Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[CH:5][CH:4]=1.[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[O:7]1[C:3]([CH2:2][P:11](=[O:15])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9])=[CH:4][CH:5]=[N:6]1
Reactant: BrCc1ccno1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccno1)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
5-(Bromomethyl)isoxazole (5.38 g, 33.2 mmol) was stirred at 0° C. as triethylphosphite (5.7 mL, 33.2 mmol) was slowly added. The mixture was stirred at room temperature for 48 h, heated under reflux for 24 h, then concentrated. Purification by distillation at reduced pressure (bp 109-115° C./0.04 mm Hg) provided pure product as a colorless oil (6.75 g, 92.7%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:27][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2cc(OCCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.29 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid. m.p. 98° C. (yield 0.61 gm, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccccn1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid methyl ester (8.4 g; 50 mmol) in DMF (100 ml)were added potassium carbonate (14.0g; 100 mmol) and 2-chloromethylpyridine hydrochloride (8.2 g; 50 mmol), and the resulting mixture was stirred at 50° C. for 24 h. The mixture was then poured into water, extracted with ethyl acetate, the acetate layer was washed with water, brine and concentrated in vacuo. The residue was purified on silica gel column (hexane-ethyl acetate 1:1) to provide 9.5 g of 4-(2-pyridylmethoxy)phenylacetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14][C:15]([O:17]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][CH2:39][CH2:40][O:41][C:42]([NH:44][CH2:45]C(O)=O)=[O:43]>>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]([NH:14][C:15](=[O:17])[CH2:45][NH:44][C:42]([O:41][CH2:40][CH2:39][NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[O:43])[CH2:10][C:11]([OH:13])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNC(=O)OCCNc1ccccn1
Reactant: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc(Cl)cc(Cl)c1
Product: O=C(O)CC(NC(=O)CNC(=O)OCCNc1ccccn1)c1cc(Cl)cc(Cl)c1

Procedure:
prepared by reaction of 3-(3,5-dichlorophenyl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid with the solid phase polystyrene A OH (Rapp, Art. No. HA 1 400 00), is reacted with [2-(pyridin-2-ylamino)ethoxycarbonylamino]acetic acid and cleaved off from the support, giving 3-(3,5-dichlorophenyl)-3-{2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]ethanoylamino}propionic acid.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=2)=O)=CC=1)([O-])=O.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][C:34]=1[C:39]#[N:40]>>[C:39]([C:34]1[CH:35]=[N:36][N:37]([CH3:38])[C:33]=1[NH:32][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:18][C:17]=2[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=1)=[O:10])#[N:40]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCOCC3)oc12
Reactant: Cn1ncc(C#N)c1N
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCOCC3)oc12
Yield: 29.1 %

Procedure:
Starting from 4-difluoromethoxy-2-(morpholin-4-yl)-benzooxazole-7-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (56 mg). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane followed by preparative thin layer chromatography eluting with 3% methanol in dichloromethane afforded the title compound as a white solid (28 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:2].[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:31])[CH2:26][O:27][CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C@@H:8]([OH:9])[C@H:26]([O:27][CH:28]([CH3:30])[CH3:29])[C:25]([N:20]2[C@@H:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][O:22][C:21]2=[O:24])=[O:31])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCOc1ccc(C=O)cc1
Product: CCOc1ccc([C@@H](O)[C@H](OC(C)C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Yield: 105.4 %

Procedure:
Under the similar conditions to those described in Production example 332a), 2.4 g of 4-ethoxybenzaldehyde and 5.6 g of (4S)-4-benzyl-3-(2-isopropoxyacetyl)-1,3-oxazolidin-2-one were reacted, to give 7.2 g of (4S)-3-[(3R,2S)-3-(4-ethoxyphenyl)-3-hydroxy-2-isopropoxypropanoyl]-4-benzyl-1,3-oxazolan-2-one as a colorless solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:8]=1[O:7][C:6]([F:5])([F:19])[F:18]
Reactant: COC(=O)c1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Fuming nitric acid (5 mL) was cooled on an ice bath. Methyl 2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was slowly added within 30 minutes keeping the temperature below 15° C. The reaction was then stirred at 60° C. for 1 hour and 2 hours at room temperature. The mixture was poured on ice water whereupon an oil separated. The aqueous supernatant was decanted and additional water (50 mL) was added to the oil. After neutralisation with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (15 mL) once more. The combined organic phases were washed with saturated sodium chloride (2×15 mL), dried (MgSO4), and concentrated in vacuo to give 5.69 g of 5-nitro-2-trifluoromethoxybenzoic acid methyl ester.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[CH:26]([O:52][C:53](=[O:55])[CH3:54])[CH:25]2OC(=O)C)=[CH:19][CH:20]=1)=[O:15].Cl>CCOCC>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[C:26]([O:52][C:53](=[O:55])[CH3:54])=[CH:25]2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)C(OC(C)=O)[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)=C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
DBU (15 μL, 0.10 mmol) was added to an ice-cold solution of diacetate 28 (32 mg, 0.048 mmol) in ether (0.5 mL). The solution was stirred at 0° C. for 30 min. and then was allowed to warm to room temperature. After stirring overnight, 1 M HCl was added and the resulting mixture was extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→100% ethyl acetate/hexanes) provided the title compound (21 mg, 71%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH2:42]>>[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH:42][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cccc(-c4ccc(F)cc4C)c3)c3ccccc23)n1
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(Oc3ccnc(NCC(C)(C)CN(C)C)n3)c3ccccc23)c1

Procedure:
Compound is prepared from 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid [4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-amide and N,N,2,2-tetramethyl-1,3-propanediamine according to conditions described in general procedure J. (23 mg). 1H NMR (400 MHz, CDCl3) δ 8.01-8.1 (m, 4H), 7.88 (dd, 1H, J=0.8 and 8 Hz), 7.5-7.65 (m, 5H), 7.26-7.33 (m, 2H), 6.98-7.08 (m, 2H), 6.21 (d, 1H, J=6 Hz), 2.3 (s, 3H), 2.0-2.2 (brm, 10H), 0.6-0.9 (brs, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30][C@@H:29]1[CH3:34])[CH3:27]
Reactant: CCN1CCNC[C@@H]1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.20 Hz, 6H) 2.33 (d, J=2.27 Hz, 3H) 3.08-3.36 (m, 4H) 3.42 (br. s., 2H) 4.11-4.93 (m, 3H) 7.64 (br. s., 1H) 7.71-7.80 (m, 1H) 7.87-8.79 (m, 4H) 9.53-10.44 (m, 1H) 12.23-14.36 (m, 1H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:29].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of 2.14 gm (0.005 mol) of 6-[4-(3,4-dichlorophenyl-mercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 50 ml of methanol, mixed with a solution of 1.3 gm (0.06 mol) of sodium metaperiodate in 10 ml of water, and stirred for two hours at ambient temperature. Then, the mixture is refluxed for three hours, the volume of the reaction mixture is reduced by evaporation to about three-quarters, and water is added. The oil precipitated is separated by decanting of the solvent and is taken up in hot isopropanol/disiopropylether. Upon cooling, crystals are obtained which have a melting point of 138°-139° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCCCCBr
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: N#CCCCCCc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 50.0 g (.284 mole) of 6-bromocapronitrile in 550 ml of benzene was cooled to 5° C. and to this was added 77.3 g (.580 mole) of anhydrous aluminum chloride in portions over a 10 minute period. The ice bath was removed and the vigorously stirred mixture was warmed slowly to reflux. After 2 hours at reflux, the mixture was cooled to room temperature, then poured slowly into a mixture of 50 ml of concentrated hydrochloric acid and 250 ml of ice water. The layers were separated and the aqueous portion was extracted twice with 125 ml portions of ether. The combined organic extracts were washed with 100 ml of saturated sodium bicarbonate solution, 100 ml of saturated sodium chloride solution, then dried over sodium sulfate, filtered, and evaporated leaving 53 g of a crude red/brown oil. Distillation under reduced pressure afforded 42.4 g (86%) of the nitrile as a pale yellow oil, bp 136°-140° C./2.5 mm of Hg.
Reaction SMILES: [C@@H:1]([C@@H:5]1[NH:6][C:7](=[O:20])[C:8]2[C:13](/[C:14]/1=[CH:15]/[C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:3][CH3:4])[CH3:2].C1COCC1.O.[Li+].[OH-].Cl>O.C1COCC1>[C@@H:1]([C@@H:5]1[NH:6][C:7](=[O:20])[C:8]2[C:13](/[C:14]/1=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)[C@@H]1NC(=O)c2ccccc2/C1=C/C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](C)[C@@H]1NC(=O)c2ccccc2/C1=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 7 (273 mg, 1.0 mmol) in a 1:1 mixture of THF—H2O (10 mL) at room temperature was added a solution of LiOH (83.9 mg, 2.0, mmol) in H2O (2 mL). The mixture was stirred at room temperature overnight, and was then acidified with 5% HCl to pH=2. THF was eliminated in vacuo and the aqueous phase was extracted with EtOAc (3×50 mL). The organic phases were washed with brine and dried over MgSO4. Once the solvent had been eliminated in vacuo the raw product was obtained, which was purified by recrystallisation of EtOAc/hexane to give the acid 8 (140 mg, 54% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH3:27])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazin-2-ylamino)butanamide (72 mg, 0.197 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (48 mg). MS 384.3 (M+H); UV 207.8, 308.9 nm; t 0.465 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.[C:15](=[O:17])=[O:16]>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:17])=[O:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
To a cooled (−78° C.) solution of 2-bromo-5-fluorotoluene (10.0 g, 52.9 mmol) in diethyl ether (100 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21.2 mL, 52.9 mmol). The mixture was stirred for 5 min, and slowly warmed to 0° C. Dry ice (100 g, 2.27 mol) was slowly added to the mixture while stirring, and it was allowed to warm to rt over 16 h. The mixture was adjusted to pH=2, and extracted with ethyl acetate (3×20 mL). The organic phase was concentrated and the resulting yellow residue suspended in water (100 mL). The suspension was adjusted to pH=12 with 2 N NaOH, and washed with diethyl ether. The aqueous phase was then acidified to pH=2 with 2 N HCl, and extracted with diethyl ether (3×50 mL). The organic extract was washed with water, dried (MgSO4), and concentrated under reduced pressure to afford the product (5.0 mg, 61%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.53 (s, 3H), 7.06-7.17 (m, 2H), 7.87 (dd, 1H), 12.85 (s, 1H).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[ClH:12]>>[Cl:12][C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Temperature: 95 °C
Reaction time: 7 h
Yield: 67.1 %

Procedure:
5.0 g of 2,4-dinitroimidazole (purity 92.3%) was added to 62 mL of 35 mass % hydrochloric acid. The reaction liquid was warmed to 95° C. and the reaction was performed for 7 hours. After the reaction, the reaction mixture was cooled to 0° C. for crystallization. The crystals were filtered and dried to obtain 2.88 g of 2-chloro-4-nitroimidazole (yield 67.1%).
Reaction SMILES: [CH:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>O1CCCC1>[CH2:23]([O:22][CH2:21][C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCCCC1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
Diethyl cyclohexylmalonate (18.7 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was refluxed, with stirring, for one hour. The mixture was cooled and benzyl chloromethyl ether (13.9 g.) in dry tetrahydrafuran (50 ml) was added and the mixture was refluxed, with stirring, for three hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzyloxymethyl-2-cyclohexyl-malonate (30 g.) was obtained as a brown oil and was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(C(C)=O)C(C)C>[OH:1][CH2:2][CH2:3][CH2:4][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCOc1ccccc1O
Solvent: CC(=O)CC(C)C
Product: CCCCCOc1ccccc1OCCCO
Yield: 95.1 %

Procedure:
50.1 g (0.36 mol) of potassiumn carbonate and 115.6 g of methyl isobutyl ketone were added to 124 g (0.69 mol) of 1-hydroxy-2-pentoxybenzene and 100.8 g (0.69 mol), after which the mixture was refluxed for 40 hours. The mixture was cooled, after which the potassium carbonate was filtered off and the methyl isobutyl ketone was distilled off under reduced pressure. The oily residue was then subjected to fractional distillation over a short column under reduced pressure from an oil pump. 78.2 g of 1-(3'-hydroxypropoxy)-2-pentoxybenzene were obtained at 5 mbar and a boiling point of 140°-148° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:59][C:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:66][S:63]([C:60]6([CH3:59])[CH2:62][CH2:61]6)(=[O:65])=[O:64])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 170 mg (58%) of the title compound 48 as an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven: m/z=764 (M+H)+. 1H NMR (acetone-d6): 0.86 (m, 2H), 1.15-1.78 (m, 19H), 1.87 (m, 2H), 2.13-2.54 (m, 3H), 2.57-2.71 (m, 4H), 2.96-3.25 (m, 4H), 3.54 (m, 2H), 4.02 (s, 3H), 4.58 (t, J=13 Hz, 1H), 5.04 (m, 1H), 5.46 (m, 1H), 5.62 (m, 1H), 7.31 (s, 1H), 7.43 (d, J=9 Hz, 1H), 7.58 (s, 1H), 8.07 (d, J=13 Hz, 1H), 8.19 (broad s, 1H), 11.44 (broad s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: OCCC1CCN(CCCCl)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCC(CCO)CC3)cc2)CCOCC1
Yield: 36.5 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (288 mg, 1.22 mmol), 2-[1-(3-chloro-propyl)-piperidin-4-yl]-ethanol (252 mg, 1.22 mmol), DMF (8 ml) and K2CO3 (674 mg, 4.88 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (180 mg, 36%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.70 (t, 2H), 3.55 (td, 2H), 2.98-2.88 (m, 2H), 2.49 (t, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H), 1.75-1.15 (m, 10H).