Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[C:17]([OH:19])=O.Cl>C(OCC)C>[C:17]([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:15][C:16]=2[C:4]=1[CH3:3])(=[O:19])[CH3:1]
Reactant: Cc1c(C(=O)O)ccc2c1[nH]c1ccccc12
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1ccc2c([nH]c3ccccc32)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
15 ml of a 1.5M solution of methyllithium (22 mmol) in diethyl ether was added to 30 ml of a solution of 1.25 g of 1-methylcarbazol-2-ylcarboxylic acid (5.5 mmol--as obtained in Example 26) in diethyl ether, at a temperature of -78° C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. After this time, the mixture was poured into a 0.5N aqueous solution of hydrogenchloride. The aqueous layer was extracted with ethyl acetate and the resulting organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 25% v/v solution of ethyl acetate in hexane) to yield 1.08 g (88%) of the title compound as an amorphous solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (8 mg, 26%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methoxybutanoic acid
Reaction SMILES: [CH3:1][N:2](C)C(=O)C.Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:1]#[N:2])=[N:9][CH:10]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Cl)cn1
Temperature: 160 °C
Yield: 59 %

Procedure:
Add in a 22-L 3-neck round bottom equipped with overhead stirrer, reflux condenser, and thermometer, N,N-dimethylacetamide (DMAC, 6 L), 2,5-dichloropyridine (347.0 g, 2.34 mol), zinc cyanide (138.0 g, 1.17 mol), bis(diphenylphosphino)dipalladium II CH2Cl2 complex (DPPF, 20.8 g, 0.02 mol), and zinc dust (1.6 g, 0.02 mol). Slowly warm the reaction mixture to 160° C. As the temperature reaches 160° C., an exotherm (controllable) may result and the internal temperature may rise to 180-185° C. Remove the heat from the dark solution and cool the mixture slowly cool to room temperature. Extract the bulk reaction mixture by taking 2 L of the dark solution, diluting with brine (2 L), filtering over celite, and addition of ethyl acetate (4 L). Repeat the process 3 times to extract all material, and dry the combined organics over magnesium sulfate. Cautious concentration at 25-30° C. might give a dark liquid. (Note: Product volatility maybe observed at higher temperatures so the temperature upon concentration is kept low in all steps.) Stir the liquid and add water (5 L), resulting in a solid After 1 h, filter, and back-wash with water (2 L). Dry the filter cake to give 215 g of crude product. Extract the aqueous filtrate with ethyl ether (8 L). Dry the organics over magnesium sulfate and concentrate to provide 51 g of crude product. Combine with the 215 g lot and purify by chromatography over silica gel (biotage 150; eluting with 5% ethyl acetate in hexanes increasing to 10% ethyl acetate in hexanes) to provide a white solid of pure title compound (193 g, 59%); 1H NMR (CDCl3) δ 8.68 (d, J=2.0 Hz, 1H), 7.84 (dd, J=2.7, 8.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:28]C[C@H:26](N)[CH2:25]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13].[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>C(O)=O>[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:25][CH2:26][C@H:1]([NH:2][CH:3]=[O:4])[CH2:28]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CN(C)C=O
Reactant: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c1F
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC=O)C4)nc32)c1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 600 mg of N,N-dimethylformamide were added 210 mg of 1-(3-amino-2,4-difluorophenyl)-7-[(3S)-3-aminopyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 40 mg of formic acid. The solution was stirred at 120° C. for 1 hour. After 8 ml of diisopropyl ether was added and stirred, the solution was allowed to stand. The supernatant was decanted off. Then 2 ml of ethanol was added, and the solution was heated at reflux for 20 minutes and allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 180 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.CCN(CC)CC.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=1)=[O:33]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=2)=[O:33])=[O:21])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)CBr)cc1Cl
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(=O)COC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (1.0 g, 5.42 mmol) in acetonitrile (20 mL) were added Et3N (5.54 mL, 43.4 mmol) and 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.07 g, 3.65 mmol) under an inert atmosphere. The reaction mixture was then stirred at RT for 1 h and concentrated in vacuo to obtain the crude product. The crude material was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-chloro-4-methoxyphenyl)-2-oxoethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 29%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=NO)c1ccc(Cl)cc1

Procedure:
33.6 g of p-chloropropiophenone was mixed with 200 ml of ethanol and 40 ml of water. 24 g of hydroxylamine hydrochloride was added. 44 g of solid sodium hydroxide was added over a 10-minute period to the stirred mixture at room temperature. The mixture was heated to 80°, then refluxed for 80 minutes. The mixture was cooled and poured into cold dilute hydrochloric acid. The resulting mixture was filtered. The solid product was dissolved in methylene chloride; the solution was dried (MgSO4) and stripped of solvent. Recrystallization of the solid product from hexane gave 1-(4-chlorophenyl)-1-propanone oxime (4A), m.p.: 56°-57.5°.
Reaction SMILES: [CH3:1][S:2][O-].[Na+].[Cl:5][CH2:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:22]([F:25])([F:24])[F:23])=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2F)[CH2:8]1.O.C(OCC)(=O)C>CN(C)C=O>[Cl:5][CH2:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:22]([F:25])([F:24])[F:23])=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[S:2][CH3:1])[CH2:8]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Reactant: CS[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1SC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.21 g (9.0 mmoles) of sodium methyl thioalcoholate (in the form of a 15% aqueous solution) was added, at room temperature, into a solution of 1.08 g (3.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein to obtain a crude product of 5-chloromethyl-3-(1-ethyl-5-methylthio-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[Cl:27][C:28]1[CH:53]=[CH:52][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([S:40]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]3[C:49](O)=[O:50])(=[O:42])=[O:41])[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C1C[C@H](C(O)=O)NCC1>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:6][NH:7][C:49]([C@H:44]1[CH2:45][CH2:46][CH2:47][CH2:48][N:43]1[S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:53][CH:52]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])=[O:50])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)[C@H]1CCCCN1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol), N,N imethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoyl-piperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (FMLC, SiO2, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1)([O-])=O.[BH4-].[Na+].C(OCC)(=O)C>CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH3:18])([CH:13]([O:14][CH3:15])[O:16][CH3:17])[C@H:10]([OH:19])[C@@H:9]([N:20]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
(2R,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.2 mmol) prepared in example 107 was dissolved in methanol (2 ml), thereto Cu(OAc)2 aqueous solution (0.38 ml, 0.4 M aqueous solution, 0.15 mmol) was added. Sodium borohydride (NaBH4, 113 mg, 3.0 mmol) was slowly added to the solution at the room temperature for 30 min. The reaction mixture was stirred for 1 hour, thereto ethyl acetate (5 ml) was added. The reaction mixture was filtered to remove the black precipitation. NaHCO3 aqueous solution (5 ml) was added to the resultant filtrate. The filtrate was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine solution, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:3), to give desired compound (60 mg, yield: 63%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>ClCCl>[F:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)=[N:4][C:3]=1[CH2:2][NH:1][C:39](=[O:41])[CH3:40]
Reactant: NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
To a suspension of 53.3 mg of 3-{4-[4-aminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-1,2,4-oxadiazol-5-one in 1 mL of dichloromethane was added 27 mg of pyridine and 19 mg of acetic anhydride. The resulting mixture was stirred for 1.5 h at room temperature and then a drop of pyridine and acetic anhydride were added. After stirring for 25 minutes at room temperature, it was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) to give 6.2 mg of N-[5-[3-fluoro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl]-acetamide.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH:10]2[NH:12][CH:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH3:21][N:22]([CH:24]=[O:25])[CH3:23]>>[CH2:1]([CH:5]1[CH2:6][CH:7]2[N:12]([CH2:9][C@@H:10]([CH3:11])[CH2:21][N:22]3[C:23]4[C:6](=[CH:5][CH:1]=[CH:2][CH:3]=4)[CH2:7][CH2:8][C:24]3=[O:25])[C@@H:10]([CH2:9][CH2:8]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCC1CC2CC[C@@H](C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21

Procedure:
Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (107LH63) (0.094 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), NaI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c4) (0.025 g). HPLC-MS (ammonium acetate) [M+H]+=369.33.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH2:14]>>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]([C:5]([OH:14])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: O=C1OC(=O)c2c(F)cc(F)cc21
Reactant: O
Product: O=C(O)c1cc(F)cc(F)c1C(=O)O

Procedure:
reacting said 3,5-difluorophthalic anhydride with excess water to produce 3,5-difluorophthalic acid; and
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH:13]([F:15])[F:14]>O1CCOCC1.O>[F:14][CH:13]([F:15])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(OC(F)F)cc1
Temperature: 70 °C
Yield: 59.4 %

Procedure:
Sodium hydroxide (48 g; 1.2 mole) is added to a stirred suspension of p-hydroxybenzaldehyde (48.9 g; 0.4 mole) in dioxane (142 ml) and water (87 ml). The mixture is heated to 70° C. and chlorodifluoromethane (33 g) added slowly. When this addition is completed, 50% sodium hydroxide solution (32 ml) is added to the reaction mixture, followed by the slow addition of chlorodifluoromethane (33 g). This recharging is repeated three times, and a total of 96 g (2.4 mole) of sodium hydroxide and 133 g (1.54 mole) of (1.54 mole) of chlorodifluoromethane is used in the reaction. The reaction mixture is cooled down, diluted with water (1500 ml) and extracted with ether several times. The ether layers are combined, washed with 10% sodium hydroxide and then dried over magnesium sulfate. Concentration of the ethereal solution yields 39 g (57%) of a yellow oil. This oil is purified by chromatography on a silica gel column using a mixture of hexane:methylene chloride (1:3), to afford 27 g (39%) of title product.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].[CH2:15]([CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH3:16]>CO>[CH2:15]([C:17]1[C:18](=[O:19])[NH:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][C:23]=1[OH:24])[CH3:16]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(O)nc(-c2ccccc2)[nH]c1=O
Yield: 50.9 %

Procedure:
A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1H-NMR (d6-DMSO) δ1.05(3H,t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:27](=[O:28])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:1]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A dry 1 L round-bottomed flask equipped with a magnetic stirrer was charged (+)-pseudoephedrine (13.92 g, 84.26 mmol, 1.0 equiv), triethylamine (13.39 mL, 96.06 mmol, 1.14 mmol), and tetrahydrofuran (340 mL). The solution was cooled to 0° C. and phenylacetyl chloride (14.33 g, 92.69 mmol, 1.1 equiv) was added via cannula over a 20 minute interval as a solution in tetrahydrofuran (90 mL). After 30 minutes, the reaction was quenched with saturated sodium bicarbonate. The amide was extracted from brine (1 L) with ethyl acetate (400 mL, 130 mL, 130 mL), and the organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a solid was obtained. The solid was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL), affording the phenylacetamide (17.90 g, 75% yield) as a white powder: mp 145°-146° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.5 (m, 10H), 4.55 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.11 (m, 1H), 3.95 (m, 1H), 3.83 (m, 1H), 3.78 (s, 2H), 3.31 (d, 2H, J=1.3 Hz), 2.76 (s, 3H), 2.12 (s, 3H), 0.95 (d, 3H, J=7.0 Hz), 0.42 (d, 3H, J=6.7 Hz); 13C NMR (75.5 MHz, CDCl3) δ173.1, 172.2, 142.2, 141.4, 135.5, 134.5, 128.7, 128.64, 128.58, 128.3, 128.1, 127.5, 126.73, 126.68, 126.6, 126.3, 76.2, 75.3, 58.6, 41.8, 41.4, 33.3, 27.0, 15.0, 14.3; FTIR (neat film) cm-1 3393 (br, m), 1618 (s), 1494 (m), 1453 (m), 1402 (m); HRMS (FAB) Calcd for C18H22NO2 (MH+): 284. 1652. Found: 284.1646.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cc1ccc([Mg]Cl)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 91 %

Procedure:
4-methylphenylmagnesium chloride (98 g, 20% solution in tetrahydrofuran) is added dropwise over five hours to a refluxing solution of 4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) and triphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC: yield 91-93%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (1:1) (200 ml) and filtered. The aqueous phase is separated off. Solvent is removed by distillation and the crude product recrystallised from ethanol to give 4'-methylbiphenyl-4-carbonitrile as a solid, m.pt. 107-109° C. 1H NMR (CDCl3): 2.41(s,3H), 7.29(d,2H), 7.49(d,2H), 7.66 (d,2H), 7.71 (d,2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]#[N:11].[H][H].C([O-])(=O)C.[K+].CO>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[C:4]([NH2:9])[C:3]([C:10]#[N:11])=[CH:2][N:7]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1N
Reaction time: 2 h

Procedure:
A suspension of 21.3 g of 6-bromo-2,4-diamino-5-cyanopyridine (JACS, 80:2838-2840 (1958)) and 1 g of 20% palladium on charcoal in 250 mL of tetrahydrofuran was shaken in a Parr apparatus under an atmosphere hydrogen. After 2 hours, the reaction was stopped and 10 g of potassium acetate and 50 mL of methanol added. The reaction was recharged with hydrogen and shaken for 18 hours. The solvents were removed under reduced pressure and the residue crystallized from isopropyl alcohol to afford the title compound 2,4-diamino-5-cyanopyridine, mp 201-202° C.