Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[C:12]([CH2:14][O:15][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1
Reactant: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Reactant: Oc1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2Cl)cc(COc2ccccc2)cn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
24 mg of 3-(2-Chlorophenyl)-5-hydroxymethyl-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran. 9.4 mg of phenol, 33 mg of triphenylphosphine polymer (3 mmol/g resin) and 17 mg of 1,1,1-azobis(N,N-dimethylformamide) were added thereto, followed by stirring at 60° C. overnight. Further, 50 mg of triphenylphosphine polymer (3 mmol/g resin) and 30 mg of 1,1′-azobis(N,N-dimethylformamide) were added, followed by stirring at 60° C. overnight. After cooling to room temperature, ethyl acetate was added thereto and the triphenylphosphine polymer was removed by filtration through Celite. The filtrate was washed with water and 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:3]=1
Reactant: On1ccc(-c2cccs2)n1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1ccc(-c2cccs2)n1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (75%, crystals).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([CH3:38])[CH2:34][C:35](Cl)=[O:36])[CH:30]=[CH:31][CH:32]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][CH:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([Br:26])[CH:28]=3)[CH3:38])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: CC(CC(=O)Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1)c1cccc(Br)c1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. γ-(3-Bromophenyl)butanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-[γ-(3-bromophenyl)-butanoyloxy] -2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Clc1ccnc2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2ccccc12
Yield: 76 %

Procedure:
To a solution of sodium methoxide (33 g) in methanol (130 ml), 4-chloroquinoline (10 g) was added under stirring. The mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated, then dissolved in dichloromethane (250 ml) and washed with water (250 ml). The organic layer was dried over sodium sulfate. The solvent was evaporated to give a yellow oil (7.39 g, 76% yield) which was not purified.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:32]([O:31][C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:27]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)OCc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(O)cc1)OCc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
A solution of methyl 3-(4-tert-butyldimethylsilyloxyphenyl)-2-[(4-tert-butoxycarbonylphenyl)methoxy]propionate (310 mg, 0.61 mmol) in THF (5 ml) at −20° C. was treated with tetrabutylammonium fluoride-acetic acid (1.0M in THF, 0.76 ml, 0.76 mmol). The mixture was stirred at this temperature for 15 minutes, quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title material (256 mg, 100%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:9]=2)=[O:5]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Yield: 75.3 %

Procedure:
3-Phenyl-6-(3-phenylpropyloxy)-1-oxo-1H-indene-2-carboxylate ethyl ester (1.65 g, 4.0 mmol) prepared in (Step 5) of Example 1 was dissolved in methanol (160 ml) and p-toluene sulfonic acid (228 mg, 1.2 mmol) was added thereto. The mixture was reacted for 1 hour at 70° C., and then washed with brine. The organic layer was extracted with ethyl acetate, dried over anhydrous sulfonate sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain the title compound (yield 75.3%) as a red solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C1(C)C=CC=CC=1.[CH2:20](O)[CH2:21][OH:22]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:7]1([C:5]2([CH2:4][CH2:3][CH2:2][Cl:1])[O:22][CH2:21][CH2:20][O:6]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Reaction time: 3 h
Yield: 121.2 %

Procedure:
A mixture of 36.5 g (0.2 mole) of γ-chlorobutyrophenone, 14 g of ethylene glycol (0.25 mole), 125 ml of toluene, and 0.1 g of p-toluenesulfonic acid is refluxed under a Dean-Stark trap for 1 hr. An additional 4 g of ethylene glycol is added and reflux continued for 3 hrs more. After cooling, the reaction mixture is washed with 5% sodium bicarbonate solution, dried with anhydrous magnesium sulfate, and concentrated. Upon standing at -10° C. overnight, the mixture partially crystallizes. The crystalline product is filtered and washed with petroleum ether to afford 17.7 g of 2-phenyl-2-(3'-chloropropyl)dioxolane, m.p. 56°-58°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)C>O1CCCC1>[CH2:10]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 20 °C
Yield: 65 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (936 mg, 5.0 mmol) in tetrahydrofuran (50 mL) was added at −78° C. under an atmosphere of nitrogen and stirring drop wise 1 M benzylmagnesium chloride solution in diethyl ether (5 mL, 5.0 mmol). The reaction was let to warm up to 20° C. over 16 h. The solvent was removed under reduced pressure and the residue was dissolved in water. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using heptane and then heptane/ethyl acetate (9:1 v/v) as eluent to yield the title compound (778 mg, 65%) as a pale-yellow viscous oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[O:46]=[S:47]1(=[O:69])[CH2:52][CH2:51][CH2:50][N:49]2[C:53](=[O:68])[N:54]([CH2:64][CH2:65][CH2:66][NH2:67])[C:55](=[O:63])[C:56]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:48]12>O.ClCCl>[O:69]=[S:47]1(=[O:46])[CH2:52][CH2:51][CH2:50][N:49]2[C:53](=[O:68])[N:54]([CH2:64][CH2:65][CH2:66][NH:67][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:55](=[O:63])[C:56]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:48]12
Reactant: O=C(O)CCCSc1cccc2nccn12
Reactant: NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCCSc1cccc2nccn12)NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane solution of 590 mg (2.5 mmol) of 4-(imidazo[1,2-a]pyridine-5-ylthio)butanoic acid and 383 mg (2.5 mmol) of HOBt, 479 mg (2.5 mmol) of WSC and 0.42 ml (3 mmol) of triethylamine were added. After the reaction mixture was stirred at 0° C. for 1.5 hours, 1.158 g (3 mmol) of 3-(1,1,6,8-tetraoxo-9-phenyl-2,3,4,8-tetrahydropyrimido[6,1-b][1,3]thiazin-7-yl)propylamine hydrochloride and 0.84 ml (6 mmol) of triethylamine were added, followed by stirring at room temperature for 16 hours. After water was added, the mixture was extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=25/1) to yield 683.9 mg (48.2%, white oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)\[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 81.2 %

Procedure:
In substantially the same manner as in example 148, methyl E-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.00 g) was reacted with 1N aqueous sodium hydroxide to obtain E-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (790 mg, yield 80%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. m.p. 134-135° C.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15]CC3C=CC(OC)=CC=3)[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])=[O:9])[CH2:4]1.FC(F)(F)C(O)=O.[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49]>C1(OC)C=CC=CC=1>[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[CH3:1][N:2]([CH3:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:9])[CH2:4]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@@H](N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.56 g of (2S,4S)-2-[(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (1) above] were suspended in 5.1 ml of anisole, and 25.5 ml of trifluoroacetic acid and 0.83 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to the resulting suspension. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, 1,2-dichloroethane was added to the residue, and excess acid was removed by azeotropic distillation. The residue was decanted using hexane and then triturated with diethyl ether, after which the mixture was decanted and dried by evaporation under reduced pressure to give 3.65 g of the title compound as a powdery product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)C(C)(C)O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-hydroxy-2-methylpropionic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (87 μL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 135 (65 mg, 35%). LCMS: RT 2.44 min [M+H]+ 449.1. 1H NMR (DMSO, 400 MHz): δ 8.24-7.90 (3H, m), 7.88-7.81 (1H, m), 7.67-7.56 (1H, m), 7.23-7.07 (2H, m), 5.90 (1H, s), 5.51 (1H, s), 5.30-3.76 (4H, br), 2.45-2.28 (1H, m), 1.93-1.61 (5H, m), 1.48-1.27 (6H, m), 1.20-1.08 (1H, m)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CO.O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1)=[N+:14]=[N-:15]
Reactant: COC(=O)c1cc(CBr)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(CN=[N+]=[N-])ccn1
Yield: 95.9 %

Procedure:
To solution of methyl 4-(bromomethyl)picolinate (350 mg, 1.52 mmol) in methanol (5 mL) was added a solution of sodium azide (198 mg, 3.04 mmol) in water (0.5 mL). The mixture was heated to reflux for 2 hours, then was concentrated. The resulting residue was dissolved in EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give methyl 4-(azidomethyl)picolinate (280 mg).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[BrH:28]>O>[Br:28][CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:20][CH2:19][C@H:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: Br
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCO)CC2)CC1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCBr)CC2)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To 350 ml of xylene were added 341 g (1280 mmol) of the crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanol obtained by the procedures described above and 881 g (5120 mmol) of 47% hydrobromic acid, water was removed by azeotropic distillation, and then the mixture was stirred at 150° C. for 2 hours. To the reaction mixture was added 1.0 l of toluene, and it was washed with 300 ml of saturated aqueous sodium carbonate solution twice and with 400 ml of water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 156 g of a crude 1-bromo-3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propane.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80](Cl)[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30](Cl)[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:109]([CH2:111][NH2:112])[OH:110]>>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80]([NH:112][CH2:111][CH2:109][OH:110])[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30]([NH:112][CH2:111][CH2:109][OH:110])[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCO
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(N(CCCCCCN(c3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3O)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C(O)C>[CH3:12][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][CH2:8][CH:7]1[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:20][CH:6]21
Reactant: Cc1c(O)ccc2c(=O)c(-c3ccccc3O)coc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(O)ccc2c1OCC1c3ccccc3OC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
To a stirred solution of 7-hydroxy-3-(2-hydroxy-phenyl)-8-methyl-chromen-4-one (3 gm, 11.2 mmol) in absolute ethanol (30 ml) at 0° C. was added NaBH4 (2.6 gm, 67.2 mmol). The reaction mixture was then stirred for 24 hours at room temperature. The reaction was stopped by adding ice-cooled water and the solution was neutralized with 10% HCl to get the white precipitate. The white precipitate was washed with water and the purified by silica gel column chromatography using hexane-chloroform as the eluent to give 4-methyl-6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (1.56 gm, 55%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C1C(C(O)=O)=NC=CC=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]([F:62])([F:61])[C:52]1[C:53]([C:58](O)=[O:59])=[N:54][CH:55]=[CH:56][N:57]=1>ClCCl.O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:58]([C:53]3[C:52]([C:51]([F:61])([F:50])[F:62])=[N:57][CH:56]=[CH:55][N:54]=3)=[O:59])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1nccnc1C(F)(F)F
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1ncccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1nccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.3 %

Procedure:
50 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 1 of PREPARATION EXAMPLE 2) was dissolved in 0.9 ml of dichloromethane and 0.085 ml of triethylamine was added at ambient temperature. Then 383 mg of 3-(trifluoromethyl)pyridine-2-carboxylic acid, 54 mg of HOBT hydrate, 76 mg of EDCI.HCl and 37 mg of 3-trifluoromethyl-pyrazine-2-carboxylic acid were added sequentially. The reaction mixture was stirred at ambient temperature for 14 hours and then water was added, the phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulphate, filtered and concentrated. Crude material was obtained as a yellow sticky solid, which was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (1:1) as a solvent. Thus, 76 mg of 3-trifluoromethyl-pyrazine-2-carboxylic acid [1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropylmethyl]-amide was obtained as a sticky solid. 1H-NMR (CDCl3): 8.80 ppm (s, 1H), 8.75 ppm (s, 1H), 8.65 ppm (s, 1H), 7.95 ppm (s, 1H), 7.70 ppm (m, 1H), 3.72 ppm (d, 2H), 1.18 ppm (m, 4H).