Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[OH:22])=[CH:17][CH2:16]2)=[CH:10][CH:9]=1.[F:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:22][CH:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)[CH2:16][CH:17]=2)[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(F)c1)OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 30.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step F of Example 2, using 0.44 gram (0.0010 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-1,2,5,6-tetrahydropyridyl)}[4-(trifluoromethyl)phenyl]methanol, 0.21 gram (0.0014 mole) of 3,5-difluorophenylisocyanate, 0.14 gram (0.0014 mole) of triethylamine, and 0.05 gram (catalyst) of 4-dimethylaminopyridine in 15 mL of methylene chloride. The reaction product was purified with column chromatography on silica gel using 10% to 25% acetone/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.18 gram of Compound 786, mp 85–92° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: c1ccc2ncccc2c1
Product: [Br-]
Product: c1ccc2c(c1)ccc[n+]2CCCCCCCCCCCC[n+]1cccc2ccccc21
Temperature: 65 °C
Yield: 92 %

Procedure:
1,12-Dibromododecane (mmol) was added to a solution (30 mL) of dry quinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 92% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.58 (1H, d, C2-H), 9.29 (1H, d, C3-H), 8.61 (1H, d, C8-H), 8.50 (1H, d, C4-H), 8.29 (1H, t, C7-H), 8.18 (1H, t, C5-H), 8.04 (1H, d, C6-H), 5.04 (2H, t, C′1-CH2), 1.95 (2H, m, C′2-CH2), 1.2-1.4 (8H, m, C′3-6-CH2); 13C NMR (75 MHz, DMSO-D6) δ 149.5, 147.4, 137.4, 135.6, 130.7, 129.9, 129.7, 122.1, 118.9, 57.3, 29.5, 28.9, 28.8, 28.5, 25.7.
Reaction SMILES: [NH3:1].C(Cl)Cl.[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](Cl)(=[O:20])=[O:19])=[O:11])[CH2:6]1>O>[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([NH2:1])(=[O:20])=[O:19])=[O:11])[CH2:6]1
Reactant: O=C(OC1COC1)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1C(=O)OC1COC1

Procedure:
2.5 g of ammonia are passed into a methylene chloride solution of 2-(oxetan-3-oxycarbonyl)phenylsulfonyl chloride (Example H6) at a temperature of 0° to 5° C. in the course of 45 minutes. By adding water to the reaction mixture, washing the organic phase with water, drying and evaporating it and crystallising the residue from a methylene chloride/diethyl ether mixture, 6.7 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide of melting point 169° to 170° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:41][CH:38]2[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36][CH2:37]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4-Fluorophenol (520 mg, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64 mmol) were added to a solution of N-boc-piperidine-4-methanol (500 mg, 2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (670 μL, 3.69 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 and concentrated. The residue was purified on column chromatography (eluent: pentane/EtOAc 95/5) to give the title compound (538 mg, 75%) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[CH:13]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10][N:29]2[CH2:30][CH2:31][N:26]([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(=O)Nc1nc(CCl)c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(Cl)s1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
A mixture of 2-acetamido-5-chloro-4-chloromethylthiazole (450 mg), 1-benzhydrylpiperazine (504 mg) and potassium carbonate (276 mg) in N,N-dimethylformamide (3 ml) was stirred at 70° C. for 20 minutes. After the reaction mixture was poured into ice-water, the precipitated crystals were collected by filtration, washed with water and then dried, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain crystals (355 mg) of 2-acetamido-5-chloro-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 227°-230° C.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C(N(CC)CC)C.[C:13]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:37])[C:20]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21][N:22]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)#[CH:14].C1(N=C=O)C=CC=CC=1>C(Cl)(Cl)Cl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[C:15]([C:13]4[O:3][N:1]=[C:4]([CH3:5])[CH:14]=4)[CH:24]=3)[C:19](=[O:37])[C:20]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]2)=[CH:30][CH:29]=1
Reactant: C#Cc1ccc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3)c2c1
Reactant: CC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3cc(C)no3)ccc2c1=O
Yield: 70.2 %

Procedure:
A solution of 9.8 g nitroethane and 13 ml triethylamine in 130 ml chloroform was added dropwise to a solution of 10.47 g ethyl 1,4-dihydro-7-ethynyl-1-(4- fluorophenyl)-4-oxo-3-quinolinecarboxylate and 15.5 g phenyl isocyanate in 80 ml chloroform over a period ofconcentrated in vacuo. The residue was crystallized in ether and recrystallized from acetonitrile to give 8.60 g ethyl 1,4-dihydro-1-(4-fluorophenyl)-7-(3-methyl-5-isoxazolyl)4 -oxo-3-quinolinecarboxylate (yellow solid, m.p. 214°-216° C.).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:7])[CH3:2].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:7].[O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][PH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Product: [Br-]
Temperature: 25 °C
Yield: 86.3 %

Procedure:
Dissolving 3,4,5-trimethoxyl benzyl bromide (16.05 g, 61.47 mmol) in toluene (150 ml) in a three-necked bottle (250 ml), adding triphenylphosphine (16.12 g, 61.47 mmol) and dissolving immediately, heating to reflux for 1 hour, white solid being separated, cooling to room temperature, suction filtering, and washing the filter cake with toluene (30 ml). After vacuum drying, 3,4,5-trimethoxyl benzyl triphenylphosphine bromide (27.81 g of white powder solid) was isolated, yield: 86.44%.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([C:12]3[N:13]=[CH:14][C:15]4[NH:16][C:17]5[C:22]([C:23]=4[CH:24]=3)=[CH:21][CH:20]=[CH:19][CH:18]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].[H-].[Na+]>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][N:16]1[C:15]2[CH:14]=[N:13][C:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: ClCCCBr
Reactant: c1ccc(-c2noc(-c3cc4c(cn3)[nH]c3ccccc34)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1c2ccccc2c2cc(-c3nc(-c4ccccc4)no3)ncc21
Yield: 97 %

Procedure:
The compound was synthesized by mixing (Compound 8) (0.6 g, 1.9 mmol), 1-bromo-3-chloropropane (0.45 g, 2.9 mmol), NaH (0.09 g, 2.3 mmol) in DMF, in the same manner as illustrated in example 3 to give the title compound (0.72 g, 97%). M.p. 192°-195° C. (and 235.5°-236° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=[CH:15][CH:16]=1.[OH2:21]>C(O)CO>[O:9]1[CH2:16][CH2:15][O:21][CH:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(C=O)n1
Solvent: OCCO
Product: Cc1cccc(C2OCCO2)n1
Temperature: 200 °C
Yield: 73.3 %

Procedure:
To a solution of 6-methylpyridine-2-carbaldehyde (3.7 g, 30.54 mmol, 1 eq.) in 10 ml of ethylene glycol was added TsOH.H2O (6.67 g, 32.07 mmol, 1.05 eq.). The reaction was heated in microwave at 200° C. for 180 s (fixed hold absorb high). The mixture was added to a stirred solution of 10 g of K2CO3 in 200 ml of water, and was extracted with DCM (3×150 ml). The combined organics were washed with water evaporated on RFE (water bath 25° C.) to give 2-(1,3-dioxolan-2-yl)-6-methylpyridine (3.7 g, 51% yield) as pale brown liquid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Yield: 98.7 %

Procedure:
Methyl 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 31) (439 mg, 1.0 mmol) was dissolved in THF (6 mL) and methanol, (2 mL) and 1 N lithium hydroxide (1.24 mL) was added. Water (8 mL) was then added dropwise and the resultant solution stirred for 1 hour at room temperature. The majority of the organic solvents were removed by distillation under reduced pressure. The aqueous residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated under reduced pressure to afford the product (406 mg, 96%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 2H), 2.29-2.43 (m, 2H), 2.55-2.69 (m, 1H), 2.96 (s, 3H), 3.36-3.59 (m, 4H), 4.26 (t, 2H), 4.71 (t, 2H), 4.98 (t, 1H), 6.95 (s, 1H), 7.29 (s, 3H), 7.34 (d, 2H), 7.55 (s, 1H), 8.09 (d, 1H), 8.30 (s, 1H); m/z 411 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:20]O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.S(Cl)([Cl:34])=O>ClCCl>[ClH:34].[Cl:34][CH2:20][CH:19]([NH:18][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:17])[CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CC(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CCl)CC(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.48 g of rac-8-[(2,6-difluorobenzyl)oxy]-2-methyl-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)-imidazo-[1,2-a]pyridine-3-carboxamide (Example 34A, 5.59 mmol) were initially charged in dichloromethane. At 0° C., 1.22 ml of thionyl chloride (16.77 mmol) were added dropwise, and the mixture was stirred at RT overnight. The reaction solution was concentrated and dried under high vacuum. This gave 2.78 g of the title compound (99.8% of theory).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]1>>[CH3:13][C:12]1[C:7]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: NC1CCCC(O)C1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC(O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by crystallization from ethanol to afford to afford the titled compound as a hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.35-1.65 (m, 11H), 2.33 (s, 3H), 3.90-4.15 (m, 2H), 4.80-4.95 (m, 2H), 7.68-7.75 (m, 2H), 8.20-8.26 (m, 1H), 8.66 (d, J=11.15 Hz, 1H); MS (ESI) m/z 328.8 (M+1)+.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][O:6][C:4]1=[O:5].[CH2:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>C(OCC)C>[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([S:1][CH2:2][CH:3]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][O:6][C:4]2=[O:5])=[O:24])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: O=C1OCC(c2ccccc2)C1CS
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)SCC2C(=O)OCC2c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
To a solution of 1.5 g of α-mercaptomethyl-β-phenyl-γ-butyrolactone in 30 ml of ethyl ether were added at room temperature 4.3 g of p-n-butylbenzoyl chloride and then 1.9 ml of pyridine. The mixture was kept at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of ethyl ether, washed with 10% hydrochloric acid, 10% aqueous sodium hydrogen carbonate and then satureated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 2.1 g (yield 79%) of the title compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:13][CH:12]=1
Reactant: FC(F)(F)CCCBr
Reactant: O=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCCC(F)(F)F)c1ccc(Br)cc1
Temperature: 24 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
Magnesium (0.636 g, 26.2 mmol) was added to a solution of 4-bromo-1,1,1-trifluorobutane (5 g, 26.2 mmol) in THF (100 mL) and under nitrogen. The solution was stirred for 18 h at 24° C., and the Grignard reagent was transferred via cannula to a solution of 4-bromobenzaldehyde (4.85 g, 26.2 mmol) in THF (50 mL) at −78° C. under nitrogen. The cold bath was removed and the reaction allowed to warm and stirred 18 h, diluted with Et2O (1 vol), quenched with sat'd NH4Cl soln, and washed with brine. Concentrate, take up in CH2Cl2 and charged to a 40M Biotage® silica gel cartridge. Gradient elution was performed from 15% to 100% B over 1 L (A/B Hexanes/EtOAc) to give 1-(4-bromophenyl)-5,5,5-trifluoropentan-1-ol 6.4 g (82%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[CH3:14][CH:15]([CH3:20])[C:16]#[C:17][Mg]Cl.CC(C)C#C.C([Mg]Cl)(C)C>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]2[C:16]([CH:15]([CH3:20])[CH3:14])=[CH:17][N:3]=[N:2]2)[CH:9]=1
Reactant: CC(C)C#C[Mg]Cl
Reactant: [N-]=[N+]=Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: C#CC(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cnnn1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A 30 mL scintillation vial was charged with 2-azido-4-chloro-1-nitrobenzene (200 mg, 1.0 mmol) and 0.75 M 3-methyl-1-butynylmagnesium chloride in THF (1.6 mL, 1.2 mmol; prepared by mixing 3-methyl-1-butyne (120 μL, 1.2 mmol) and iPrMgCl (1.5 mL, 1.0 M in THF) at room temperature, heating to 40° C. for 30 minutes then cooling to room temperature). The reaction was allowed to stir at room temperature for 1 hour after which the reaction was quenched with SiO2 and the solvent removed. The product (adsorbed to SiO2) was then loaded on a SiO2 column and purified to give 1-(5-chloro-2-nitro-phenyl)-5-isopropyl-1H-[1,2,3]triazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCOC(C)=O.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(=O)C[C@H]1C(=O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)[C@H](C(=O)OCc3ccccc3)C2)cc1

Procedure:
Similar to example 24c, 9.43 g of (2S)-4,6-dioxo-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester [176436-10-5] are reacted with p-toluene sulfonyl chloride to afford the title compound as a yellow oil Rf=0.64 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[NH:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>O>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[NH:7])[NH:10]1
Reactant: N=C1CSC(=O)N1
Reactant: N=C1NC(=N)c2ccccc21
Solvent: O
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21

Procedure:
11.4 parts of 2-oxo-4-iminothiazolidine are stirred with 15 parts of 1,3-diiminoisoindoline in 300 parts of water for 40 hours at about 25° C., whilst passing a slight stream of nitrogen over the mixture. The product is then filtered off and washed with water, giving 22 parts of 1-imino-3-(2'-oxo-4'-iminothiazolidinylidene)-isoindoline (Formula II, Z=>O), the spectroscopic properties of which correspond to those of the product obtained as described in Example 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=O)[C:7](=[O:16])[N:6]2[CH3:17].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)=[O:15])[C:7](=[O:16])[N:6]2[CH3:17]
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2nc(C(=O)O)c(=O)n(C)c2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)c(=O)n(C)c2c1

Procedure:
3,4-Dihydro-6-methoxy-4-methyl-3-oxo-2-quinoxalinecarboxylic acid (1.2 g) and N,N'-carbonyldiimidazole (0.8 g) in tetrahydrofuran (25 ml) and dimethylformamide (20 ml) were heated under reflux for 1 hour. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour and allowed to cool. The solid was collected and dried, m.p. 295°-296° (d) (70%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1I
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A stirred solution of 2-iodo-5-methylbenzoic acid (17.3 g, 66.0 mmol) and concentrated H2SO4 (3 mL) in MeOH (200 mL) was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt, concentrated to one third volume, diluted with EtOAc (300 mL), washed with saturated NaHCO3 (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dried under high vacuum to afford methyl 2-iodo-5-methylbenzoate as a colorless oil (18.2 g, quant.). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.99-6.96 (m, 1H), 3.92 (s, 3H), 2.33 (s, 3H). A stirred suspension of methyl 2-iodo-5-methylbenzoate (18.2 g, 66.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.2 g, 73.3 mmol), K2CO3 (27.5 g, 200 mmol), and Pd(PPh3)4 (11.5 g, 9.99 mmol) in 1,4-dioxane (150 mL) and H2O (50 mL) was heated at 100° C. for 18 h under nitrogen. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (400 mL), washed with saturated NaHCO3 (2×300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 80% EtOAc/hexanes to afford methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate as a colorless oil (13.3 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.55-7.25 (m, 5H), 3.94 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H).