Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:33]([N:32]([CH2:31][C:11]([OH:30])([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10]([F:37])([F:36])[F:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:34][CH3:35]
Reactant: O=C(O)c1cccs1
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 11 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([NH2:14])=[O:13])#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(OCC(N)=O)c1
Temperature: 70 °C
Reaction time: 17.5 h
Yield: 76.6 %

Procedure:
A mixture of 3-hydroxybenzonitrile (2.38 g, 20.0 mmol), 2-bromoacetamide (3.04 g, 22.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (20 mL) was stirred at 70° C. for 17.5 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.70 g, 77%).
Reaction SMILES: [BrH:1].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[N:10]=1)[C:3]([NH2:5])=[NH:4].[OH-].[K+].[ClH:28]>O>[ClH:28].[BrH:1].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)cs1
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: O
Product: N=C(N)Nc1nc(CCCCN)cs1
Temperature: 100 °C

Procedure:
A mixture of 2-guanidino-4-(4-phthalimidobutyl)thiazole hydrobromide (3.43 g.) and potassium hydroxide (1.68 g.) in water (50 ml.) was heated at 100° C. for 15 minutes. The reaction mixture was then acidified to pH 2 with 2 N HCl, and the mixture heated at 100° C. for 1 hour. The cooled reaction mixture was extracted three times with ethyl acetate, the aqueous layer was evaporated to dryness and to the residue was added toluene which was evaporated to dryness. The resulting gummy solid was dissolved in methanol, the insoluble material filtered off and the filtrate evaporated to dryness to give 2-guanidino-4-(4-aminobutyl)thiazole hydrobromide hydrochloride. The free base (1.2 g.) was obtained by passage down an ion-exchange column [Amberlite IRA-400 (OH)] in 50% v/v methanol/water.
Reaction SMILES: ClC1C=CC(S([N:11]2[CH:16]([C:17]3[CH:22]=CC=C(F)[CH:18]=3)[CH2:15][C:14]3[NH:24][N:25]=[CH:26][C:13]=3[CH2:12]2)(=O)=O)=CC=1.FC1C=C(C2CC(=O)CCN2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])C=CC=1.ClC1C=CC(C2CC(=O)CCN2C(OCC2C=CC=CC=2)=O)=CC=1.FC1C=C([Mg]Br)C=CC=1.O.NN.N1CCC(=O)CC1>>[CH:17]([CH:16]1[N:11]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:12][C:13]2[CH:26]=[N:25][NH:24][C:14]=2[CH2:15]1)([CH3:18])[CH3:22]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2cccc(F)c2)C1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1c1cccc(F)c1
Agent: Fc1cccc([Mg]Br)c1
Agent: NN
Agent: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
5-(4-Chlorophenylsulfonyl)-6-(3-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Enantiomers A and B) Benzyl 2-(3-fluorophenyl)-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using (3-fluorophenyl)magnesium bromide, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using HPLC Method [2].
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCNCCN(C)C
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCN(C)C)CCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(2-(dimethylamino)ethyl)-N′,N′ dimethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13].[CH3:14][O-:15].[Na+]>CO>[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][NH:13][CH:14]=[O:15]
Reactant: C[O-]
Reactant: Cn1ncc(CCCN)c1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(CCCNC=O)c1N

Procedure:
To a solution of 3-(5-amino-1-methylpyrazol-4-yl)propylamine dihydrochloride (9.3 g, 40 mmol) in methanol (80 ml) was added 28% sodium methoxide solution in methanol (15.9 g). The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. A solution of the oily residue in ethyl formate (60 g) was stirred under reflux for 20 hours. After cooling, to the reaction mixture was added chloroform. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give N-[3-(5-amino-1-methylpyrazol-4-yl)propyl]formamide (6.7 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29](C(OC(C)(C)C)=O)[C:28]([CH3:38])([CH3:37])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[NH:29][C:28]([CH3:38])([CH3:37])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccnc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: CC(C)=CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)=CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 28.7 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.1 g of 1-bromo-3-methyl-2-butene were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.50 g of 2-(3-methyl-2-butenyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (78)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[N:11]([O-])=O.[Na+].[F:15][B-:16]([F:19])([F:18])[F:17].[H+]>O>[F:15][B-:16]([F:19])([F:18])[F:17].[F:1][C:2]1[CH:3]=[C:4]([N+:5]#[N:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: O=N[O-]
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 3,4,5-trifluoroaniline (2.00 g; 13.6 mmol) in 50% tetrafluoroboric acid (5.0 ml) was added dropwise, with stirring, a solution of sodium nitrite (1.04 g; 15.1 mmol) in water (1.5 ml). After a further 15 minutes at 0° C., the precipitated solid was filtered off and washed with cold diethyl ether. After drying under reduced pressure, 2.91 g (11.8 mmol; 87% of theory) of the title compound were obtained in the form of a colorless powder.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.C(O)(=O)C>O>[OH:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(O)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A mixture of 13.5 g or 7-benzyloxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 15, 40 ml of concentrated aqueous hydrochloric acid and 80 ml of acetic acid was heated under reflux for 3 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The benzene solution was washed with water and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Cyclohexane was added to the residue to crystallize it. 9.55 g of the title compound were obtained as a pale red powdery substance.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(O)C>[OH-].[Na+]>[C:16]([NH:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
Compound 6 (6.20 g) was acetylated with acetic anhydride (9 ml) in aqueous sodium hydroxide at pH 9 and 4° C. according to the procedure of Yoshida and Ishii [J. Biochem., 71, 185-191 (1972)]. Obtained 5.32 g (71.4%), mp 165°-166° C., [α]D25 =-46.2 °(c =2.8, ethanol)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:29]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:21][CH2:20][CH2:19][N:18](CC4C=C(C)ON=4)[CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.O1C=CC=C1C1C=C2N=C(S(C)(=O)=O)N=C(N)N2N=1.O1C=CC=C1C1N=C2N=C(S(C)(=O)=O)N=C(N)N2N=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:29]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: Cc1cc(CN2CCCN(c3nc(N)n4nc(-c5ccco5)cc4n3)CC2)no1
Agent: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)cc2n1
Agent: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Product: Nc1nc(NCC2CCCN2)nc2cc(-c3ccco3)nn12

Procedure:
7-Furan-2-yl-N2-pyrrolidin-2-ylmethyl-pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine was prepared in the same manner as described in Example 6(a) and (b) above, except that 7-furan-2-yl-2-methanesulfonyl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine was used as the starting material instead of 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[BrH:28]>>[Br:28][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2
Reactant: Br
Reactant: COc1cc2nc(N3CCc4c(CO)cccc4C3)[nH]c(=O)c2cc1OC
Product: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
2-(5-Hydroxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-1H-quinazolin-4-one 22a (0.2 g, 0.54 mmol) was dissolved to room temperature in 5 mL of 48% hydrobromic acid and stirred to room temperature for 24 h. The precipitated product was separated by filtration, rinsed with water, dried to yield 0.21 g (91%) 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[N:23]=1)[CH2:16][CH3:17]
Reactant: CCCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCN(Cc1ccc(COc2ccc(C3CC3C(=O)OC)cc2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), {4-[(propyl{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]phenyl}methanol (0.303 g, 0.745 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 m1) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.366 g, yield 77%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.CO.Cl[CH2:17]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 4-(4-aminophenyl)butanoic acid (180 mg, 1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 4-(4-aminophenyl)butanoate as an yellowish oil (55 mg, 28% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]2[O:9][C:8]1=[O:17].C1(C)C=CC=CC=1.O>CCCCCC>[Cl:3][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]2[O:9][C:8]1=[O:17]
Reactant: O=S(Cl)Cl
Reactant: O=c1oc2cc(Cl)cnc2n1CO
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=c1oc2cc(Cl)cnc2n1CCl
Reaction time: 4 h
Yield: 83 %

Procedure:
39 Parts of thionyl chloride are added dropwise, in a manner ensuring that the internal temperature does not exceed 50° C., to a solution of 45 parts of 3-hydroxymethyl-6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one in 200 parts of toluene; and the whole is stirred for a further 4 hours at 40°-50° C. The resulting solution is subsequently freed from gases in a water-jet vacuum, and sufficient toluene is evaporated off to leave a crystal sludge that can still just be stirred. After the addition of 100 parts of hexane, filtration is carried out and the filter cake is washed twice with cold hexane. There are obtained 40 parts of 3-chloromethyl-6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (83% of theory), m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([CH2:37]O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][C:30]2[C:31]([C:33]([F:35])([F:34])[F:36])=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:40])([F:18])[F:39])=[CH:26][CH:25]=3)=[CH:28][CH:29]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]2[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:29][CH:30]=2)=[O:39])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(SCc2noc(Cc3ccccc3)n2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of the sulfide of Example 20 (1.00 g, 2.35 mmol) in dichloromethane (12 mL) at 0° C. was added purified mCPBA (0.423 g, 2.45 mmol) in dichloromethane (5 mL). After 1 h the ice/water bath was remove and the reaction was run for 1 h more. TLC shows no starting material and one slower running product spot. Additional dichloromethane was added and the mixture was washed with dilute aqueous sodium dithionite (1×) followed by 50% aqueous sodium bicarbonate (2×). The organic phase was dried (Na2SO4), filtered and evaporated. The residue was taken up into a solution of dichloromethane and diethyl ether and passed through a 5 cm pad of silica gel. Thorough removal of solvent in vacuo afforded 0.928 g of the title compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.CS(C)=O>C(Cl)(Cl)Cl>[CH3:14][O:13][C:11]([CH:7]1[CH2:8][CH2:9][C:10]2[N+:1]([O-:23])=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1CCc2ncccc2C1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2c(ccc[n+]2[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
A 1-L flask was charged with methyl 5,6,7,8-tetrahydroquinoline-6-carboxylate (12.53 g, 65.52 mmol), chloroform (400 mL) and m-chloroperbenzoic acid (22.6 g, 91.7 mmol). The resulting solution was stirred at room temperature for 1 hour then dimethyl sulfoxide (2.8 mL, 39 mmol) was added to quench any remaining m-chloroperbenzoic acid and stirred at room temperature for 30 minutes. The mixture was poured into 2M Na2CO3 (400 mL). The aqueous layer was extracted with CHCl3 (3×200 mL), dried (Na2SO4), filtered and concentrated to afford a white solid (16.67 g). Chromatography on silica (0-15% MeOH in DCM) produced an off white solid (13.90 g, greater than theoretical), which was carried forward without additional purification. m/z=208.3 (M+H)+. NMR (400 MHz, CDCl3) δ 8.16 (d with fine str., J=5.8 Hz, 1H), 7.10-7.03 (m, 2H), 3.74 (s, 3H), 3.20 (app dt, J=13.9, 5.6 Hz, 1H), 3.11-2.99 (m, 2H), 2.93-2.82 (m, 1H), 2.79-2.71 (m, 1H), 2.39-2.30 (m, 1H), 2.05-1.92 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[C:23]([F:30])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].N1(C(=O)CC2C(F)=C[C:40]([OH:44])=CC=2F)CCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:44][CH3:40])=[O:29])=[C:23]([F:30])[CH:22]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cc1c(F)cc(O)cc1F)N1CCC1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CCO)c(F)c3)CC2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]ethanol (0.200 g, 0.726 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 1-(azetidin-1-yl)-2-(2,6-difluoro-4-hydroxyphenyl) ethanone (0.160 g, 0.871 mmol) in 5 ml anhydrous dichloromethane. Triphenylphosphine, polymer-bound (0.571 g, 1.90 mmol), and di-tert-butyl azodicarboxylate (0.334 g, 1.45 mmol) was added and the slurry stirred at RT for 3 hours. The mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 442.3 (M+H)+.