Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:35])[CH:29]=[C:30]([CH3:34])[O:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:35])[CH:29]=[C:30]([CH3:34])[O:31]2)=[CH:26][CH:25]=1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Oc3ccc4c(=O)cc(C)oc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), 7-hydroxy-2-methylchromone (88 mg, 0.5 mmol), (Bull Soc. Chim. Fr. 1995, 132, 233), and potassium carbonate (83 mg, 0.6 mmol) was heated at 100° C. for 1.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4), and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170 mg, 92%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[NH:12]1)=[O:10].I[CH3:24]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[N:12]1[CH3:24])=[O:10]
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NCCc3cccs3)c(=O)c12
Reactant: CI
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NCCc1cccs1)n2C

Procedure:
In analogy to example 2, 100 mg (0.297 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (2-thiophen-2-ylethyl)amide were reacted with 22.2 μl of iodomethane in THF. Yield: 18 mg (77%), M+H+: 351.12.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)(=O)=O)C=CC=CC=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[N:19]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 105 °C
Reaction time: 2.75 h

Procedure:
A solution of trans 3-carbomethoxycyclobutyl benzenesulfonate* (6.1 g, 22.6 mmol) in hexamethylphosphoramide (35 ml) was treated with sodium azide (289 g, 44.5 mmol) and stirred at 105° C. for 2.75 h. The reaction mixture was cooled to 23° C., diluted with water (350 ml) and extracted with ether (4×125 ml). The organic extracts were combined, washed with water (2×15 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to a slightly yellow liquid which was distilled under high vacuum; bp 66°-7° C. (0.6 mm); 2.8 g; 80%; ir (neat) νmax : 2100 (N3) and 1735 cm-1 (C=O); Hmr (CDCl3) δ: 40.34 (m, H-1), 3.7 (s, methyl) and 2.9-2.1 ppm (5H, 2H-2, H-3 and 2H-4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Br)cn1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
To a stirred solution of (5-Bromo-pyridin-2-yl)-methanol (1 g, 5.319 mmol) in CH2Cl2 (20 mL) is added drop wise thionyl chloride (0.57 mL, 7.979 mmol) at 0° C. then stirred for another 4 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography using 7% ethyl acetate in hexane as an eluent to afford the title compound (0.8 g). 1HNMR (400 MHz, DMSO-d6) δ: 4.7 (s, 2H), 7.53 (d, 8.36 Hz, 1H), 8.09-8.11 (dd, J1=2.44 Hz, J2=8.23 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), LC-MS (m/z): [M+H]=206.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:15])[CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 338 mg (7.5 mmol) of ethylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 524 mg (yield: 72.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[C:13]([CH2:12][NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:15])=[O:14]
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNc1ncccc1C(=O)O

Procedure:
2-(Carboxymethyl-amino)-nicotinic acid 501 is prepared by reacting commercially available 2-Amino-nicotinic acid 500 with 2-chloroacetic acid in the presence of base (e.g. sodium carbonate) typically at room temperature for 1-4 hours followed by purification and isolation by conventional means (e.g. acid base extraction and recrystallization).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])O)[C:6]=2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.Br.[ClH:23].CCOCC>CO>[ClH:23].[CH2:16]([C:9]1[N:10]([CH:11]=[C:12]([CH3:14])[CH3:15])[C:6]2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CC(C)(C)O
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1C=C(C)C

Procedure:
4-Amino-2-butyl-α,α,6,7-tetramethyl-1H-imidazo[4,5-c]pyridine-1-ethanol (about 200 mg) was combined with concentrated hydrobromic acid (50mL) and heated at reflux overnight. The reaction mixture was concentrated under vacuum. The residue was taken up in methanol then diluted with ether. The resulting precipitate was collected then partitioned between methylene chloride and 10% sodium hydroxide. The organic layer was separated, dried over magnesium sulfate then concentrated to provide an oil. The oil was taken up in methanol then combined with 0.05 mL of concentrated hydrochloric acid followed by dilution with ether. The resulting precipitate was collected, rinsed with ether and dried to provide 60 mg of the desired product as a white solid, m.p. 205° C.(dec.). Analysis: Calculated for C16H24N4 +1.6 HCl: % C, 58.10; % H, 7.80; % N, 16.94; Found: % C, 57.95; % H, 7.87; % N, 16.89.
Reaction SMILES: Cl[C:2]([F:6])=[C:3]([F:5])[F:4].C([Li])CCC.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>>[F:4][C:3]([F:5])=[C:2]([F:6])[Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)=C(F)Cl
Agent: [Li]CCCC
Product: C[Si](C)(C)C(F)=C(F)F

Procedure:
Chlorotrifluoroethylene of the formula (10) is treated with n-butyl lithium and then reacted with chlorotrimethylsilane of the formula (11) to obtain 1,1,2-trifluoro-2-trimethylsilylethylene of the formula (12). Then, without isolation, this compound (12) is reacted further with a lithium compound of the formula (13) to obtain a difluoroethylene compound of the formula (14).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1ccccn1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.62 g (2.46 mmol) 2-bromomethyl-pyridine and 0.85 g (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT and is diluted with 60 mL of EtOAc. The organic phase is washed twice with water, separated, dried over MgSO4 and the solvent is evaporated to afford the product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>[OH-].[Na+]>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol)1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0.1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2:MeOH=99:1) to yield 3.3 g (83.7%) product as a beige foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: COCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: COCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Methoxypentyl)-4-piperidone oxime is prepared from 1-(5-methoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13]S(C)=O.[H-].[Na+]>O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH3:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccncc2c1Cl
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1nccc2ccc(Cl)c(Cl)c12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
7,8-Dichloroisoquinoline (0.019 mole) in 100 ml. of dimethylsulfoxide is added to a solution of sodium hydride (0.11 mole) in 100 ml. of dimethylsulfoxide at 70° C. The reaction mixture is stirred at 70° C. for 4 hours under a nitrogen atmosphere. The reaction mixture is cooled, 100 ml. of water is added, and the mixture is poured into 1500 ml. of water. The aqueous mixture is extracted with benzene. The extract is washed, dried over sodium sulfate and evaporated to give 7,8-dichloro-1-methylisoquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[C:8]([C:16]#[C:17][Si](C)(C)C)=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1COCC1>[C:16]([C:8]1[C:7]2[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[S:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[CH:17]
Reactant: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1c(C(=O)OCC)sc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-nitro-3-[(trimethylsilyl)ethynyl]-1-benzothiophene-2-carboxylate obtained in Example (183c) (110 mg, 0.32 mmol) was dissolved in ethanol (8 mL) and THF (8 ml). Potassium carbonate (13 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the title compound.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])(=O)=O.O[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([O:5][CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1ccc(-c2nc(CCCOS(C)(=O)=O)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 35 °C
Reaction time: 0.58 h
Yield: 126.4 %

Procedure:
To a solution of methyl 4-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate (630 mg, 1.78 mmol, 1.00 equiv) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol, 2.79 equiv) in N,N-dimethylformamide (20 mL) maintained under nitrogen at 35° C. was added potassium tert-butoxide (350 mg, 3.12 mmol, 1.75 equiv) in 20 min. The resulting solution was stirred at 35° C. for another 35 min then the reaction was quenched with 50 mL of water. The pH value of the solution was adjusted to 2-3 with 2N hydrochloric acid. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.0 g of crude 4-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)propyl)-5-methyloxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 445[M+H]+, 389, 115.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1>ClCCCl>[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:8](=[O:10])[CH3:9])[CH2:30]1
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCOc1ccc(C2CCCC(NC(C)=O)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Triethylamine (15 μl) and acetic anhydride (10 ml) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (29 mg) in anhydrous 1,2-dichloroethane (2 ml) at room temperature. After 0.5 hr, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (22 mg, 66%) and a mixture of diastereoisomers; m/z (ES+) 338 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.[CH2:16]=[C:17](N1CCOCC1)[CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:18]([C:17]1[O:15][N:14]=[C:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)[CH:16]=1)[CH3:19]
Reactant: C=C(CC)N1CCOCC1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc([C@H]2CC[C@H](C(=O)O)CC2)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (2.35 g, 10.1 mmol) and 4-(1-methylene-propyl)-morpholine (4.26 g, 30.2 mmol) in dichloromethane (100 ml) was added triethylamine (1.40 ml, 10.1 mmol at 0-5° C. The cooling bath was removed 30 minutes after completed addition. After stirring for 20 h the solvent was evaporated. The residue was redissolved in 6 M aqueous hydrochloric acid solution (100 ml), and the mixture was heated at reflux for 3 h. After cooling to room temperature the reaction mixture was partitioned between crushed ice (300 g) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/tert-butyl methyl ether as eluent gave the title compound (0.42 g, 19%) as white solid. MS m/e: 222 ([M−H]−)
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)C.[NH2:19][NH2:20].O>CO>[F:16][C:5]([F:17])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:4]([NH:19][NH2:20])=[O:3]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Solvent: CO
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 45 °C
Yield: 84.7 %

Procedure:
To a solution of difluoro-quinolin-6-yl-acetic acid ethyl ester (5.5 g, 21.9 mmol) in methanol (85 mL) was added hydrate hydrazine (5.3 mL, 109.5 mmol). The mixture was heated to 45° C. for 10 min., cooled to room temperature, concentrated, and taken up in dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a light orange solid (4.4 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=2)[C:12]([OH:14])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.O>CN1C(=O)CCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH:44][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=[C:9]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:10]=2)=[CH:38][CH:37]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1cccnc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccnc1-c1cc(C(=O)NCCc2ccc(F)cc2)cc(-n2cnnn2)c1
Reaction time: 0.67 h
Yield: 7.6 %

Procedure:
3-(3-Methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid (140 mg) and dissolved in dry NMP (15 mL), and CDI (80 mg, 0.49 mmol) was added. The reaction mixture was stirred for 40 minutes, and then 2-(4-fluorophenyl)-ethylamine (0.16 mL, 1.22 mmol) was added. The reaction mixture was stirred for 24 hours at room temperature, and then poured into 30 mL water. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc/hexanes (30%-100%) to give 15 mg of N-[2-(4-fluoro-phenyl)-ethyl]-3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzamide, MS (M+H)=419.
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25][C:2]2[C:3]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[C:4]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)[C:5]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[C:6]3[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=23)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c21

Procedure:
2 g (7.02 millimols) of tetrachlorophthalimide, 4.36 g (28.08 millimols) of p-nitrothiophenol, 5.82 g (42.12 millimols) of potassium carbonate and 30 ml of tetrahydrofuran are stirred at 25° C. for 14 hours. The mixture is acidified and extracted with tetrahydrofuran/toluene and the extracts are dried and evaporated. The residue is washed with methylene chloride and recrystallised from dioxane/toluene. This yields 3.02 g (57% of theory) of tetrakis-(p-nitrophenylthio)-phthalimide; melting point 297°-301° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:27][CH:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][C:7]=2[C:8]=1[CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc2oc(C(O)CC(C)C)c(C)c2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2oc(C(Cl)CC(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution (10 mL) of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (761 mg) synthesized above in toluene were added pyridine (297 μL) and thionyl chloride (268 μL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (769 mg, 94%) as a brown oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22](O)([CH3:24])[CH3:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22]([CH3:24])=[CH2:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Solvent: c1ccccc1
Product: C=C(C)c1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1

Procedure:
The title compound was prepared by reacting of 2-[4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-propan-2-ol with Burgess Inner salt (Et3NS(Q)2NCOOMe in benzene at reflux for 30 min. 1H NMR(CDCl3) d 7.17(s, 2H), 6.08(s, 1H), 5.34(s, 1H), 5.02(s, 1H), 3.72(d, 1H), 3.32(m, 1H), 2.12 and 2.15 (two sets of s, 12H), 1.4-1.6(m, 4H), 0.97(t, 6H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>CCOCC>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:20]=[O:21])[CH:7]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To 2-bromo-4-(trifluoromethyl)pyridine (700 mg, 3.1 mmol) in ether (30 ml) at −78° C., BuLi (1.6M in hexanes, 2.13 ml) was added. After 40 min, DMF (340 mg) was added and the reaction mixture was stirred at −78° C. for a further 45 minutes and the reaction mixture was allowed to come to rt over a period of 1 h. Then the reaction mixture was quenched with solid ammonium chloride and partitioned between water and ether. Organic layers were dried and evaporated to provide 4-(trifluoromethyl)picolinaldehyde as a crude residue which was carried to the next step without further purification.