dry argon was added sodium hydride (60% suspension in mineral oil) (290 mg, 0.12 mmol) and the mixture stirred at 0° C. for 15 minutes. 2,5-Dichloro-benzenesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (2.14 mmol, 6.29 mmol) was added to the reaction mixture to form a yellow solution which was stirred at ambient temperature for 5 minutes before warming to 100° C. for 10 minutes. The reaction mixture which by now contained a heavy precipitate was cooled to ambient temperature, diluted with ethyl acetate, cooled to 0° C. and treated with an equal volume of water. The stirred mixture was acidified to pH≈4 with 1 M aqueous hydrochloric acid. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (three times), dried over sodium sulfate, filtered through a thin pad of silica gel and concentrated in vacuo to give (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid as a pale yellow solid foam which was of adequate purity for subsequent use in step 33-G without additional purification (1.96 g, 96%). HR-MS: calcd for C25H26FlN4O5 [M+H+] 609.1005. Found 609.1006.
Reaction SMILES: [OH-].[K+].Cl.NO.CC1[N:8]([C:13]2[CH:21]=[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[N:14]=2)C(C)=CC=1>O.C(O)C>[NH2:8][C:13]1[CH:21]=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][N:15]2[N:14]=1
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCCC2
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1cc2n(n1)CCCC2
Reaction time: 0.25 h

Procedure:
A solution of 8.19 g (146 mmol) potassium hydroxide in 122 ml water and 122 ml ethanol was added to 19.19 g (292 mmol) hydroxylamine hydrochloride in 200 ml ethanol. The mixture was stirred for 15 minutes, 12.5 g (58 mmol) 2-(2,5-dimethyl-1-pyrrolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine added and the mixture heated under reflux for 30 hours. After distilling the ethanol, the mixture was treated with ethyl acetate, solid material filtered off, the aqueous phase saturated with sodium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccc(Cl)c(Cl)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1Cl)([O-])=O.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O-:26])([O-])=O.[Na+].[Cl-].[NH4+].NC1C=C([N+]([O-])=O)C=CC=1[O-].[Na+].[SH-]>O>[NH2:14][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26]
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: Nc1cc([N+](=O)[O-])ccc1[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1O
Temperature: 15 °C

Procedure:
202.6 parts of 2,4-dinitrochlorobenzene are converted into sodium 2,4-dinitrophenolate in accordance with the statements in Example 1 and, after adding 400 parts of water and 184 parts of ammonium chloride, the pH value is adjusted to 7.0. Reduction to sodium 2-amino-4-nitrophenolate is carried out with 580 parts of 31.9% strength hydrosulphide solution at pH values of at most 9, whilst stirring and monitoring the pH. After addition of the hydrosulphide, the mixture is subsequently stirred at 70° to 75° C. for about 45 minutes and the sulphur which has precipitated is filtered off. 100 g of sodium sulphite are added to the filtrate and the mixture is cooled to about 15° C. and adjusted to a pH of 5.6 to 5.8 with 136 parts of 30% strength hydrochloric acid. The mixture is subsequently stirred for about a further hour at 5° to 10° C. and filtered and the filter cake is rinsed with about 200 parts of 26% strength aqueous sodium chloride solution. 277.6 parts of a 53.3% strength aqueous press cake of 2-amino-4-nitrophenol, corresponding to 147.9 parts of 100% pure 2-amino-4-nitrophenol (96% of theory, relative to 2,4-dinitrochlorobenzene) are obtained. The product has a sulphur content of <0.1% and a melting point of 144° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].[Na]>CCO.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccn2)CCN(C)C1
Yield: 2.5 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (400 mg, 2 mmol), 2-vinylpyridine (500 mg, 5 mmol), sodium (30 mg, 1.3 g atom), and CuSO4 (20 mg, catalytic) were heated in EtOH (8 mL) at 150° C. overnight (16 h). The contents were evaporated to dryness under vacuo. Water was added and the contents were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6])=[O:4].P([O-])([O-])([O-])=[O:18].[K+].[K+].[K+]>C(O)C>[OH:18][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:15]=1)[CH:12]([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)C(C)c1ccc(C(O)C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Experimental description: 150 mg ibuprofen methyl ester was dissolved in 1.4 mL ethanol and added to 150 mL potassium phosphate buffer pH 8.0. P450BM3 was added to the mixture at a final concentration of 10 μM. The mixture was split in 4 mL-aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL 10 mM NADPH in KPi buffer was added to each vial and stirred for 2 minutes. 500 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 48 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5-40% ethyl acetate/hexane) afforded the activated product (methyl 2-(4′-(1″-hydroxy-2″-methylpropyl)phenyl)propanoate, 73 mg). 15 mg (0.06 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 11 μL DAST (0.72 mmol) was added. The reaction was stirred in dry ice for 16 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, methyl 2-(4′-(1″-fluoro-2″-methylpropyl)phenyl)propanoate (10 mg, 65% yield, colorless oil). 1H-NMR (300 MHz, CDCl3): δ 0.84 (d, J=6.9 Hz, 3H, CH3), δ 1.01 (d, J=6.9 Hz, 3H, —CH3), δ 1.49 (d, J=8.7 Hz, 3H, CH3), δ 2.05-2.08 (m, 1H), δ 3.66 (s, 3H, OCH3), δ 3.73 (q, J=7.5 Hz, 1H), δ 5.07 (dd, J=40.0, J=6.9 Hz, 1H, CHF), δ 7.25 (m, 4H); 13C-NMR (75 MHz, CDCl3): δ 15.5, 17.82 (d), 18.54 (d), 34.48 (d, J: 85.7 Hz), 45.37, 52.31, 99.3 (d, J=174 Hz), 175.6; 19F-NMR (282 MHz, CDCl3): δ −179.8 (m). HRMS (EI+): exact mass calculated for C14H19FO2 requires m/z 238.1369, found 238.1367.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cccc(-c2nc(C)cc(Cl)n2)c1
Product: COc1ccc(Nc2cc(C)nc(-c3cccc(C)c3)n2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) and p-anisidine (56 mg, 0.457 mmol), similar to Example 11 as a pale green solid (39 mg, 28%). 1H NMR (DMSO-d6): 8.04 (s, 1H), 8.01-7.99 (m, 1H), 7.56-7.51 (m, 4H), 7.04 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.79 (s, 3H), 2.44 (s, 6H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:25]1(=[O:30])[O:29][CH2:28][CH2:27][CH2:26]1.[C:31](=O)([O:34]C)[O:32][CH3:33].Cl>O1CCCC1>[CH3:33][O:32][C:31]([CH:26]1[CH2:27][CH2:28][O:29][C:25]1=[O:30])=[O:34]
Reactant: O=C1CCCO1
Reactant: COC(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCOC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
To a tetrahydrofuran solution (150 ml) of lithium hexamethyldisilazide prepared at −78° C. under an argon atmosphere from hexamethyl disilazane (55.4 ml, 262 mmol) and normal butyl lithium (2.62 M hexane solution, 100 ml, 262 mmol), a tetrahydrofuran solution (60 ml) of gamma butyrolactone (9.84 ml, 128 mmol) was added dropwise at −78° C. 10 minutes later, dimethyl carbonate (11.3 ml, 134 mmol) was added, followed by further stirring at room temperature for 10 hours. The reaction mixture was poured onto a mixture of concentrated hydrochloric acid (44 ml) and ice (500 g), followed by extraction twice with ethyl acetate. The extract was washed with brine, and subsequently dried over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, to obtain the desired compound (pale brown oil, 15.1 g, 82%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>CN(C)C=O>[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:8]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[OH:9])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(O)Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 23.0 g of anhydrous sodium carbonate in 75 ml of dry dimethylformamide is added 3.78 g of hydroxylamine hydrochloride followed by 24.72 g of p-tert-butylbenzyl bromide. After stirring at room temperature, the insoluble inorganic residue is removed by filtration and the mixture is concentrated under reduced pressure. Preparative liquid chromatography on the crude product affords a white solid, mp 108°-110° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(C(F)(F)F)ccc12
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(C(F)(F)F)cc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-9-trifluoromethyl-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-benzamide to provide 403. LC-MS (M+H=475, obsd.=475). 1H NMR (400 MHz, DMSO-d6): δ 6.96 (d, 1H), 7.18 (d, 2H), 7.54 (m, 3H), 7.76 (m, 2H), 7.78 (d, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 8.99 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:18]I>O.CC(O)=O>[I:18][C:9]1[CH:10]=[CH:11][C:6]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: II
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A solution of H2SO4 (0.1 mL) in water (1 mL) and AcOH (4 mL) in a 25 mL flask was added trans-2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol), iodine (173 mg, 0.68 mmol) and KIO3 (61 mg, 0.28 mmol). The reaction mixture was heated to reflux, and added AcOH (6 mL) in portions of 2 mL to rinse iodine down the condenser. After 4 hours, when no further color changes appeared, the reaction was cooled to room temperature, quenched with 1M Na2S2O4 and added water. The mixture was extracted with EtOAc (3×), and the combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product containing minor impurities of starting material and the ortho-iodinated product, was recrystallized from PE to provide 157 mg (44%) trans-2-(4-iodophenyl)cyclopropanecarboxylic acid as a pure and white crystalline product: Rt=11.33 min (HPLC method I); 1H NMR (CDCl3) δ 7.62-7.58 (m, 2H), 6.87-6.84 (m, 2H), 2.56-2.51 (m, 1H), 1.89-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.39-1.34 (m, 1H); 13C NMR (CDCl3) δ 179.3, 139.2, 137.6, 128.3, 91.7, 26.5, 23.9, 17.4; ESI-MS m/z 311.0 (M+Na+).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:26]=[CH:27][CH:28]=1.Cl.C(N=C=N)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:30])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:24]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and (3-amino-phenyl)phenyl-methanone (148 mg, 0.75 mmol) in DMF (5.0 mL) were added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-diisopropylethylamine (DIPEA) (0.13 ml, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=12:3:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(3-benzoyl-phenyl)-acetamide as a white solid (173.1 mg, 74.3% yield).