Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:16])[C:12]=2[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[H-].[Na+]>O1CCCC1>[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][C:21]3[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c(O)cccc1-c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)O)n1
Yield: 160.8 %

Procedure:
This compound was prepared in a manner analogous to that of Example 5, Step D, using 0.5 gram (0.003 mole) of 6-phenylsalicylic acid, 0.6 gram (0.003 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and 0.3 gram (0.005 mole) of 50% sodium hydride in mineral oil in 60 mL of tetrahydrofuran. This reaction mixture was combined with a second reaction mixture of 1.7 grams (0.008 mole) of 6-phenylsalicylic acid, 1.7 grams (.008 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.8 gram (0.016 mole) of 50% sodium hydride in mineral oil in 120 mL of tetrahydrofuran. The combination was treated as described in Example 5, Step D, to yield 1.7 grams of 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[C:21]2[CH2:33][CH3:34])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[C:21]2[CH2:33][CH3:34])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To the methanolic (15 mL) solution of (±) ethyl-2-ethoxy-3-[4-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate (420 mg, 0.909 mmol) obtained in example 1 was added NaOH (365 mg, 9.125 mmol) in H2O (10 mL), the mixture was stirred at 25° C. for 1 hr, evaporated the solvent under reduced pressure. The residue was added to 50 mL of cold water and washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water, brine, dried (Na2SO4) and evaporated the solvent, to give a stick compound, which was solidified by either long drying under vacuum or trituration with dry ether to give a white solid (380 mg, 96%) mp: 138–140° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N+:15]([O-])=O)=[C:9]([NH:18][CH3:19])[CH:8]=1.[OH-].[NH4+]>C(O)C>[NH2:15][C:10]1[C:11]([C:13]#[N:14])=[N:12][C:7]([Cl:6])=[CH:8][C:9]=1[NH:18][CH3:19]
Reactant: CNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1cc(Cl)nc(C#N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Tin(II) chloride dihydrate (21 g) was added to a suspension of 6-chloro-4-methylamino-3-nitro-pyridine-2-carbonitrile (6.6 g) in ethanol (150 ml). The mixture was stirred at room temperature for 3 hours. To above red-brown coloured solution was then added ethyl actetate (1000 ml) and followed by 10% aqueous ammonium hydroxide (200 ml). The organic layer were separated, the sticky solid pad was washed with ethyl acetate (5×200 ml). Combined organic layer was then washed with saturated sodium chloride aqueous solution (2×200 ml), dried over sodium sulphate, solvent removed to give a brown solid as expected product (5.7 g). 1H NMR (CD3OD) δ: 6.45 (s, 1H), 2.89 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=O)=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1.C(O)(C(F)(F)F)=O>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:48])=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.112 g, 0.445 mmol) in tetrahydrofuran (1.780 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.490 ml, 0.490 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 0.230 g, 0.445 mmol) in THF (1.5 mL) was added drop wise, and the reaction was stirred for two hours. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 12-g Redi-Sep Gold column with 0-50% EtOAc/Heptane. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.48 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.8, 8.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.25 (dd, J=1.8, 8.1 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 434.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([OH:16])=O)=[CH:8][CH:9]=2)[N:4]=1.[Br:19][C:20]1[C:21]([C:26]2[NH:30][CH:29]=[N:28][N:27]=2)=[C:22]([NH2:25])[S:23][CH:24]=1.C1C=NC2N(O)N=NC=2C=1>>[Br:19][C:20]1[C:21]([C:26]2[NH:30][CH:29]=[N:28][N:27]=2)=[C:22]([NH:25][C:14](=[O:16])[CH2:13][C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([C:2]([F:1])([F:18])[F:17])=[N:4]3)=[CH:9][CH:8]=2)[S:23][CH:24]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)Cc1ccc2ccc(C(F)(F)F)nc2c1
Agent: On1nnc2cccnc21
Product: O=C(Cc1ccc2ccc(C(F)(F)F)nc2c1)Nc1scc(Br)c1-c1nnc[nH]1

Procedure:
The title compound was synthesized via protocol B from 2-(2-(trifluoromethyl)quinolin-7-yl)acetic acid and 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine, using HOAt instead of HOBt. HPLC purification afforded the product as a white solid. HPLC method [7], retention time 8.68 min; MS(ESI) 484.2 (MH+, 81Br); 1H NMR (300 MHz, CD3OD) δ 8.76 (d, J=9.5 Hz, 1H), 8.25 (d, J=9.0 Hz, 1H), 7.96 (dd, J=8.7, 7.3 Hz, 1H), 7.92-7.81 (m, 1H), 7.11-6.97 (m, 1H), 4.45 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[I-].[Na+]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][O:5][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13]
Reactant: OCc1cc(Br)ccc1F
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1ccc(Br)cc1COCCCCCCl

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (25 ml). To this solution sodium hydride (60%, 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added and the resulting mixture was stirred at ambient temperature for three hours. The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](C(OC)=O)#[C:10][C:11](OC)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:9][CH:10]=[C:11]2[OH:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1Cl
Product: Oc1ccnc2c(Cl)cccc12

Procedure:
In the manner of Examples III.A. and B., 8-chloro-4-hydroxyquinoline was prepared from 2-chloroaniline and dimethyl acetylenedicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:20]([NH2:22])=O>CN(C=O)C.C(O)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[NH:3][C:2]3[N:1]=[CH:20][N:22]=[C:7]([OH:8])[C:6]=3[CH:5]=2)=[CH:13][CH:14]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c1N
Solvent: CN(C)C=O
Solvent: O=CO
Product: COc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1

Procedure:
Under a protective gas, 611 mg (2.3 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-methoxy-phenyl)-1H-pyrrole in 5 ml of formamide, 2.5 ml of DMF and 1.25 ml of formic acid are heated at 150° C. overnight. Working-up analogously to Step 8.2 yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =242.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:28])[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:28])[C:13]=1[C:8]1[NH:7][C:6]2[CH:29]=[CH:30][C:3]([NH:2][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 89.4 %

Procedure:
A solution of Example 32B (0.050 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[CH:11](N)=[O:12]>>[OH:10][C:3]1([CH2:2][NH:1][CH:11]=[O:12])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1
Reactant: NC=O
Reactant: CN1CCC(O)(CN)CC1
Product: CN1CCC(O)(CNC=O)CC1
Temperature: 145 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
A mixture of 50 g (0.35 mole) of 4(aminomethyl)-1-methyl-4-piperidinol and 15.8 g (0.35 mole) of formamide was stirred at 145° C. for 6 hr and allowed to stand overnight. The mass spectra indicated the starting amine was still present. The reaction mixture was reheated to 160° C. and stirred for 1 hr. The heat was removed and 150 ml of toluene was added. On cooling 61 g of crystals were formed, m.p. 116°-122° C. A 5 g sample was recrystallized from toluene to give 4.2 g of the title compound, m.p. 122°-124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:17])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:17])=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CO)c1C
Reaction time: 4 h

Procedure:
To a solution of Ethyl 3-(2,6-dimethylbenzyloxy)-2-methylbenzoate (Step B, 5.94 g, 19.93 mmol) in dry THF (35 ml) was added drop wise LiAlH4(1M in THF, 0.832 g, mmol) at 0° C. under argon. The reaction mixture was stirred for 4 hours or until all the starting material is consumed, then quenched slowly with 0.1N HCl at 0° C., and EtOAc (20 ml) was added to the reaction mixture. The reaction mixture was filtered and precipitate was washed with EtOAc (25 ml×2). The combined organic layer was washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])/[CH:12]=[CH:13]/[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].C.[H][H].[K+].[Br-]>C(O)C.C1COCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9]
Reactant: CN(C)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl
Reactant: [H][H]
Agent: [Pt]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl

Procedure:
A solution of 1.05 g (2.248 mmol) of (E)-3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 104) in 110 ml of an ethanol-THF mixture (10/1 v/v) was hydrogenated at ambient temperature in the presence of 0.5 g of platinum on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and purified by chromatography on silica gel using dichloromethane/methanol/conc. ammonia (95/5/0.3 v/v/v) as eluant. 0.36 g (34% of theoretical) of a colourless substance were obtained, Rf 0.31 (El A). IR (KBr): 1672, 1660 (C═O) MS: M+=468/470 (Cl)
Reaction SMILES: N#[C:2][Br:3].C(N(CC)C[C:8]#[C:9][CH:10]([O:18][C:19](=[O:21])[CH3:20])[C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])C>CCOCC>[Br:3][CH2:2][C:8]#[C:9][CH:10]([O:18][C:19](=[O:21])[CH3:20])[C:11]([CH3:16])([CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#CBr
Reactant: CCCCC(C)(C)C(C#CCN(CC)CC)OC(C)=O
Solvent: CCOCC
Product: CCCCC(C)(C)C(C#CCBr)OC(C)=O
Reaction time: 16 h

Procedure:
A solution of cyanogen bromide (36.0 g., 0.340 mole) in ether (400 ml.) is treated with 1-diethylamino-4-acetoxy-5,5-dimethyl-2-nonyne (82.3 g., 0.293 mole) to give a mildly exothermic reaction. The clear solution is allowed to stand at room temperature for 16 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>CCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1O
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Reaction time: 5.5 h

Procedure:
To a stirred solution of (4-methoxyphenyl)-naphth-1-yl carbinol of formula II (5.0 gm, 0.018 mol )and o-cresol (2.4 ml, 0.022 mol) in a mixture of anhydrous benzene, anhydrous pentane (50 ml, 1:1), and AlCl3 (2.5 gm) was gradually added, after addition stirring was continued for 5-6 hrs at 0-4° C. The reaction mixture was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed successively with water, dried over Na2SO4 and concentrated to give an oil, which was chromatographed over silica gel using benzene-hexane as the eluent to give the title compound of formula III, yield 4.5 gm (67.16%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:11][CH3:10])=[CH:4][N:3]=1
Reactant: CN
Reactant: ClCc1ccc(Cl)nc1
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1
Yield: 60.3 %

Procedure:
A mixture of 15.05 g of 2-chloro-5-(chloromethyl) pyridine and 50 ml of acetonitrile was dropwise added to a mixture of 36 g of 40% methylamine aqueous solution and 200 ml of acetonitrile during an hour at room temperature and stirred for an hour and a half. The reaction mixture was concentrated. The resulting residue to which 100 ml of water was added, was neutralized by sodium hydrogen carbonate, saturated with sodium chloride and extracted with dichloromethane (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 8.77 g of 2-chloro-5-(methylaminomethyl)pyridine as a yellowish brown liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][C:13](C)(C)C)=[O:11])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:5]=[C:4]([Cl:24])[N:3]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:5]=[C:4]([Cl:24])[N:3]=1
Reactant: CC(C)(C)OC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Reaction time: 2 h
Yield: 64.4 %

Procedure:
tert-Butyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate (2.44 g, 6.31 mmol) was dissolved in anisole (6 ml) and trifluoroacetic acid (30 ml) added and the solution allowed to stand at 21° for 2 h, then evaporated in vacuo. The residue was dissolved in toluene (40 ml)-methanol (10 ml), and a 2M solution of trimethylsilyldiazomethane in hexanes added (8 ml), and the solution allowed to stand for 0.5 h. The solution was evaporated in vacuo, and the resulting oil purified by flash chromatography over silica eluting with cyclohexane-ethyl acetate (100:0-65:35) to give the title compound as a viscous gum (1.40 g, 64%)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9].[CH2:15]([O:22][CH2:23][CH:24]1[CH2:26][O:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[CH2:15]([O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:10]([CH2:8][CH3:9])[S:11]([CH3:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCNS(C)(=O)=O
Reactant: c1ccc(COCC2CO2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCN(CC(O)COCc1ccccc1)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Triethylamine (0.043 ml, 0.1 equiv) was added to a mixture of N-ethylmethanesulfonamide (413 mg, 1.1 equiv) and 2-benzyloxymethyloxirane (500 mg, 3.04 mmol) prepared according to (J. Am. Chem. Soc., 1996, 118, 7094-7100) in anhydrous dioxane (1 ml). The reaction mixture was then heated to 50° C. overnight. As the reaction was not complete, it was heated to 100° C. for another 5 hours (reaction complete according to TLC). The volatiles were then removed in vacuo. Flash chromatography eluting with cyclohexane/Ethyl acetate (6/4 then 1/1) afforded 836 mg (2.91 mmol, 96%). LCMS (Method E) 1.44 min, M+H 288. 1H-NMR (CDCl3, 400 MHz): 7.43-7.27 (m, 5H), 4.57 (s, 2H), 4.11-3.90 (m, 1H), 3.62-3.44 (m, 2H), 3.43-3.20 (m, 4H), 2.90 (s, 3H), 1.14-1.33 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]#[N:10])=[N:4]1)[CH3:2].C([O-])(=O)C.[K+].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]([C:9]#[N:10])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH3:8]
Reactant: CCn1nc(C#N)cc1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1nc(C#N)c(Br)c1C

Procedure:
1-Ethyl-5-methyl-1H-pyrazole-3-carbonitrile (2.98 g, 22.0 mmol) was treated with potassium acetate (4.93 g, 31.0 mmol) and bromine (3.87 g, 24.0 mmol) in glacial acetic acid (43 mL) according to the general method described in Part F of Examples 1-4. Methyl tert-butyl ether was used instead of dichloromethane in the extraction during the work-up. The organic layers were combined and concentrated under reduced pressure to yield 4-bromo-1-ethyl-5-methyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]4)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)(=O)[CH3:2].[NH2:39][OH:40].O>C(O)C>[OH:40][N:39]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:36])([F:37])[F:35])=[N:29]4)[CH2:24][CH2:25]3)[S:18][CH:19]=2)[CH2:11]1)[CH3:2]
Reactant: CC(=O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Reactant: NO
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (150 mg) in ethanol (5 ml) was added dropwise hydroxylamine (50% in water, 4 eq.) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 1-[4-(4-{5-[2-(N-hydroxyethanimidoyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (33 mg).
Reaction SMILES: [CH:1]1([N:7]2[CH2:33][CH2:32][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[N:25][CH:26]=5)=[CH:17][CH:16]=4)[CH2:12][C@H:11](O)[CH2:10]3)[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(S(F)(F)[F:41])CC)C>>[CH:1]1([N:7]2[CH2:33][CH2:32][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[N:25][CH:26]=5)=[CH:17][CH:16]=4)[CH2:12][C@@H:11]([F:41])[CH2:10]3)[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CNC(=O)c1ccc(-c2ccc(CN3C[C@H](O)CC34CCN(C3CCCCC3)C4=O)cc2)cn1
Product: CNC(=O)c1ccc(-c2ccc(CN3C[C@@H](F)CC34CCN(C3CCCCC3)C4=O)cc2)cn1

Procedure:
5-(4-{[(3R)-7-Cyclohexyl-3-hydroxy-6-oxo-1,7-diazaspiro[4.4]non-1-yl]methyl}phenyl)-N-methylpyridine-2-carboxamide (prepared according to a procedure analogous to that described for the synthesis of Example 42) was treated with diethylaminosulfur trifluoride as outlined in the synthesis of Example 81 to afford the desired product. LC/MS: 465.2 (M+1H)+.