Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:17]F>C(=O)(O)[O-].[K+]>[F:17][N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: FF
Reactant: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Yield: 56.7 %

Procedure:
N-Neopentyl-p-toluenesulfonamide (2.41 g, 10 mmole) was dissolved in 1:1 fluorotrichloromethanechloroform (450 mL) and the solution was cooled to -78° under nitrogen. Fluorine (approximately 15 mmole, 5% in nitrogen) was bubbled into the solution through a vibrating mixer shaft for 2 h. The cold reaction mixture was poured into aqueous 10% potassium bicarbonate solution (200 mL) and the layers were separated. The organic phase was washed with aqueous 10% sodium thiosulfate (200 mL) and saturated sodium chloride (200 mL) solutions and dried over anhydrous magnesium sulfate. Filtration and removal of solvent under reduced pressure left a solid. Purification of the solid by flash column chromatography (silica, 25% methylene chloride in hexane) yielded N-fluoro-N-neopentyl-p-toluene-sulfonamide as a solid (1.47 g, 57% yield). This material, and additional samples prepared by this procedure, were analyzed and provided the following results: mp 58°-62.5°; IR (KBr) γmax (cm-1) 3440 (b), 2980 (w), 1370 (m), 1175 (s), 734 (m); 1H NMR (80 MHz, CDCl3) δ1.00 (s, 9H, C(CH3)3), 2.50 (s, 3H, CH3), 3.00 (d, J=44 Hz, 2H, NCH2), 7.40 (d, J=8 Hz, 2H, aromatic), 7.83 (d, J=8 Hz, 2H, aromatic); 19F NMR (94.1 MHz, CDCl3) -36.88 (t, J=44 Hz, 1F, NF); HRMS calcd. for C12H18NO2SF: 259.1042; found: 259.1029.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH2:15][C:25]1[CH:26]=[CH:27][CH:28]=[C:21]([CH3:20])[C:22]=1[C:23]#[N:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cccc(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1C#N
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (2.99 g, 9.27 mmol) and Pd(PPh3)4 (536 mg, 0.464 mmol) in DME (10 mL) is heated to 60° C. for 2 min. in a microwave. 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (5.96 g of crude, ˜13.9 mmol) in DME (10 mL) and EtOH (2 mL) is added along with Na2CO3 (2 M, 3.3 mL). The reaction mixture is heated to 110° C. for 30 min. by microwave. Then the reaction is heated to 120° C. for an additional 15 min. by microwave. The reaction mixture is diluted with DCM (150 mL) and extracted with water (50 mL). The aqueous layer is extracted with DCM (30 mL) and the combined organics is dried over Na2SO4. Evaporation yields a brown oil, and it is then purified by flash column to yield a tan solid as the title compound: MS (M−H)−=357.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[F:1][C:2]1[CH2:3][C:4]([N+:11]([O-:13])=[O:12])([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)c(F)c(F)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])C1(O)C=C(F)C(F)=C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trifluorophenol (14.81 g, 0.1 mol) was dissolved in glacial acetic acid (50 mL) and cooled to 4° C. while concentrated nitric acid (5 mL, 70%) was added dropwise over 15 min, during which time the color of the mixture becomes yellow. Upon complete addition of HNO3, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. TLC analysis of an aliquot extracted into ethyl acetate indicates that a new non-polar spot was formed and the complete consumption of starting material. The mixture was then diluted with ethyl acetate (200 mL), transferred to separatory funnel, and washed copiously with water (3×100 mL). The organic layer was finally washed with brine, dried over anhyd MgSO4, and evaporated under reduced pressure to afford crude product as a yellowish oil. (17.3 g, 90%). This crude material was used directly in the subsequent reaction described in Intermediate 6. 1H NMR (400 MHz, CDCl3): 6.84 (m, 1H, ArH), 10.28 (brs, 1H, OH).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C.C(OCC)(=O)C>O1CCCC1>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N)c1ccc2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3-fluorophenyl)quinoline (0.146 g, 0.500 mmol) in tetrahydrofuran (1 mL) and water (0.360 mL, 20.0 mmol) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.600 mL, 0.600 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with the same desired mass and was used directly in next step. LCMS calculated for C17H16FN2(M+H)+: m/z=267.1; found: 267.0.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH2:9](C(CC)C=O)[CH3:10]>O>[CH2:5]([CH:4]([CH2:9][CH3:10])[CH:3]=[CH:2][C:1]([OH:8])=[O:7])[CH3:6]
Reactant: CCCC=CC(=O)O
Reactant: CCC(C=O)CC
Solvent: O
Product: CCC(C=CC(=O)O)CC
Temperature: 90 °C
Yield: 84.1 %

Procedure:
The procedure followed was analogous to part (b) of Example 1, with the exception that, before the cracking reaction, the mixture, together with the added water, was boiled under reflux for 50 minutes at 90° C. and under a correspondingly reduced pressure. 260 g of 4-ethylhexenoic acid (boiling point 139°-141° C./25) were obtained, corresponding to a yield of 84.1%, relative to 2-ethylbutanal which had reacted.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[C:13]([CH3:15])[C:10]([C:11]#[N:12])=[C:9]([CH3:16])[CH:8]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>O1CCCC1>[C:11]([C:10]1[C:13]([CH3:15])=[CH:14][C:7]([B:17]([OH:22])[OH:18])=[CH:8][C:9]=1[CH3:16])#[N:12]
Reactant: Cc1cc(Br)cc(C)c1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.55 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 1.39 g of 4-bromo-2,6-dimethylbenzonitrile in 25 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 20 minutes, 1.88 ml of triisopropyl borate are added. After 45 minutes, 15 ml of 1N aqueous HCl are added to the reaction mixture, which is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1:1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 50 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in the title compound as a beige solid. Rt=3.20.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][O:30][NH:31][CH3:32]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([N:31]([CH3:32])[O:30][CH3:29])=[O:14])[O:7][CH2:6][CH2:5]2
Reactant: CNOC
Reactant: COc1c(Br)ccc2c1CCOC2C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1c(Br)ccc2c1CCOC2C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid (600 mg, 2.08 mmol) and CDI (475 mg, 2.93 mmol) in 20 mL of dry DCM was stirred at r.t. for 0.5 hours and then O,N-dimethyl-hydroxylamine (285 mg, 2.93 mmol) was added. The result mixture was stirred overnight. The solvents were removed under vacuum, and the residue was purified by preparative TLC to give 6-bromo-N-methyl-N,5-bis(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 32.4 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with p-toluenesulfonyl chloride (1.07 g, 5,62 mmol) to provide 750 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a solid, m.p. 189-191° C. Analysis: Calculated for C23H27N5O3S 0.50H2O: % C, 59.72; % H, 6.10; % N, 15.14; Found: % C, 59.73; % H, 5.95; % N, 15.08.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[O:13]>CS(C)=O>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:12](=[O:13])[N:11]([C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH3:1])[C:12](=[O:13])[N:11]([C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH3:1])[C:12]2=[O:13])=[C:2]([CH3:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1-n1c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c1=O
Temperature: 85 °C
Yield: 78.1 %

Procedure:
To 2-methyl-4-nitrophenylisocyanate (36.0 g) in a 250 ml flask was added DMSO (50 ml) and the flask was sealed with a glass stopper which was kept in place with a plastic clip. The flask was immediately lowered into an oil bath heated to 85° C. and the dark brown reaction solution was heated for 16 h 30 min. The oil bath was removed and the reaction solution was allowed to cool to room temperature before being poured into water (800 ml), sonicated, and the precipitate was filtered off. The filter cake was added to ethanol (500 ml) and was refluxed for 4 hours, then allowed to cool to room temperature and the product was filtered off to give an off-white powder (28.1 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([NH:37][NH2:38])=[O:36])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH:38][NH:37][C:35](=[O:36])[C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:39])[CH:30]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)NNC(=O)c4cccc(C)c4)s3)c2cc1OC
Yield: 3.8 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and m-toluic acid hydrazide (15.0 mg, 0.1 mmol, Lancaster) gave 3-Methyl-benzoic acid N′-[4-(3-chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carbonyl]-hydrazide (2.1 mg, 3.8%) as a white solid. MS m/z 548 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6](Cl)=[O:7].Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:16]=1)=[O:7]
Reactant: O=C(Cl)COCCCl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)COCCCl)cc1

Procedure:
14.6 g (92.7 mmol) of (2-chloroethoxy)acetyl chloride are added to a suspension of 20.0 g (92.7 mmol) of ethyl 4-aminophenylacetate hydrochloride in 25 ml of toluene, and the mixture is heated at the boil for 24 hours. The reaction mixture is evaporated and dried, giving ethyl {4-[2-(2-chloroethoxy)acetylamino]phenyl}acetate as a yellowish solid; ESI 300.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(=O)c2cccnc2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3.2 g (14.3 mmol) of 3-cyclopentyloxy-4-methoxy-phenylamine (Garcia et al., JOC, 2005, 70, p 1050) were dissolved in 120 ml of DCM. The solution was cooled to 0° C. and 15 ml (107.6 mmol, 7.5 eq.) triethylamine and 3.7 g (26.1 mmol; 1.8 eq) nicotinoyl chloride in 50 ml DCM were added to the reaction mixture. The reaction mixture was stirred for 2 h and then a solution of 1.3 g NaOH in 50 ml water was added to the mixture. The organic phase was separated and washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 1:1) to afford 4 g (85%) of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[O:21][C:15]=2[CH:16]=1
Reactant: O=C(Nc1ccc(F)cc1O)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3

Procedure:
In the same manner as in Example 74 and using 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one is obtained.
Reaction SMILES: [CH:1]1([N:7]2[CH2:27][CH2:26][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=4)[CH2:12][C@H:11]([OH:25])[CH2:10]3)[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[N:34][CH:35]=1.CN(C=O)C.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([N:7]2[CH2:27][CH2:26][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:30]5[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[N:34][CH:35]=5)=[C:17]([F:24])[CH:16]=4)[CH2:12][C@H:11]([OH:25])[CH2:10]3)[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)NC(=O)c1ccc(Br)cn1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(-c2ccc(CN3C[C@H](O)CC34CCN(C3CCCCC3)C4=O)cc2F)cn1
Temperature: 130 °C

Procedure:
To a solution of (4-{[(3R)-7-cyclohexyl-3-hydroxy-6-oxo-1,7-diazaspiro[4.4]non-1-yl]-methyl}-2-fluorophenyl)boronic acid (24.0 mg, 0.0000614 mol; which was prepared by using procedures that were analogous to those described for the synthesis of Example 32, steps 1-3 using peak 2 from step 2) and 5-bromo-N-isopropylpyridine-2-carboxamide (18 mg, 0.000074 mol) in DMF (0.8 mL, 0.01 mol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (3.01 mg, 3.68E-6 mol) and potassium carbonate (25 mg, 0.00018 mol). The resulting mixture was heated at 130° C. under an atmosphere of nitrogen for 16 h to afford the desired product which was purified by prep-HPLC. LC/MS: 509.2 (M+1H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.CN(C)[N:15]=[CH:16][C:17]([F:20])=[CH:18][CH3:19]>C(Cl)(Cl)Cl>[F:20][C:17]1[CH:16]=[N:15][C:9]2[C:7](=[O:8])[C:5]3[C:4]([C:11](=[O:12])[C:10]=2[C:18]=1[CH3:19])=[CH:3][CH:2]=[CH:1][CH:6]=3
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CC=C(F)C=NN(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cnc2c1C(=O)c1ccccc1C2=O
Yield: 15 %

Procedure:
A solution of naphthoquinone (553 mg, 3.5 mmol) and 2-fluoro-2-butenal N,N-dimethylhydrazone was refluxed for 8 days in chloroform (15 ml.) After the solvent was evaporated at reduced pressure, the residue was chromatographed over silica gel column, eluting with petroleum ether-ethyl acetate (9:1) and yielded 63 mg (10%) of compound (I-k) and 90 mg (15%) of 3-fluoro-4-methyl-1-azaanthracen-9-10-dione. m.p. 190°-192° C. (CDCl3).
Reaction SMILES: [CH:1]([C:3]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:4]=1[O:5][CH3:6])=[CH2:2].Cl[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>>[CH:1]([C:3]1[C:4]([O:5][CH3:6])=[CH:7][CH:8]=[CH:9][C:10]=1[N:11]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1)=[CH2:2]
Reactant: ClC1=NCCN1
Reactant: C=Cc1c(N)cccc1OC
Product: C=Cc1c(N=C2NCCN2)cccc1OC
Yield: 47 %

Procedure:
Reaction of the 2-ethenyl-m-anisidine with 2-chloro-imidazoline by the method described in Example 2 gives a 47% yield of 2-(2-ethenyl-3-methoxyphenylimino)imidazolidine, m.p. 125.5°-126° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)([CH3:3])[CH3:2].[F-:12].[K+]>>[CH:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([F:12])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)Nc1ncc(Br)cn1
Agent: [K+]
Product: CC(C)Nc1ncc(F)cn1
Yield: 83 %

Procedure:
Stoichiometric proportions of 2-isopropylamino-5-bromo-pyrimidine, prepared as described in example 1, and potassium fluoride were reacted together for 5 hours. After appropriate working up, the title compound was obtained as a white powder in a yield of 83%. Elemental analysis showed that the compound had the expected empirical formula of C7H10N3F.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:13]([O:15][C:16]([C:18]1([NH2:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: CCOC(=O)C1(N)Cc2ccc(F)c(F)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)c(F)c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (1.31 g, 5 mmol), 2-amino-4,5-difluoro-indan-2-carboxylic acid ethyl ester HCl salt (D7, 1.38 g, 5 mmol), HATU [O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6, 3.8 g, 10 mmol) in anhydrous DMF (20 mL) is added DIPEA (N,N-diisopropylethylamine, 3.3 mL, 15 mmol). The resulting solution is stirred at room temperature for two days. After the removal of DMF in vacuo, the residue obtained is dissolved in ethyl acetate (200 mL) and washed with saturated NaHCO3 (1×100 mL) and brine (2×100 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The obtained residue is purified by flash column chromatography (24 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (386) as white solid (1.93 g, 79%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1.[CH3:11]I>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[N:8]([CH3:11])[CH:9]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)ccc1=O
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0° C. The resulting mixture was stirred for 1 h and CH3I (35.5 g, 0.25 mol) was added. The mixture was stirred for 3 h. The reaction was quenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column chromatography to give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g, 96.78%). 1H NMR (CDCl3): δ=3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H), 7.45 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH:9]1[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:9]1([CH2:8][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:11][CH2:10]1
Reactant: BrCC1CC1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Iodo-1H-pyrazole (0.50 g, 2.5 mmol), bromomethyl cyclopropane (0.75 mL, 7.5 mmol), and cesium carbonate (1.20 g, 3.75 mmol) were combined in DMF (10 mL) and stirred at room temperature for overnight. The mixture was subjected to standard aqueous workup, and the crude residue was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:15]1[O:19][N:18]=[C:17]([OH:20])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].[Cl-].C(C(CCCC)C[N+]1C=CC=CC=1)C>C1(C)C=CC=CC=1>[C:11]([C:15]1[O:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:17](=[O:20])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)c1cc(O)no1
Agent: CC(C)(C)[O-]
Agent: CCCCC(CC)C[n+]1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])cc2)o1
Yield: 6.5 %

Procedure:
5.0 g of 4-fluoronitrobenzene, 5.0 g of 5-t-butyl-3-hydroxyisoxazole, 4.0 g of potassium t-butoxide, and 70 ml of toluene were mixed, and after adding 0.5 g of 1-(2-ethylhexyl)pyridinium chloride to the mixture, the resultant mixture was refluxed for 10 hours. The reaction mixture obtained was cooled and carefully applied to silica gel column chromatography to provide 0.6 g of the above-described compound with a yield of 6.5%. The melting point thereof was 125° C. to 127° C.