Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2]
Reactant: CSC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To a solution of 3-[2-(3-cyano-2-methyl-isothioureido)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole (0.7 g.) in ethanol (20 ml.) was added a 33% w/v solution of methylamine in ethanol (30 ml.) The solution was kept for 18 hours at 20°, evaporated in vacuo and the residue finally dried at 30°/0.05 mm. to give 3-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole as a white solid, m.p. 185°-188°.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:35]=4[CH3:36])[C:26]3=[O:37])[CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:38])=O)(C)(C)C.C(OC(=O)C)C>CCCCCC>[CH3:36][C:35]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[N:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[C:24]3[C:19]([CH2:18][CH2:17][C:16](=[O:38])[NH:15]3)=[CH:20][CH:21]=2)[C:26]1=[O:37]
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)N(C(=O)OC(C)(C)C)C(=O)CC3)C1=O
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)NC(=O)CC3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
Dioxane hydrochloride (3 mL) was added to 7-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.145 g, 0.00034 mol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (40% ethylacetate in hexane). Purification by preparative HPLC, followed by column chromatography on silica gel (5% MeOH in CHCl3) afforded 48 mg of the product (35.47% yield).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:9]([C:3]1[CH:2]=[CH:1][C:6]([Cl:7])=[CH:5][CH:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Clc1ccc(Cl)cc1
Reactant: CCCC[Mg]Cl
Solvent: CCOCC
Product: CCCCc1ccc(Cl)cc1
Yield: 23.6 %

Procedure:
To 2.00 g (13.61 mmoles) of p-dichlorobenzene, and 0.050 g of [NiCltriphos]PF6 in 20 mL of ether at -78° C. was added 7.0 mL (14 mmoles) of 2M nBuMgCl in ether. After refluxing overnight and workup with NH4Cl solution, the residue (602 mg of 1.698 g) was flash-chromatographed with 5% EtOAc/hexane on silica gel to give 542 mg (67%) of 1-butyl-4-chlorobenzene. 1H NMR (200 MHz, CDCl3): δ7.22 (m,2H), 7.05 (m,2H), 2.59 (t, J=5.5 Hz, 2H), 1.58 (m, 2H), 1.34 (m,2H) 0.95 (t, J=5.2 Hz, 3H). IR(neat): 2958s, 2930s, 2859s, 1492s, 1466m, 1407m, 1901s, 1016s cm-1.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4](/[C:6](=[CH:12]/N(C)C)/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25]>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4](/[C:6](=[CH:12]/[NH:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25])/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)c(F)cc1F
Reactant: CC(C)[C@H](N)CO
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C\N[C@H](CO)C(C)C)C(=O)c1cc(I)c(F)cc1F

Procedure:
A solution of 13 (14.6 g, 35.6 mmol) and (S)-2-amino-3-methylbutan-1-ol (14) (3.95 g, 36.7 mmol) in THF (35 mL) was stirred at rt for 30 minutes (min). The mixture was concentrated under reduced pressure to give crude 15 as a yellow oil which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=1[C:5]1([C:3]([OH:4])=[O:2])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C#N)cc2Cl)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.6 g, 2.0 mmol) is dissolved in THF/water 3:2 (20 mL) and to it is added LiOH (0.17 g, 4.0 mmol). The mixture is stirred at room temperature for 2 h before being neutralized to pH 6 with 1M HCl. The solution is evaporated to dryness to give acid, 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid as a solid. MS (ESI) m/z 288.2, 290.2 (M+H); 1H NMR (400 MHz, MeOD) (ammonium salt) δ ppm 2.64-2.74 (m, 1 H), 2.77-2.86 (m, 1 H), 2.94-3.02 (m, 1 H), 3.74 (ddd, J=13.1, 9.1, 8.0 Hz, 1 H), 6.74 (d, J=8.1 Hz, 1 H), 6.85 (s, 1 H), 7.59 (dd, J=8.1, 1.5 Hz, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.91 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 4.2 g of 2-bromo-1-(4-fluorophenyl)ethanone in 10 ml of DMF and 3.6 g of potassium phthalimide. The mixture is stirred at RT for 4 h and the precipitate formed is filtered off on a glass frit and washed with 3 times 50 ml of isopropyl ether. This, after drying under RP, gives 5 g of 2-[2-(4-fluorophenyl)-2-oxoethyl]isoindole-1,3-dione (white solid), which is used as it is in the following step. Melting point (Kofler): 140° C.; MS (E/I): m/z=283 (M+); 1H NMR: 5.25 (s, 2 H) 7.44 (t, J=9.0 Hz, 2 H) 7.85-8.00 (m, 4 H) 8.19 (dd, J=9.8, 5.4 Hz, 2 H).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C@@H:13]([OH:15])[CH3:14].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][C@@H:13]1[O:15][S:1](=[O:2])[N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)[CH2:12]1
Reactant: C[C@H](O)CNc1ccccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(c2ccccn2)S(=O)O1
Yield: 115.9 %

Procedure:
Thionyl chloride (8.8 ml, 14.35 g 0.12M) in dichloromethane (20 ml) was added dropwise to a cooled stirred solution of (S)-N-(2-pyridinyl)-1-amino-2-propanol (18.28 g, 0.12M) in dichloromethane (180 ml) and diisopropylethylamine (31 g, 0.24M) keeping the temperature below 5° C. After stirring at 0° for 1 h a solution of saturated sodium bicarbonate solution was added keeping the temperature below 5° C. The organic layer was separated, dried (Na2SO4) and concentrated to give 27.6 g of a yellow oil. The oil was chromatographed on silica using 40% ethyl acetate in hexane to give 20.28 g of a yellow oil containing a 4:3 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](OC1C=C(C(C)(CCCCC)C)C=CC=1Br)C1C=CC=CC=1.C1(=O)CCCC=C1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:30])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1
Reactant: CCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: O=C1C=CCCC1
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1

Procedure:
3-[2-Benzyloxy-4-(1,1-dimethylhexyl)phenyl]cyclohexanone as an oil (11.0 g., 35%) from 2-(3-benzyloxy-4-bromophenyl)-2-methylheptane (30.2 g., 0.0806 mole) and 2-cyclohexen-1-one (8.5 g., 0.0886 mole).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.O=C1CC(=O)N(C2C=CC(C(OCC)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3.[Cl:53][C:54]1[CH:64]=[CH:63][CH:62]=[CH:61][C:55]=1[CH:56]=[CH:57][C:58](Cl)=[O:59].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Cl:53][C:54]1[CH:64]=[CH:63][CH:62]=[CH:61][C:55]=1[CH:56]=[CH:57][C:58]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:59]
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCOC(=O)c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: O=C(C=Cc1ccccc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 50 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3) (40 mg, 0.126 mmol), and 2-chlorocinnamic acid chloride (0.151 mmol), the title compound (30 mg, yield 50%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-(4-Nitrophenyl)-1-Butanol (2.5 g, 12.166 mmol) was dissolved in DCM (50 ml). The solution was cooled in an ice-bath. Triethylamine (2.45 ml, 15.2 mmol) was added and then methanesulfonyl chloride (1.533 g, 13.382 mmol) was dropped in. After 1 hour, the ice-bath was removed. The mixture was stirred for 4 hours more. The reaction mixture was washed with water, sodium hydrogencarbonate aqueous solution (1%) and water (×3) and dried with magnesium sulfate. The solvent was evaporated in vacuum and the desired product (3.25 g) was obtained, yield 98%.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC4C=CC=CC=4)=[CH:18][CH:17]=3)[CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].CCCCCC.C(OCC)(=O)C>O1CCCC1.CO.[C].[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[N:14]=[CH:13][N:12]=2)=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Nc2cc(NC(=O)N3CCCC3)ncn2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Nc2cc(NC(=O)N3CCCC3)ncn2)cc1
Reaction time: 5 h
Yield: 71.1 %

Procedure:
Benzyl N-{4-[6-(pyrrolidin-1-ylcarbonyl)aminopyrimidin-4-ylamino]phenyl]carbamate (210 mg) was dissolved in tetrahydrofuran (5 ml)-methanol (5 ml), and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 5 hrs. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with tetrahydrofuran and ethanol in this order. The filtrate was concentrated under a reduced pressure to give a residue, to which hexane-ethyl acetate was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (103 mg, 71%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:31][OH:32])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:32][CH2:31][C:19]4[CH:20]=[CH:21][C:22]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)=[C:17]([F:16])[CH:18]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(3-fluorophenoxy)phenyl) methanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:25][CH:24]=[N:23][C:22]=3[N:21](C(OC(C)(C)C)=O)[CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:25][CH:24]=[N:23][C:22]=3[NH:21][CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOc1ncnc2c1c(-c1cn(Cc3ccccc3)nn1)cn2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOc1ncnc2[nH]cc(-c3cn(Cc4ccccc4)nn3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 195 mg (1.40 mmol) of potassium carbonate are added to a solution of 197 mg (0.56 mmol) of tert-butyl 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxy-ethoxy)pyrrolo[2,3-d]pyrimidine-7-carboxylate in 2.8 ml of methanol, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/ammonia water as eluent: 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine (“A1”) as colourless crystals; m.p. 240° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15].CC#N.O.FC(F)(F)C(O)=O>O1CCCC1>[F:12][C:9]([F:10])([F:11])[O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:14](=[O:15])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=c1[nH]c2cc(OC(F)(F)F)ccc2o1
Temperature: 70 °C
Yield: 98.1 %

Procedure:
2-amino-4-(trifluoromethyloxy)phenol (1.0 g, 5.2 mmol), was dissolved in 25 mL of anhydrous tetrahydrofuran under argon. The mixture was heated to reflux (70° C.) and then 1,1′-carbonyldiimidazole (1.1 g, 6.7 mmol) was slowly added in small portions over a one hour period. After the addition was complete, the reaction continued to reflux for another 2.5 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.3 min and m/e 220 [M+1]+. The mixture was allowed to cool to room temperature before all volatiles were removed by rotary evaporation. The crude residue was dissolved in 100 mL of ethyl ether and washed with water (3×30 mL) and brine (3×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-one (1.12 g, 5.1 mmol, 98%) as a brown amorphous solid. MS (ES) m/e 220 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=1[C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[C:37]3[C:36]([F:35])=[CH:44][CH:43]=[CH:42][C:41]=3[F:45])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3c(F)cccc3F)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 2,6-difluorobenzoyl chloride.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:4][CH2:3]1.NC1(C2C=C3C(=CC=2)NC=C3CCN(C)C)CCC=CC1>>[CH:5]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: CN(C)CCc1c[nH]c2ccc(C3CCC(N)CC3)cc12
Agent: CN(C)CCc1c[nH]c2ccc(C3(N)CC=CCC3)cc12
Product: CN(C)CCc1c[nH]c2ccc(C3CCCCC3)cc12

Procedure:
5-(1-Aza-1-methylcyclohex-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1H-indole: (74%) from 5-(1-aza-1-methylcyclohex-3-en-yl)-3-[2-(N,N-dimethylamino)ethyl]-1H-indole (Example 16); HRMS-FAB+ for C18H28N3 : calculated MH+ :286.22833; found MH+ :286.22703.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH2:6].[CH:7]1[N:12]=[C:11](Cl)[C:10]2[N:14]=[CH:15][N:16]([C@@H:17]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]3[OH:25])[C:9]=2[N:8]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:11]1[C:10]2[N:14]=[CH:15][N:16]([C:9]=2[N:8]=[CH:7][N:12]=1)[C@@H:17]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]1[OH:25]
Reactant: COCCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.3 %

Procedure:
The title compound was prepared by the procedure described in example 7 by reacting 2-methoxyethylamine hydrochloride (0.27 g, 3.6 mmol) with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-6-chloro-9H-purine)(1.0 g, 3.5 mmol) in dioxan (30 ml) at room temperature for 72 h with triethylamine (1.04 ml, 7.5 mmol) present. The reaction mixture was filtered and evaporated and the resultant residue was recrystallised from methanol (100 ml) to provide the title compound (0.80 g, 82%) as a solid, mp 151°-152° C., 1H NMR (DMSO-d6)δ 3.26 (3H, s, --CH3), 3.50-3.58 (3H, m, H-5'a and --CH2 --), 3.60-3.70 (3H, m, H-5'b, and --CH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, dd, H-3'), 4.60 (1H, dd, H-2') 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.42 (1H, t, 5'-OH) 5.87 (1H, d, H-1'), 7.80 (1H, br s, --NH) 8.22, 8.35 (2H, 2s, H-2 and H-8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][OH:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(NC(=O)[C@H](CO)NS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)c1cccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 65 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.38 g) was reacted with mesyl chloride to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (915 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH2:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH3:12].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=1
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: NCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)NCc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 2,4-difluorobenzylamine (3.58 g, 25.0 mmol) in methylene chloride (250 mL) were added 4-ethylbenzoic acid (3.94 g, 26.3 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over Na2SO4. Concentration in vacuo afforded 6.49 g (94%) of white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6 M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[C:7]([Si](C)(C)C)=[CH:6][O:5][CH:4]=1.[I:14]I>C1COCC1.CCOCC.FC(F)(F)C([O-])=O.[Ag+].[Ag]>[I:14][C:7]1[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[CH:4][O:5][CH:6]=1
Reactant: C[Si](C)(C)c1cocc1[Si](C)(C)C
Reactant: II
Agent: [Ag+]
Agent: [Ag]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)c1cocc1I
Temperature: -78 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir-bar was placed the 3,4-bis(trimethylsilyl)furan (2.00 g, 9.41 mmol) as a solution in THF (138 mL). Silver trifluoroacetate (4.16 g, 18.8 mmol) was added and the mixture was stirred for 5 min at room temperature until the silver salt dissolved. The resulting colorless solution was cooled to −78° C. and I2 was then added as a solution in THF (50 mL) over 10 min. The mixture was stirred at −78° C. for 3 h after which time it was warmed to room temperature diluted with Et2O (200 mL) and then filtered through a cake of celite. The resulting brown solution was then washed with 50% aqueous Na2S2O3 (2×80 mL) followed by saturated aqueous NaHCO3 (50 mL), and then brine (50 mL). The organic layer was then dried over Na2SO4. Evaporation of the solvent in vacuo gave a yellow oil that was eluted through a plug of silica gel (hexanes, ca. 400 mL eluent) to give a colorless solution. Evaporation of the solvent gave (4-iodofuran-3-yl)trimethylsilane as a pale pink oil (2.20 g, 87%). 1H NMR: δ 7.49 (d, 1H, J=1.5 Hz), 7.22 (d, 1H, J=1.5 Hz), 0.30 (s, 9H). Ref.: Song, Z. Z., Wong, H. N. C. Liebigs Ann. Chem. 1994, 29-34.