Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[CH2:6][CH2:5]2.[Br:17][CH2:18][CH2:19][CH2:20]Br>[H-].[Na+].C(OCC)(=O)C>[Br:17][CH:18]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]21[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:19][CH3:20]
Reactant: O=C1NC(=O)C2(CCc3cc(F)ccc32)N1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(Br)C1Cc2cc(F)ccc2C12NC(=O)NC2=O
Temperature: 50 °C

Procedure:
(+/−)-5′-fluoro-spiro[imidazolidine-4,1′indan]-2,5-dione (331 mg.,1.5 mmol) was dissolved in dry dimethylformaride (4 mL) and 60% sodium hydride in mineral oil (72 mg., 1.8 mmol) was added. The mixture was warmed at 50° C for 20 minutes and then 1,3-dibromo-propane (1.1 mL, 10.9 mmol) was added. The reaction mixture was warmed at 50° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate and the organic solution was washed with aqueous Na2CO3 and water (3×). The dried extract was evaporated and chromatographed on silica gel using a 10-30% ethyl acetate/hexane gradient. The appropriate fractions were combined and evaporated to give the racemic product as a glassy solid which was used as is.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2](/[CH:1]=[CH:18]/[C:17]3[CH:20]=[CH:21][C:14]([N:13]([CH3:22])[CH3:12])=[CH:15][CH:16]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1nc2cc(Cl)ccc2s1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc(/C=C/c2nc3cc(Cl)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The procedure of Cuadro, et al., Il Farmaco., 47:477-488 (1992), was followed. A suspension of 2-methyl-5-chloro-benzothiazole (3.78 g, 20.6 mmol), 4-(dimethylamino)benzaldehyde (3.04 g, 20.4 mmol), and 0.5 g of benzyltriethylammonium chloride in 30 mL of 50% aqueous sodium hydroxide solution was mechanically stirred in an ultrasonic bath at room temperature for 12 hours. Water (20 mL) was added, the mixture was cooled, filtered, and the solid was washed with water to give the title compound as a yellow solid, mp 182-184° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: C[N+](=O)[O-]
Product: Cc1ccc(C=C[N+](=O)[O-])o1
Yield: 88 %

Procedure:
In close analogy to the procedure described above, 5-Methyl-furan-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: COC(=O)C1Cc2cc(Cl)ccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloroindoline-2(R/S)-carboxylic acid methyl ester (1.2 g, 5.69 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (1.27 g, 6.25 mmol) dissolved in dried dichloromethane (10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.98 ml, 6.30 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 20:1 dichloromethane: diethyl ether as eluent. A white foam was obtained which was the mixture of two diastereomers. The two diastereomers were separated by column chromatography on silica gel using 7:3 petroleum spirit:diethyl ether as eluent, and the pure (S,S) form was obtained as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C@H:4]([CH2:44][CH2:45][S:46][CH3:47])[NH:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:36])[C@H:14]([CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:9][C:8]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OCC)C>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:48])[C@H:4]([CH2:44][CH2:45][S:46][CH3:47])[NH:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:36])[C@H:14]([CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)[NH2:15])=[CH:9][C:8]=1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@H](Cc2c[nH]cn2)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1
Reaction time: 6 h

Procedure:
[4-(bis-tert-butoxycarbonyl-L-histidyl)-2-phenylbenzoyl methionine methyl ester (0.992 g, 1.42 mmol), prepared as in Example 184A, was dissolved in 4 M HCl/dioxane (15 mL), upon which gas evolution was observed. The clear amber solution was stirred for 6 hours, during which time a white precipitate formed. The mixture was treated with ethyl ether and the precipitate was isolated by filtration to provide 0.779 g (100%) of [4-(L-histidyl)-2-phenylbenzoyl methionine methyl ester (believed to be the mono-hydrochloride salt); 1H NMR (CD3OD) δ 1.72-1.87 (m, 1H), 1.95-2.03 (comp, 4H), 2.08-2.28 (comp, 2H), 3.38-3.60 (comp, 2H), 3.67 (s, 3H), 4.45-4.57 (comp, 2H), 7.30-7.46 (comp, 6H), 7.53 (d, 1H), 7.69 (d, 1H), 7.77 (app s, 1H), 8.90 (s, 1H). LRMS (CI): 496 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2c1CCCC2
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nnc(CF)n1-c1ccc(C)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Triethylamine (0.087 mL, 0.623 mmol) and ethyl 2-bromoacetate (63 μL, 0.571 mmol) were added to a solution of 5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.144 g, 0.519 mmol) in dichloromethane (2.1 mL) and stirred at room temperature for 2 hours. The crude reaction mixture was purified by SGC (0-100% EtOAc/Hexanes) to afford ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.168 g, 89%).
Reaction SMILES: Cl.[C:2](#[N:4])[CH3:3].CO.C(N(CC)CC)C.C1C=[C:18]2[C:20]([C:22](O)([OH:25])[C:23](=[O:24])C2=CC=1)=[O:21]>C1COCC1>[NH2:4][CH2:2][CH2:3][CH2:18][CH:20]([CH:22]([CH2:23][OH:24])[OH:25])[OH:21]
Reactant: CC#N
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: NCCCC(O)C(O)CO

Procedure:
3-Aminopropyl solketal (2.43 g, 12.8 mmole) was dissolved in THF (30 ml) and aqueous hydrochloric acid (1M, 30 ml) was added. After 1 hour at room temperature TLC (acetonitrile/methanol/triethlyamine 80/18/2) indicated that all starting material Rf 0.33 had been hydrolyzed to the diol Rf ca.0.0 (detection by ninhydrin spray). THF was evaporated in vacuo and the aqueous residue was applied to a Dowex 50 ion exchange column (100 ml, H form). The resin was washed with water to remove all Cl ion and the desired amine was eluted with aqueous ammonia. The ammonia soution was evaporated to remove all volatile material and the aqueous residue used for subsequent reactions without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CCCCCCCCCCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCCCCCCC
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a mixture of 307 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 828 mg (5.53 mmol) of 2-cyclopropyl-6-methylphenol were added undecane (2.76 g) and 322 mg (5.46 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 340 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 68%) and 1.8 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(Cl)=[S:32].CO>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:31]=[S:32])[C:14]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 6-amino-2-tert-butyl-5[4-carbethoxypiperazin-1-yl]benzothiazole and 2 g of sodium bicarbonate in 200 ml of chloroform is cooled in an ice bath and 4 ml of thiophosgene in 10 ml of chloroform is added and the mixture is stirred at ambient temperature for 2 hours. The solid is filtered off and the filtrate is evaporated to give an oil which is applied on a silica gel column with 1% methanol in chloroform to yield 2-tert-butyl-5-[4-carbethoxypiperazin-1-yl]-6-isothiocyanato-benzothiazole, melting at 131°-134°.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:23]\[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=2)/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(/C=C2\NC(=O)CN(C(C)=O)C2=O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (10.0 g, 50 mmol), prepared by the published procedure mentioned in Example 3, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120° C. After 21/2 h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:22][C:23]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=1[CH2:25][CH2:26][C@H:27]1[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[N:29](C(OC(C)(C)C)=O)[CH2:28]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:22][C:23]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=2[CH2:25][CH2:26][C@H:27]2[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[NH:29][CH2:28]2)=[O:7])[NH2:1])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)C1CCOCC1
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)C1CCOCC1

Procedure:
The title compound was prepared from (2S,3R)-2-azido-3-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (Example 1033, step 1) and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=629 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Br[CH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][N:19]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]2[N:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[CH:22][N:23]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2cnc(CBr)nc2)cc1
Product: CCOC(=O)CCc1ccc(OCc2ncc(-c3ccc(C(F)(F)F)cc3)cn2)cc1C

Procedure:
A] In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with 2-bromomethyl-5-(4-trifluoromethyl-phenyl)-pyrimidine (example 63C]) to give 3-{2-methyl-4-[5-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH:18]1[O:20][CH2:19]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:19][CH:18]([OH:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1C1CO1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCC(O)c2ccccc2OC)cc1OC
Reaction time: 8 h

Procedure:
A mixture of 33,5 g. (0.185 mol) of 3,4-dimethoxyphenylethylamine and 28 g. of o-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. A sample is chromatographed to obtain a pure sample of the product. This pure seed and 200 ml. of 2:1 ethyl acetatepetroleum ether are added to the reaction mixture. Chilling and stirring yields the product N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-methoxyphenyl)ethylamine. m.p. 88° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[F:20][C:21](I)([F:23])[F:22].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:20][C:21]([F:23])([F:22])[C:11]1[N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: FC(F)(F)I
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1ncnc2c1nc(C(F)(F)F)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 6.7 %

Procedure:
0.27 g (1.0 mmol) of adenosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyladenosine (19F-NMR yield: 6.7%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyladenosine was obtained as a white solid (0.01 g, yield: 3.1%) by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[O:33][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:33][CH:34]=2)[N:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
An amount of 150 mg (0.39 mmol) of the compound from example 3A and 98 mg (0.43 mmol) of the compound from example 5A were suspended together with 99 mg (1.18 mmol) of sodium hydrogencarbonate in 2 ml of dry DMF. The reaction mixture was stirred at RT for 20 hours. The batch was thereafter purified directly by means of preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; eluent gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C@H:27]3[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]3)=[O:31])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(O)[C@H]1CC[C@@H](O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A DMA (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), (1S,3R)-3-hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFID Therapeutics Inc.] and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (56 mg, 0.17 mmol) was first cooled in an ice-water bath, then DIEA (0.083 mL, 0.48 mmol) was added to reaction drop-wise. Ice bath was then removed and the reaction was stirred at ambient temperature for 1 hour to reach completion. The reaction mixture was diluted with water (10 mL) and vacuum-filtered, yielding the crude product as a beige solid. The crude was purified by reverse phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a solid (20 mg, 30% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.NCCCCN(C)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:16][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH3:10])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(CCCCN)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. tert-Butyl 4-aminobutyl(methyl)carbamate (0.177 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The product was recrystallised from EtOAc to yield colourless solid. The solid was dissolved in DCM (2.0 mL), treated with trifluoroacetic acid (0.50 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. Evaporation of appropriate fractions gave the product as a colourless solid (0.042 g, 49%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:17][C:16]=3[N:15]=[C:14]([NH2:29])[C:13]=2[N:12]=[C:11]1[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[NH2:29][C:14]1[C:13]2[N:12]=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]([CH2:9][CH2:8][NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:22]=2[C:21]2[CH:20]=[CH:19][C:18]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][C:16]=2[N:15]=1
Reactant: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)NC(C)C
Yield: 47.8 %

Procedure:
Isopropyl isocyanate (0.29 mL, 3.1 mmol) was added slowly to a suspension of 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1.13 g, 3.1 mmol) in chloroform (113 mL). A precipitate formed within 15 minutes, was isolated by filtration, and was dried overnight in an oven to provide 0.66 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea as a white solid, mp 240-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 99 %

Procedure:
A suspension of 16.0 g (64.1 mmole) of 4-(4'-chlorophenoxy) nitrobenzene and 75% Pt, 161 mg of platinum oxide (641 μmole, 1 mole %) in 200 ml of ethanol was stirred vigorously under hydrogen until hydrogen uptake ceased (about 4 hours). The suspension was filtered through celite and the solution was evaporated to dryness to obtain 13.94 g (99.3%) of the desired product as a pale brown solid.