Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.390 g, 1.504 mmol) in CH2Cl2 (10 mL) were added benzylamine (0.164 mL, 1.504 mmol), HOAt (0.205 g, 1.504 mmol) and EDC (0.346 g, 1.805 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (3×) and the organics were then dried over Na2SO4 and concentrated to afford the title compound (0.551 g). LC-MS (ES) m/z=249 [M+H-Boc]+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:47])[C@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])=[O:38])=[CH:32][CH:31]=1)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)(=[O:18])=[O:17])=[CH:12][C:11]=1[Cl:28])=[O:9]>CO.O1CCCC1>[Cl:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([Cl:45])[C:39]=1[C:37]([NH:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C@@H:6]([C:5]([OH:47])=[O:4])[NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:28])=[O:9])=[CH:35][CH:34]=1)=[O:38]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
An aqueous 1N lithium hydroxide solution (0.25 mL) was added to a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine methyl ester (51 mg; 0.0738 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.35 mL). After the reaction was stirred at room temperature for 90 minutes, the solvents were removed under reduced pressure. The crude product in the minimum amount of methanol was then applied to a column of silica eel (5 g) made up in a mixture of chloroform, methanol, acetic acid and water (15:3:1:0.6). The column was eluted with the same solvent mixture and the appropriate fractions were combined and evaporated. The residue was lyophilized from deionized water to give 36 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine as an off white solid. FAB HRMS: (C30H24Cl3N3O7S) Obs. Mass 676.0482 Calcd. Mass 676.0479 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:16][CH:15]=[C:14]([Cl:34])[N:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1.C(N(CC)CC)C.[F:42][C:43]1([F:60])[C:47]2[N:48]([CH2:55][C:56](O)=[O:57])[N:49]=[C:50]([C:51](F)([F:53])[F:52])[C:46]=2[C@H:45]2[CH2:59][C@@H:44]12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:34][C:14]1[N:13]=[C:12]([C@@H:2]([NH:1][C:56](=[O:57])[CH2:55][N:48]2[C:47]3[C:43]([F:42])([F:60])[C@@H:44]4[CH2:59][C@@H:45]4[C:46]=3[C:50]([CH:51]([F:53])[F:52])=[N:49]2)[CH2:3][C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:16][CH:15]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude (S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (60A, 400 mg, 0.76 mmol) in DMA (6 mL) was added triethylamine (0.32 mL, 2.28 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J, 0.61 mmol), then HATU (173.4 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then additional HATU (86.7 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for an additional 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound (60B). MS (m/z) 790.05 [M+H]+.
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH3:4])=[CH:13][CH:14]=1)#[N:17]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: O=CO
Product: CNc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)(C)C>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([NH:28][CH2:27][CH2:25][OH:26])=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:6]=1[OH:24])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Reactant: NCCO
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NCCO)s2)cc(C(C)(C)C)c1O
Yield: 84 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (4.0 g, 0.0109 mole) in isopropyl alcohol (15 ml) is added ethanolamine (1.9 g, 0.0326 mole). The resulting mixture is heated to reflux for 18 hours. The reaction is cooled and concentrated in vacuo. The resulting solid is recrystallized from methanol/water to give 3.2 g (3.8 g theor., 83%) of 2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol after drying in vacuo at 65° C., mp 212°-213.5° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C@H:9]([CH2:12][C@H:13]([OH:38])[C@@H:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:15]([O:28][CH3:29])[CH2:16][C@@H:17]([CH3:27])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:10][OH:11]>N1C=CC=CC=1>[C:1]([O:11][CH2:10][C@H:9]([CH3:8])[CH2:12][C@H:13]([OH:38])[C@@H:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:15]([O:28][CH3:29])[CH2:16][C@@H:17]([CH3:27])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CO[C@@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@H](OCc1ccccc1)[C@@H](O)C[C@@H](C)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CO[C@@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@H](OCc1ccccc1)[C@@H](O)C[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pivaloyl chloride (870 microliters, 1.05 equiv) was added to a solution of (2R,4S,5R,6S,8R)-2,8-dimethyl-4-hydroxy-5-benzyloxy-6-methoxy-9-t-butyldimethylsilyloxynonanol 21 (Source: Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I.; Tetra. Lett., 1988, 29, 277.) (3.07 g, 6.75 mmol) in 50 ml of anhydrous pyridine at 0° C. The solution was warmed to 25° C. over 1 hr and then was stirred at 25° C. for 16 hr. The reaction mixture was quenched by the addition of 10 ml of saturated aqueous sodium bicarbonate solution and then partitioned between75 ml of water and 150 ml of diethyl ether. The aqueous phase was extractedwith an additional 2×100 ml portions of ether. The organic phases were combined, washed with 1×50 ml of water and 1×50 ml of saturated sodium chloride solution, and dried over magnesium sulfate. Concentration in vacuo gave 3.67 g of 22 as a crude oil. The oil was purified by chromatography on 180 g of silica gel eluting with 5:1 hexanes:ethylacetate to give 3.52 g of pivaloate 22 (97% yield). The material was homogeneous by 1H and 13C NMR.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[ClH:1].[F:21][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]2(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1cccc(F)c1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2cccc(F)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(3-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (32 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (26 mg):
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: Cc1c(F)cccc1Cl
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(Cl)ccc(C(=O)O)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
29.0 g (0.200 mol) of 6-chloro-2-fluorotoluene are dissolved, with stirring, in 200 ml of dry THF. After cooling to -70° C., 151.0 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After 2 hours, the reaction mixture maintained at -70° C. is poured onto solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24%; melting point: 198° C.).
Reaction SMILES: O.[N+:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(CCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 62.9 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 25.1 g of 1,2-bis(4-(4-nitrobenzyl)phenyl)ethane in 400 milliliters of tetrahydrofuran were introduced and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a toluene solvent, to obtain 13.7 g of 1,2-bis(4-(4-aminobenzyl)phenyl)ethane. Melting point was from 138.8° to 140.4° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:12][C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:12]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: CI
Reactant: Cc1ccnc2[nH]c(CO)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc2c1nc(CO)n2C

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 5.00 g of 2-hydroxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine, 1.34 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.0 ml of methyl iodide and 120 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 4.4 g of the title compound, melting at >300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To 2,4-difluoro-phenol (35, 7.60 g, 0.0584 mol) in N,N-dimethylformamide (50.0 mL) were added benzyl bromide (8.0 mL, 0.067 mol) and potassium carbonate (9.00 g, 0.0651 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as white solid (525, 3.20 g, 25%).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:33]([O:32][C:30]([C:23]1([CH3:29])[C:22]2[C:26](=[CH:27][C:19]([NH:18][C:15]([C:12]3[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=3)=[O:16])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])=[O:31])[CH3:34]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(N)ccc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)ccc21

Procedure:
22.1 ml. Triethylamine and 9.4 g. (0.053 mol) pyridine-4-carboxylic acid chloride hydrochloride are added to a cooled solution of 13 g. (0.048 mol) 6-amino-3-ethoxycarbonyl-3-methylindolin-2-one in 500 ml. methylene chloride and the reaction mixture then stirred at ambient temperature for about 2 hours. Subsequently, the reaction mixture is evaporated to dryness and the residue is stirred with water, filtered with suction and the product obtained is recrystallised from ethanol/methylene chloride. Yield: 11.9 g. (73% of theory); m.p. 222°-224° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][OH:21].[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[F:1][C:2]1[C:3]([CH2:20][OH:21])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19]2)=[N:12][CH:13]=1
Reactant: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
{2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg) was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetyl chloride (48 mg) were added thereto at 0° C. The reaction mixture was concentrated under reduced pressure, the residue was mixed with MeOH, and a 1 M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1 M hydrochloric acid was added to the reaction mixture, and CHCl3/water was added to the reaction liquid. The aqueous layer was extracted with CHCl3, and the prepared organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone (90 mg).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.C1C2C3C=CC(C2C=C1)C3.[CH3:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:22]1([C:5]2[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=2[NH2:7])[CH2:23][CH2:24][CH:20]=[CH:21]1
Reactant: Cc1ccc(N)cc1N
Reactant: CCCCC
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: Cc1cc(C2C=CCC2)c(N)cc1N
Temperature: 205 °C

Procedure:
A 200g (1.64 mol) portion of 2,4-toluenediamine, 162g (1.23 mol, 2,45 equiv) of dicyclopentadiene, 200g (2.78 mol) of pentane, and 20.0g of an amorphous alumina-silica catalyst comprised of 13% alumina and 87% silica were charged to a 1000cc pressure vessel equipped with a mechanical stirrer. The vessel was sealed and purged with nitrogen leaving a 32 psig nitrogen blanket. The vessel contents were heated to 205° C. with stirring and were maintained at that temperature for 22 hours. The contents were cooled to 150° C. and isolated catalyst free by hot filtration. Selective removal of residual hydrocarbons by vacuum distillation and analysis by gas chromatography (GC) provides the following product mixture.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Br)=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:18][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Fc1cc(CCBr)ccc1OCc1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(CCN2CCOCC2)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.6 %

Procedure:
To a solution of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene (1.0 g, 3.2 mmol) and morpholine (278 mg, 3.2 mmol) in DMF (5 mL), was K2CO3 (432 mg, 3.2 mmol) added. The reaction mixture was heated to 60° C. and maintained for 6 hours. The reaction was cooled to room temperature and poured into H2O (50 mL). The organic compound was extracted with ethyl acetate (50 mL) and dried over MgSO4. The ethyl acetate layer was concentrated under vacuum and dissolved in methanol (50 mL). The solution was treated with Pd/C (20 mg) and stirred under H2 (1 atm) for 3 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (790 mg, 93%) as a white oil. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.33-7.45 (m, 5H), 7.09-7.15 (m, 2H), 6.97-7.01 (m, 1H), 5.13 (s, 2H), 3.56 (m, 4H), 2.64-2.68 (m, 2H), 2.44-2.50 (m, 2H), 2.39 (b, 2H). LCMS 310.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[Cl:21].CO>C1COCC1.[Ni]>[Cl:21][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(C=C/C=C/c2ccc(Cl)c(Cl)c2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 77.1 %

Procedure:
The title compound was prepared from (trans), (trans)-1,2-dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene (15.42 g, 0.048 mol), Ra—Ni (1 g) at 20° C. to 26° C. (ΔP=19.3 psi) under a hydrogen atmosphere in THF (75 mL) and MeOH (75 mL) using the procedure described in Example 1, Step B. This procedure yield a solid, 10.97 g (0.037 mol, 78%) of the desired product. mp 50-52° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[F:21][N+]1C=C(OC(F)(F)F)C=CC=1S([O-])(=O)=O>ClCCl>[F:21][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: CCCc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Reactant: O=S(=O)([O-])c1ccc(OC(F)(F)F)c[n+]1F
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc3c(F)c(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
3.4 g of 4-propylphenylboric acid (obtained by reacting a Grignard reagent prepared from 1-bromo-4-propylbenzone with trimethyl borate, and then subjecting the product to hydrolysis with hydrochloric acid) and 25.5 g of 6-bromo-2-naphthol ware dissolved in a mixture of 92 ml of toluene, 46 ml of ethanol and 92 ml of water. To the solution were then added 25.5 g of potassium carbonate and 1.3 g of tetrakia (triphenyl phosphine) palladium (0). The reaction mixture was then stirred at a temperature of 75° C. for 7 hours. To the reaction solution were then added water and toluene. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate The solvent was then distilled off under reduced pressure to obtain 41.4 g of 6-(4-propylphenyl)naphthalone-2-ol. 12.7 g of 6-(4-propylphenyl)naphthalene-2-ol was then dissolved in 50 ml of dichloromethane. To the solution was then added 13.1 g of N-fluoro-5-trifluoromethoxypyridinium-2-sulfonate. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was post-treated in the same manner as mentioned above to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 10 g of 1-fluoro-6-(4-propylphenyl)naphthalene-2-ol. The product was converted to S-ethyl dithiocarbonate which was then trifluoromethoxylated in the same manner as in Example 1 to obtain 2.3 g of the titled 1-fluoro-2-trifluoromethoxy-6-(4-propylphanyl)naphthalene.