Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](/[CH:9]=[CH:10]/[CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[FH:20]>O1CCCC1>[F:20][C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH2:13][CH:12]([CH3:19])[CH2:11]/[CH:10]=[CH:9]/[C:2]([CH3:1])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Reactant: F
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/CC(C)CCCC(C)(C)F
Reaction time: 15 h

Procedure:
One gram of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate is added to a solution of 1 equiv. of dry hydrogenfluoride in dry tetrahydrofuran. The mixture is allowed to stand at 0° for 15 hours and is then washed with water, dried and evaporated under reduced pressure to yield trans ethyl 11-fluoro-3,7,11-trimethyldodeca-2,4-dienoate which can be purified by chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>C(O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1SCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a mixture of 225.6 g of 4-chloro-3-nitrobenzotrifluoride and 136 g of benzyl mercaptan in 1.5 l of ethyl alcohol, at reflux, was added a solution of 72.5 g of 85% KOH in 120 ml of water over a 45 minute period. Reflux was continued for an additional three hours. The reaction mixture was cooled to 5° C. The precipitate was filtered off, washed with ethanol and water and dried to give 273.2 g of 2-nitro-1-[(phenylmethyl)thio]-4-trifluoromethylbenzene as a bright yellow solid, m.p. 132°-136°.
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)cc(Br)c2)cc1
Yield: 36 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (1) in Example 3, the reaction of 3,5-dibromobenzoyl chloride (20.13 g, 0.06747 mole) with 4-octoxybenzoyl hydrazide (17 g, 0.06747 mole) gave the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (12.87 g, 36% yield). Cyclocondensation of the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]-benzohydrazide (12.17 g) with POCl3 (63 mL) gave the required 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (5) (6.12 g, 52% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18](=[O:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15](Cl)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18](=[O:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(-c2ccc(Br)cc2)nn2c(Cl)cccc12
Reactant: CCCCN
Product: CCCCNc1cccc2c(C(C)=O)c(-c3ccc(Br)cc3)nn12
Yield: 76 %

Procedure:
In a similar manner as described in Example 1, from 1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (2.55 g, 7.3 mmol) and butylamine, 1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone (2.15 g, 76%) was obtained as a yellow oil. 1H NMR (CDCl3): δ 7.61 (m, 3 H), 7.43 (m, 3 H), 6.08 (d, 1 H), 6.02 (broad s, 1 H), 3.33 (q, 2 H), 2.12 (s, 3 H), 1.70 (m, 2 H), 1.44 (m, 2 H), 0.94 (t, 3 H); MS m/z 386 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.1 eq triisopropylsilyl chloride. Purification by HPLC using 1:19 ethyl acetate/hexanes gave 5.5 g of the desired product as of a clear oil, a 75% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2)=[O:12]
Reactant: CNC
Reactant: O=C(O)c1ccc2c(c1)CCN2
Product: CN(C)C(=O)c1ccc2c(c1)CCN2

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using indoline-5-carboxylic acid and dimethylamine; MS: 191.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCNCC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) and homopiperazine (801 mg) were treated in the same manner as in Preparation Example 4 to obtain the title compound.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].CS(O[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O>CN1C(=O)CCC1.O.CO>[CH2:28]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14]O.N1C=CC=CC=1.S(Cl)([Cl:24])=O.O>O1CCCC1>[Cl:24][CH2:14][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COCCOc1cccc(CO)c1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cccc(CCl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.37 g, 1.7 mmol) and pyridine (0.23 mL 2.8 mmol) in tetrahydrofuran (8 mL) at 0° C. was added thionyl chloride (0.14 mL, 1.9 mmol) and the reaction mixture warmed to room temperature and stirred for one hour. Then it was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give 1-(chloromethyl)-2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.4 mmol, 82% yield). 1H NMR (400 MHz, CDCl3): 7.01-6.89 (m, 3H), 4.63 (s, 2H), 4.16-4.13 (m, 2H), 3.95 (s, 3H), 3.79-3.77 (m, 2H), 3.44, m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][O:10][C:7]2=[CH:8][N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][O:10][C:7]2=[CH:8][N:9]=1)[CH3:2]
Reactant: CC(=O)c1cc2ccoc2cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(O)c1cc2ccoc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
5-Acetylfuro[2,3-c]pyridine obtained in Example 4(2.42 g, 15.0 mmol) was dissolved in toluene (30 mL), and the solution was cooled to 0° C. To the cooled solution,16.0 mL (16.0 mmol) of 1.0 M solution of diisobutyl aluminum hydride in toluene solution was added, and the solution was stirred for 2 hours at the same temperature, the reaction mixture was then poured into 100 mL of a 5% ammonium chloride aqueous solution which had been cooled on ice, and it was extracted twice with 100 mL of ethyl acetate. After washing with 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of saturated saline water, the extract was concentrated to give 2.36 g of crude product. This product was purified by column chromatography on silica gel, giving 2.25 g (92.0% yield) of 5-(1-hydroxyethyl)furo [2,3-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:23]=[C:22]([CH3:24])[O:21][N:20]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:23]=[C:22]([CH3:24])[O:21][N:20]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)OC(C)(C)C)nc3c2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)O)nc3c2)no1
Yield: 70.8 %

Procedure:
A solution of tert-butyl 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10C, 25 mg, 0.0534 mmol), was treated with 5 mL 20% TFA in DCM for 14 hours. The reaction was concentrated and purified by reverse phase prep LC to yield 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetic acid (10, 15.6 mg, 64% yield). MS (M+H)=413.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]=1[O:28]C)=[O:7].B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>ClCCl>[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]=1[OH:28])=[O:7]
Reactant: COc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)NCCN(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc2c1ccc1nc3ccc(O)c(C(=O)NCCN(C)C)c3nc12
Reaction time: 6 h
Yield: 21.1 %

Procedure:
To a cold solution of 4,10-dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (300 mg) in dichloromethane (25 mL) was added a 1.0M solution of boron tribromide in dichloromethane (1.63 mL, 2.2 equivalents). The reaction mixture was stirred for 6 hours and then ice was added with sodium carbonate and sodium chloride. The organics were extracted into dichloromethane, dried (MgSO4), and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the title compound (61 mg)
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1.[CH2:10]([OH:14])CCC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Fe+2].C1(C)C=CC(S([O-])(=O)=O)=CC=1>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([CH:10]=[O:14])[S:5][CH:6]=2)[O:2]1
Reactant: CCCCO
Reactant: c1scc2c1OCCO2
Agent: [Fe+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O=Cc1scc2c1OCCO2
Temperature: 80 °C
Reaction time: 144 h

Procedure:
A di-ol triblock copolymer, of the structure HO-BAB-OH, was synthesized from 3,4-ethylenedioxythiophene and a precursor that contained a hydroxyl group at one end and an EDOT group at the other end. This precursor was prepared by reacting a mono-amino mono-hydroxyl terminated poly(ethylene glycol) oligomer with 3,4-ethylenedioxythiophene-2-carboxaldehyde under the conditions described in Example #18, Part A. 3,4-Ethylenedioxythiophene-2-carboxaldehyde was prepared according to the Mohanakrishnan method in high yield (Mohanakrishnan et al., Tetrahedron, 55, 11745-11754 (1999)). The tri-block copolymers were made as follows: 2 mmol of PEGmonoEDOT with average molecular weight of 1500 Dalton and 170 mmol EDOT were mixed in butanol and heated at 80° C. To this solution, a solution of Baytron® C from Bayer (50% iron p-toluenesulfonate in butanol) was added drop-wise over 30 minutes. The reaction was stirred at room temperature for 6 days then the product was filtered and extracted with copious amount of water. Butyl acetate (150 mL) was added under stirring and the butanol was removed by fractional distillation. The resulting butyl acetate suspension was mixed with a trimer of hexamethylene diisocyanate at a ratio NCO/OH of 1.2 (Bayhydrur XP 7007 from Bayer). This mixture was used to cast coatings on primed iron panels. The resulting polyurethane coatings had a conductivity of 1×10−4 S/cm.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:11]=[CH:10]1>C(#N)C>[Br:1][C:10]1[NH:9][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:11]=1
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under an argon atmosphere 3.30 g (18.54 mmol) N-bromosuccinimide were added to a solution of 2.60 g (12.25 mmol) diethyl imidazole-4,5-dicarboxylate in 30 ml acetonitrile. The solution was stirred for 24 hours in the dark at ambient temperature and then evaporated down. The residue was taken up in 150 ml of ethyl acetate and washed twice each with saturated aqueous sodium chloride solution and saturated aqueous sodium thiosulphate and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and the solvent was removed.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[O:7])[CH2:2]1.[C:18](=O)([O:26]C1C=CC=CC=1)[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:1]1[CH2:4][CH:3]([O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:18](=[O:26])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:16])=[O:15])=[O:7])[CH2:2]1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccccc1C(=O)OC1COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1C(=O)OC1COC1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 2.57 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide, 2.14 g of diphenyl carbonate, 1.38 g of potassium carbonate and 13 ml of dimethylformamide is stirred at a temperature of 20°-25° C. for 15 hours. The reaction mixture is then poured into ice-water, the pH is brought to a value of 5-6 by dropwise addition of 10% hydrochloric acid and the mixture is extracted with ethyl acetate and washed with water. After drying over sodium sulfate, evaporation and crystallisation of the residue from diethyl ether, 2.2 g of phenyl N-[2-(oxetan-3-oxycarbonyl)phenylsulfonyl)carbamate (compound 1.030) of melting point 91°-92° C. are obtained.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1>CN(C)CCO>[CH3:18][N:17]([CH3:21])[CH2:14][CH2:13][O:23][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: CN(C)CCO
Agent: [Na]
Product: COc1cc(Nc2nc(C)cc(OCCN(C)C)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under an atmosphere of nitrogen in 2-dimethylaminoethanol (0.92 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to 100° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using dichloromethane/methanol/saturated aqueous ammonia solution (19:1:0.2 v/v/v) as eluent to yield the title compound as a brown viscous oil (37 mg, 33%). MS ISP (m/e): 383.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (s, 1H), 7.62 (s, 1H), 7.15 (d, 1H), 7.07 (s, 1H), 7.05 (d, 1H), 6.87 (s, 1H), 6.16 (s, 1H), 4.45 (t, 2H), 3.86 (s, 3H), 2.71 (t, 2H), 2.36 (s, 3H), 2.34 (s, 6H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][O:8][C:6]2[CH:5]=[CH:4][C:3]([C:9]([N:11]3[CH2:15][CH2:14][CH2:13][C@H:12]3[CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:10])=[C:2]([F:1])[CH:7]=2)=[CH:27][CH:28]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCc2ccc(Cl)nc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-chloro-5-(chloromethyl)pyridine [CAS 70258-18-3]. MS (ES+) 418.3
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:17]([CH2:16][CH2:15][NH:14][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])=[O:18]
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNS(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
It is obtained by reacting 4-chlorosulfonyl-benzoic acid (1 eq) with H-βAla-OMe×HCl in CH2Cl2 using diisopropylethylamine (2 eq) as base. After 30 minutes at room temperature the reaction mixture is extracted with water and the organic layer is dried over Na2SO4. Removal of the solvent gives the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:20]([O-])=O)=[C:13]([C:15](=[O:19])/[CH:16]=[CH:17]\[CH3:18])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:20][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[C:15](=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: C/C=C\C(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)c1cc(O)ccc1N
Yield: 97 %

Procedure:
Analogously to the procedure of Example X, starting from 1.31 g (4.42 mmol) of E/Z-1-[5-(benzyloxy)-2-nitrophenyl]-2-buten-1-one with 0.17 g of palladium/carbon (10%) in 30 ml of ethanol under hydrogen, after 3 h 770 mg (97%) of 1-(2-amino-5-hydroxyphenyl)-1-butanone are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([NH:26][CH2:27][C:28]#[CH:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(N(CC)CC)C>ClCCl>[Cl:12][C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([NH:26][CH2:27][C:28]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Yield: 78.8 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (54 g, 230 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine (30.2 g, 115 mmol), prepared as described in Part A of Example 3, in dichloromethane (1 L) at room temperature. Triethylamine (26 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16.5 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, and the work-up and isolation procedures described in Part B of Example 18 were followed to provide 36.12 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.CC#N.O>[C:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:19])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(CCCCCBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCNCCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
N-Boc-ethylenediamine (81 μl, 0.51 mmol) was added to a solution of Br—(CH2)5—CONH—(CH2)2-STrt (230 mg, 0.46 mmol) and Na2CO3 (196 mg, 1.85 mmol) in DMF (0.8 ml). The reaction mixture was stirred for 10 h at 70° C. After cooling to RT the mixture was diluted with 4 ml (MeCN/H2O=25:75, with 0.1% TFA) and purified by RP-HPLC to get Boc-NH—(CH2)2—NH—(CH2)5—CONH—(CH2)2-STrt.