Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([O:27]CC)=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37].[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O[Pd]OC(=O)C)(=O)C>[CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:3]=2)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:6]=1[C:25]([OH:27])=[O:26])([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(Cl)ccc2n1CCCOc1cccc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(-c3ccccc3)cc12
Temperature: 180 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 5-chloro-3-(2-isopropylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (the synthesis of this compound was similar to the intermediate described in EXAMPLE 134) (56 mg), phenylboronic acid (26 mg), diacetoxypalladium (2.39 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (8.74 mg) and K3PO4 (67.8 mg) was heated at 180° C. in a CEM microwave synthesizer for 1 hour. The reaction was concentrated and the residue was purified by flash chromatography, eluting with 0-50% dichloromethane in hexane. The collected desired ester was saponified with NaOH in tetrahydrofuran-methanol-H2O at 50° C. overnight to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.76 (s, 1H), 8.17 (d, J=8.29 Hz, 1H), 7.86 (d, J=7.67 Hz, 1H), 7.78 (d, J=8.90 Hz, 1H), 7.43-7.58 (m, 6H), 7.32-7.44 (m, 5H), 7.28 (t, J=7.21 Hz, 1H), 7.22 (d, J=1.84 Hz, 1H), 7.16-7.21 (m, 1H), 7.06-7.12 (m, 1H), 6.87 (d, J=7.36 Hz, 1H), 4.95 (t, J=7.06 Hz, 2H), 4.21 (t, J=6.14 Hz, 2H), 2.68-2.82 (m, J=7.06 Hz, 1H), 2.37-2.47 (m, 2H), 1.03 (d, J=6.75 Hz, 3H), 0.96 (d, J=6.75 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:7](O)[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]>O.CO>[C:1]([C:3]1[NH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)n1O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#N)[nH]1
Temperature: 70 °C

Procedure:
A 20% solution of TiCl3 (25 ml, 32 mmol) in water was added to a solution of methyl 5-cyano-1-hydroxy-1H-pyrrole-2-carboxylate (Intermediate 128, 2.55 g, 15 mmol) in MeOH. The reaction was heated to an external temperature of 70° C. for 3 hours. The reaction mixture was concentrated to remove MeOH and the residue was partitioned with EtOAc and water. The organic portion was dried with MgSO4 and concentrated to an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12](=[N:14][O:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=O)[NH2:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[N:13]=[C:16]([CH:18]2[CH2:19][CH2:20]2)[O:15][N:14]=1
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NOC(=O)C1CC1
Solvent: c1ccncc1
Product: O=C1N(Cc2noc(C3CC3)n2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Yield: 158.1 %

Procedure:
A stirred solution of 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamide (0.24 g, 0.52 mmol) in pyridine (1 mL) was heated at 170° C. for 30 min in a microwave reactor. The solution was concentrated in vacuo to dryness, purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.36 g, 16%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ7.19 (dd, J=8.1, 8.1 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.28 (s, 1H), 5.86 (d, J=1.2 Hz, 1H), 5.04 (ABq, 2H), 4.94 (ABq, 2H), 2.20-2.10 (m, 1H). 1.26-1.12 (m, 4H); 13C NMR (75 MHz, CDCl3) δ182.9, 177.0, 165.4, 156.8, 149.2, 143.0, 142.1, 131.6, 130.0, 128.4, 124.6, 116.5, 107.4, 103.0, 101.5, 93.2, 58.7, 36.1, 10.57, 10.53, 7.8; MS (ES+) m/z 438.1 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:20]4([CH2:24][O:23][C:22]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:21]4)[C:17]4([CH2:19][CH2:18]4)[CH2:16][O:15][C:12]3=[CH:13][CH:14]=2)O1.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42]([C:9]3[CH:10]=[C:11]4[C:20]5([CH2:24][O:23][C:22]([NH2:25])=[N:21]5)[C:17]5([CH2:18][CH2:19]5)[CH2:16][O:15][C:12]4=[CH:13][CH:14]=3)[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21CC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cnc4[nH]ccc4c3)ccc1OCC21CC1
Temperature: 100 °C
Reaction time: 7 h
Yield: 48.5 %

Procedure:
The mixture of di-tert-butyl [6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]imidodicarbonate (140 mg, 0.25 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (87 mg, 0.44 mmol), Pd(PPh3)4 (58 mg, 0.050 mmol), and Na2CO3 (80 mg, 0.76 mmol) in 1,4-dioxane-H2O (2.8 ml, 4:1) was stirred for 7 hours at 100° C. After dilution with EtOAc and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=100:0-85:15) to give white solid. The solid was washed by diisopropyl ether to give 6′-(1H-pyrrolo[2,3-b]pyridin-5-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (42 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14].C(O)C.[OH-].[Na+]>O>[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13]1[CH:14]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: COC(OC)C(C)=O
Reactant: Nc1ncccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(OC)c1ccc2cccnc2n1
Temperature: 7.5 °C

Procedure:
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 l 4-necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 l), and water (2 l). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15° C. The solution was stirred for 3 h at 0-20° C. and then concentrated under vacuum. The resulting solution was extracted with 3×1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3×300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 (s, 1H), 3.41 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C:11]=2[O:10][N:9]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:27]([O:29][CH3:30])=[O:28].O>O1CCCC1.C(OCC)(=O)C>[C:27]([CH:14]1[C:13](=[O:17])[C:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][O:10][C:11]=2[CH2:16][CH2:15]1)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)Cl
Reactant: O=C1CCCc2onc(-c3ccccc3F)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCc2onc(-c3ccccc3F)c2C1=O
Temperature: -78 °C

Procedure:
In a 600 ml anhydrous tetrahydrofuran was dissolved 6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (20.0 g) under nitrogen. The solution was cooled to -78° C. and 87 ml lithium diisopropylamide was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 8.7 ml methyl chloroformate was added. Upon warming to room temperature, the reaction mixture was poured into water and ethyl acetate. The layers were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Column chromatography on silica gel (starting with 10% dichloromethane in hexane and gradually increasing the polarity to 100% DCM) gave 13.5 g of crude product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:26])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[Si:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][C:44]#[CH:45])=[CH:40][CH:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Si](OCCCCCCCC#CC1C2C(=CC(OC)=CC=2)SCC1(C1C=CC(OC)=CC=1)C)(C(C)(C)C)(C)C>>[Si:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]#[C:45][C:9]2([OH:26])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=3)[O:12][CH2:11][C:10]2([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=2)[CH3:15])=[CH:46][CH:47]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C#CCOc1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Agent: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1

Procedure:
The title compound was prepared from 7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman-4-one and 3-[4-(3-t-butyldimethylsilyloxypropyl)phenoxy]-1-propyn according to the same method for the synthesis of 4-[9-(t-butyldimethylsilyloxy)1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:154][CH2:155][O:156][Si](C(C)(C)C)(C)C)[S:12]([C:15]1[CH:20]=[C:19]([S:21](=[O:44])(=[O:43])[N:22]([CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][C:16]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][O:120][Si](C(C)(C)C)(C)C)[CH2:108][CH2:109][O:110][Si](C(C)(C)C)(C)C)=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][O:144][Si](C(C)(C)C)(C)C)[CH2:132][CH2:133][O:134][Si](C(C)(C)C)(C)C)[C:46]1[CH:51]=[CH:50][C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][O:66][Si](C(C)(C)C)(C)C)[CH2:54][CH2:55][O:56][Si](C(C)(C)C)(C)C)=[CH:48][C:47]=1[S:76](=[O:99])(=[O:98])[N:77]([CH2:88][CH2:89][O:90][Si](C(C)(C)C)(C)C)[CH2:78][CH2:79][O:80][Si](C(C)(C)C)(C)C)(=[O:14])=[O:13])(C(C)(C)C)(C)C.C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:80][CH2:79][CH2:78][N:77]([CH2:88][CH2:89][OH:90])[S:76]([C:47]1[CH:48]=[C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][OH:66])[CH2:54][CH2:55][OH:56])[CH:50]=[CH:51][C:46]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][OH:120])[CH2:108][CH2:109][OH:110])=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][OH:144])[CH2:132][CH2:133][OH:134])[C:16]1[CH:17]=[CH:18][C:19]([S:21](=[O:43])(=[O:44])[N:22]([CH2:33][CH2:34][OH:35])[CH2:23][CH2:24][OH:25])=[CH:20][C:15]=1[S:12](=[O:13])(=[O:14])[N:11]([CH2:10][CH2:9][OH:8])[CH2:154][CH2:155][OH:156])(=[O:98])=[O:99]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=S(=O)(c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c(S(=O)(=O)N(CCO)CCO)c1)N(CCO)CCO
Temperature: 50 °C
Yield: 79.5 %

Procedure:
13.59 g of the tris(2,4-bis(N,N-bis(2-t-butyldimethylsilyloxyethyl)sulfamoyl)phenyl)bismuthine preparation prepared in Example 5 was dissolved in a mixed solvent containing 13.6 ml of ethanol and 27 ml of dichloromethane, and 0.272 g of p-toluenesulfonic acid monohydrate was added thereto. The mixture was refluxed under heating at 50° C. for 6 hours, and then cooled to room temperature. The crystals were collected by filtration, washed with 29.5 ml of dichloromethane and dried. As a result, 5.54 g of the title compound was obtained as crystals with a melting point of 110°-113° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1([C:12]([OH:14])=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH:7]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
K2CO3 (35.0 g, 255 mmol) was added to a solution of cyclopent-3-enecarboxylic acid (20.0 g, 178 mmol) in acetonitrile (500 mL) followed by addition of benzyl bromide (36.6 g, 214 mmol). The reaction mixture was stirred for 12 h at ambient temperature. The mixture was filtered and washed with acetonitrile (200 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=10:1) to afford benzyl cyclopent-3-enecarboxylate (26.5 g, 74% yield) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CCOCC>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COCCOCCl
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-iodophenol (10 g, 45.45 mmol) in 200 ml of anhydrous tetrahydrofuran was treated at 0° C. with sodium hydride (2.36 g, 60% dispersion, 59.09 mmol) for 5 minutes. To the resulting mixture, methoxyethoxymethyl chloride (8.3 ml, 72.73 mmol) was slowly added over a 5-minute period. The mixture was stirred at 0° C. under nitrogen for 30 minutes, warmed to room temperature, and stirred for 24 hours. The solvent was removed under reduced pressure. The residue was taken into 500 ml of ether, washed with 5% sodium hydroxide (4×200 ml), water (4×200 ml), saturated sodium chloride (1×200 ml), and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an oily product in 14.1 g. TLC (silica gel, ether): Rf 0.5.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH3:25][C:26]([NH2:33])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:27]>>[CH3:25][C:26]([NH:33][C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:27]
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(N)c1cccs1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(C)c4cccs4)[C@@]3(C)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound was prepared in a yield of 50% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-methyl-1-(2-thienyl)ethylamine.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:66]=[CH:65][C:46]3[N:47]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:48]([C:50]4[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:61]([N:47]1[C:46]2[CH:65]=[CH:66][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)(C)n1c(-c2cc(F)ccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(F)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of acetic acid (52 mg, 0.86 mmol) and HATU (326 mg, 0.86 mmol) in DMF (4 mL) is added triethylamine (0.12 mL, 0.86 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-N-hydroxy-benzamidine (300 mg, 0.72 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (30 mL) is added and the organics washed sequentially with saturated NaHCO3 solution (30 mL) and H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via flash chromatography (10 g silica gel, 1.5-3% MeOH/CH2Cl2) affords the title compound (43 mg, 10%). LCMS (ESMS): m/z 444.32 (M++1)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]([O:17][Si](C(C)(C)C)(C)C)[C:10]=2[F:25])[OH:8])[NH:5][CH:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:7]([OH:8])[C:9]2[C:10]([F:25])=[C:11]([OH:17])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=2)[NH:5][CH:6]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 206.1 (500 mg, 0.744 mmol) in 7 mL THF at 0° C., was added TBAF (1M in THF, 0.744 mL, 0.744 mmol). The mixture was stirred at 0° C. for 30 min, then concentrated. The mixture was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was triturated with 10% EtOAc/hexanes (10 mL) to afford after filtration 399 mg of Intermediate 191.2 as a white powder. LCMS (2 min gradient) RT=2.18 min, 579.13 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=NO)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-:36].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[O:36])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 65 °C
Yield: 76.2 %

Procedure:
A mixture of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde oxime (14.20 g, 31.34 mmol), triethyl silane (10.3 mL, 7.53 g, 62.8 mmol), sodium carbonate (5.43 g, 39.3 mmol), palladium bis(diphenylphosphine)-ferrocene dichloride CH2Cl2-complex (1.28 g, 1.57 mmol) and DMF (250 mL) were stirred under an atmosphere of carbon monoxide at 65° C. over night. After cooling to room temperature, the solvent was evaporated and the residue taken up in MTBE, filtered and the filtrate was concentrated in vacuum. Purification of the residue on silica gel afforded the title compound (9.60 g, 76%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:18])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)Nc1ccccc1C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)C(Cl)=Nc1ccccc1C(F)(F)F
Yield: 99.3 %

Procedure:
A solution of 11.56 g of the product of Step A in 200 ml of toluene was added over 15 minutes to a suspension of 11.45 g of phosphorus pentachloride in 25 ml of toluene and after gas evolution ceased, the mixture was refluxed for 11/2 hours and was evaporated to dryness to obtain 12.4 g of N-(2-trifluoromethylphenyl)-2-methyl-propanimidoyl chloride as a yellow oil which was used as is for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-Nitro-1-octyl-1H-pyrazole (134 mg, 0.60 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-octyl-1H-pyrazol-3-ylamine (48 mg, 41%) as a golden oil: ESI-LRMS m/e calcd for C11H21N3 [M+] 195.18, found 196.2 [M+H+].
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[OH:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[O:8]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2-:1][C:2]([CH3:4])=[O:3].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[O:8]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Reactant: Oc1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [CH2-]C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O[C@@H]1[C@H](O)[C@H](n2cnc3c(NC4CCOC4)ncnc32)O[C@@H]1COc1ccccc1F
Temperature: 25 °C

Procedure:
To a solution of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide (500 mg, 1.33 mmol), 2-fluorophenol (179.4 mg, 1.6 mmol), and triphenylphospine (418.3 mg, 1.6 mmol) in anhydrous tetrahydrofuran (20 mL), DIAD (diisopropylazodicarboxylate, 320 μL, 1.6 mmol) was added and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was purified by column chromatography (eluting with ethyl acetate:hexane 50:50) to give (4S,2R,3R,5R)-2-(2-fluorophenoxy)methyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide as a pure white solid.