Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[CH2:19]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH3:20].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.CO>[CH2:19]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]3[C:7]4[CH:18]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=4[O:10][C:9]3=[O:11])[CH2:17][CH2:16]2)[CH2:24][CH2:23]1)[CH3:20]
Reactant: O=c1oc2ccc(F)cc2n1C1CCNCC1
Reactant: CCOC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCO[C@H]1CC[C@H](N2CCC(n3c(=O)oc4ccc(F)cc43)CC2)CC1
Reaction time: 2 h

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one hydrochloride D138 (0.2 g), 4-(ethyloxy)cyclohexanone (WO2007107566) (0.2 g), and Hunig's base (0.1 g) in N-methylpyrrolidone (5 mL) was stirred for 2 hours then treated with sodium triacetoxyborohydride (0.5 g) was added and stirring was continued for four days. The mixture was diluted with methanol, loaded onto a SCX column and the column was eluted with methanol followed by 2M ammonia in methanol. The methanolic ammonia fractions were evaporated and the residue was purified by high pH MDAP. Two peaks were collected and evaporated separately. The fast eluting isomer gave 3-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one E52 as a white solid (7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH2:15][CH2:16][CH:17]([C:19]3[CH:32]=[CH:31][C:22]4[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27][C:21]=4[CH:20]=3)O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:33])[CH2:15]/[CH:16]=[CH:17]/[C:19]3[CH:32]=[CH:31][C:22]4[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27][C:21]=4[CH:20]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)N1CCc2ccc(C(O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCc2ccc(/C=C/CC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Yield: 54.7 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-1-piperidinyl]-1-(3-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-oxo-1-butanol (0.14 g, 0.30 mmol) obtained in Example 212 and p-toluenesulfonic acid monohydrate (0.03 g, 0.16 mmol) in toluene (10 mL) was refluxed for 24 hours under heating. The reaction solution was concentrated under reduced pressure, and the resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1), whereby 0.09 g free base of the title compound was obtained as colorless amorphous powder. The resultant powder was dissolved in ethyl acetate and treated with 4 N hydrochloric acid in ethyl acetate under cooling with ice-bath, whereby 0.04 g of the title compound was obtained as colorless amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:7]=1)=[O:5])[CH3:2].S(OCC)(O[CH2:18][CH3:19])(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:18][CH3:19])[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: CCOS(=O)(=O)OCC
Product: CCCc1cc(C(=O)OCC)n(CC)n1

Procedure:
This pyrazole was prepared from 3-n-propylpyrazole-5-carboxylic acid ethyl ester and diethyl sulphate, following the procedure described in Example 1, and was obtained as a colourless oil (72%). Rf 0.5 (silica; ethyl acetate, hexane; 1:1).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14].C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[CH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]#[N:14]
Reactant: O=CC1CCCCC1
Reactant: COC(CC#N)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C#N)=CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexanecarboxaldehyde (50.0 g, 0.45 mol) was added to a stirred mixture of 3,3-dimethoxypropionitrile (11.5, g, 1.0 mol) and sodium methoxide (54.0 g, 1.0 mol) in methanol over a period of 15 minutes. The mixture was then stirred overnight at room temperature.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:17][F:7])[N:14]=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cc(Cl)ncn1
Solvent: ClCCl
Product: FCc1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
(Diethylamino)sulphur trifluoride (0.145 mL, 1.096 mmol) was added to DCM (5.5 mL), cooled to −78° C. and treated dropwise with a solution of (6-chloro-4-pyrimidinyl)methanol (Intermediate 25, 132 mg, 0.913 mmol) in DCM (2 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by adding water (5 mL) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-25% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (40 mg);
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[C:20]=[O:21]>ClCCl>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH:18][C:20]([NH:19][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:29]([F:30])([F:32])[F:31])[CH:23]=1)=[O:21]
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2c(C)ccc3c2ncn3Cc2ccncc2)cc1C(F)(F)F
Reaction time: 4 h

Procedure:
Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask and dissolved in dichloromethane (3 mL). 4-Isocyanato-1-methyl-2-trifluoromethyl-benzene (85 mg, 0.42 mmol) is added as a solid and the homogeneous mixture is stirred for 4 h. The precipitate is collected via filtration and the solids are washed with ether and collected to yield compound 2h as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH3:18])=[CH:12][CH:11]=1)[C:6](=[N:8][OH:9])[CH3:7])[CH3:2].[H-].[Na+].[CH3:28][O:29][C:30](=[O:43])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Br)=[CH:32][O:33][CH3:34]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:43])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][O:9][N:8]=[C:6]([CH3:7])[C:5](=[N:4][O:3][CH2:1][CH3:2])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH3:18])=[CH:12][CH:11]=1)=[CH:32][O:33][CH3:34]
Reactant: CCON=C(C(C)=NO)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(C(C)=NOCc1ccccc1C(=COC)C(=O)OC)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7 g of 1-[4-(1-{4-chlorophenyl)-ethoxy}-phenyl]-1,2-propanedione-[ethyloxime]-2-oxime dissolved in 25 ml of N,N-dimethylformamide are added dropwise to a suspension of 0.9 g of sodium hydride (55% in oil) in 40 ml of N,N-dimethylformamide and the reaction mixture is then stirred for 10 minutes at room temperature. 5.5 g of 2-(bromomethyl)-α-(methoxymethylene)-phenylacetic acid methyl ester in 20 ml of N,N-dimethylformamide are then added dropwise and the reaction mixture is stirred for a further 1 hour at room temperature. The mixture is then rendered acidic with acetic acid and concentrated by evaporation in vacuo. The residue is dissolved in ethyl acetate and the solution is washed three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:3) yields the E isomer of the title compound having a melting point of 107-109° C. (compound 1-4.2).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:17](Cl)=[O:18].Cl>O.CC(C)=O>[F:15][C:16](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:17]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(C=C(F)C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C=C(F)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
L-phenylalanine (13.2 g, 0.080 mole) and 6N NaOH (43 ml, 0.086 mole) were dissolced in a solvent prepared by mixing water (77 ml) with acetone (240 ml). To the mixture, while cooling to less than 10° C., the acetone solution of α-fluoro-4-methyl cinnamic acid chloride prepared as above and 2N NaOH (38 ml, 0.076 mole) were alternately added over 20 minutes. Next, the mixture was stirred at normal temperature for 30 minutes, and the reaction solution was made acidic by the addition of 2N HCl. Then, water (200 ml) was gradually added thereto. The thus precipitated crystals were recovered by filtration and dried to give crude crystals (16.7 g). The crude crystals were recrystallized from a mixture of methanol and water to obtain N-(α-fluoro-4-methylcinnamoyl)-L-phenylalanine (yield 15.5 g) in the form of white needle-like crystals having a melting point of 163° to 163.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1I
Yield: 92.9 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-6-iodobenzamide (1.0 g, 3.5 mmol), oxalyl chloride (0.538 g, 4.2 mmol) and EDC (20 mL) to afford 1.00 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17]1
Reactant: CCCI
Reactant: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(trifluoro-methyl)phenyl]piperazine (0.97 g, 3.9 mmol), acetonitrile (50 ml), potassium carbonate (0.81 g, 5.86 mmol) and 1-iodopropane (0.457 ml, 4.6 mmol). Yield: 0.57 g (50%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 180-181° C. MS m/z (relative intensity, 70 eV) 290 (M+, 22), 262 (13), 261 (bp), 218 (18), 190 (22).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1>CCOC(C)=O.[Pd]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([F:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(F)cc1N
Reaction time: 3 h

Procedure:
To a solution of methyl 4,5-difluoro-2-nitrobenzoate 1b (23.0 g, 106 mmol) in EtOAc (200 mL), was added 10% Pd/C (wet, 50% water, 6.0 g), and the mixture was shaken on a Parr hydrogenator at 50 PSI for 3 hr. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated by rotary evaporation to yield methyl 2-amino-4,5-difluorobenzoate 1c as a colorless solid, 19.0 g (96%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCOCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and morpholine are converted to the named compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.[O:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][C:28](Cl)=[O:29])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:16][C:28](=[O:29])[CH2:27][C:20]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=2[O:17][CH3:18])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: N#Cc1c(N)cc(N)nc1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
To a solution of 50 mg (0.24 mmol) of 4,6-diamino-2-phenyl-nicotinonitrile in 2 mL of CH2Cl2 was added 150 mg (0.70 mmol) of (2,5-dimethoxyphenyl)acetyl chloride (Example 68A), then 100 μL (1.23 mmol) of pyridine. The mixture was stirred at ambient temperature for 10 minutes then the solvent was removed under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, then extracted with 1 M HCl(aq.) (2×5 mL), saturated NaHCO3(aq) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 40% ethyl acetate:hexanes to provide 11 mg (12%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.43 (m, 1H), 7.75 (m, 2H), 7.51 (m, 4H), 6.99 (m, 2H), 6.91 (m, 1H), 6.81 (m, 2H), 3.69 (m, 8H); MS (ESI) m/e 389 (M+H)+, 387 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[CH:22][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:25]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:21]=1)=[CH:7]3
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3)cc12
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CN4CCCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(pyrrolidin-1-ylmethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzaldehyde (from Example 172/Step 1) and pyrrolidine following the procedures described for Example 172, step 2. 1H NMR (Acetone-d6) TFA Salt: δ 8.88 (s, 1H), 8.82 (s, 1H), 8.82 (s, 1H), 8.43 (d, 1H), 8.38 (d, 1H), 7.58 (s, 1H), 7.51 (m, 1H), 7.33 (d, 2H), 4.16 (s, 2H), 3.32-3.38 (m, 4H), 2.55 (s, 3H), 2.20-2.32 (m, 4H), 1.90-1.99 (m, 4H). LRMS [M+H]=397.2
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1
Yield: 47.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 g, 14.8 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. The solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (SiO2, 60 g; eluted with 1% methanol in dichloromethane, 1 liter). The purest fractions were combined and gave 2.8 g, 48% of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy)phenyl]ethanone, m.p.=111-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(#N)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: BrCCOc1ccccc1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(=O)n(CCOc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (1 eq, 0.30 mmol, 60 mg) in THF (3 mL) was added K2CO3 (10 eq, 3.00 mmol, 0.41 g). The reaction was stirred at room temperature for 30 minutes then 1-(2-bromoethoxy)benzene (3 eq, 0.90 mmol, 0.18 g) was added. The reaction was stirred at 60° C. for 12 hours. After concentration of the solvent, acetonitrile (3 mL) was added followed by K2CO3 (10 eq, 3.00 mmol, 0.41 g) and 1-(2-bromoethoxy)benzene (10 eq, 3.00 mmol, 0.60 g) then the reaction was microwaved for 5 minutes at 180° C. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford 5-(4-methoxyphenyl)-1-(2-phenoxyethyl)pyridin-2(1H)-one (0.13 mmol, 42 mg, 44%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](C(O)=O)[C:5]([F:14])=[C:4]([F:15])[C:3]=1[CH2:16]C(O)=O.CN1CCCC1=O.Cl>C(N(CC)CC)C>[CH3:16][C:3]1[C:2]([F:1])=[C:7]([CH:6]=[C:5]([F:14])[C:4]=1[F:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)Cc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Reaction time: 48 h

Procedure:
To 27 g of 2-(2,5,6-trifluoro-3,4-dicarboxyphenyl)acetic acid was added 28 ml of N-methylpyrrolidone and 10 ml of triethylamine and the mixture was stirred at 140° C. for 2 days. The reaction solution was poured into 6N hydrochloric acid with cooling, and separated by adding diethylether and aqueous solution of sodium hydroxide. The aqueous layer was acidified and extracted with diethylether.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:10](=[N:18][OH:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].[H-].[Na+].O>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:19][N:18]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: CC(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=NOc1ncc(F)c(N)n1)c1ccccc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2NHCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-Phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([O:24][C:25]([C:27]1[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].[CH3:36][C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C.C(OCC)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([O:24][C:25]([C:27]1[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].[CH3:36][C@@H:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:44]
Reactant: C#CC(C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Agent: C[C@H](N)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: C#C[C@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 27.00 g (0.056 mol) of rac-1,2-benzenedicarboxylic acid [3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester in 50 mL of 95% ethanol was added, with stirring 7.02 (0.058 mol) of (S)-(-)-α-methylbenzylamine in 250 mL of diethylether. The resulting solution was stirred at 25° C. for 0.5 h, then cooled in an ice bath until crystallization occured. It was further stirred at 0° C. for 0.5 h and the crystals were collected and air dried to give 16 g of white solid. This white solid was dissolved in 50 mL of ethanol (95%) and 150 mL of diethylether. The solution was kept at 25° C. for approximately 1.0 h and crystallization occurred. It was further stored at 0° C. for 1.0 h and the crystals were collected, dried at 25° C./0.5 mm for 24 h to yield 10.1 g of (S)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester(S)-α-methyl benzenemethanamine (1:1) (salt) as a white solid (30% yield from racemic starting materials), m.p. 162°-165° C.