Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][C:25]#[CH:26])[C:17](=[O:27])[NH:16][C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C#CC2N(C)C3C(=O)N(CC#C)C(=O)N(C)C=3N=2)C=CC=1OC.C(=O)([O-])[O-].[K+].[K+].[C:62]([O:68][CH2:69]Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C>[C:62]([O:68][CH2:69][N:16]1[C:15]2[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:21]([CH3:22])[C:20]=2[C:19](=[O:23])[N:18]([CH2:24][C:25]#[CH:26])[C:17]1=[O:27])(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]
Reactant: C#CCn1c(=O)[nH]c2nc(C#Cc3ccc(OC)c(OC)c3)n(C)c2c1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The crude 8-[(3,4-dimethoxyphenyl)ethynyl]-7-methyl-1-prop-2-ynyl-3,7-dihydro-1H-purine-2,6-dione (ca. 452 mg, 1.24 mmol), contaminated with the starting material and with the dimethylated derivative (8-[(3,4-dimethoxyphenyl)ethynyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-1H-purine-2,6-dione), was suspended in dry DMF (7 mL). Subsequently dry potassium carbonate (514 mg, 3.72 mmol) and chloromethyl pivalate (654 mg, 4.34 mmol) was added. The mixture was stirred at room temperature for 3 h (TLC-control: dichloromethane/methanol, 9.5:0.5, Rf=0.60 for the main product) and the product was precipitated by adding water (30 mL), filtered under reduced pressure and dried at 70° C. The crude product was dissolved in a minimum of ethyl acetate (by slightly heating) and purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1:1) affording 471 mg (79% yield over two steps) of {8-[(3,4-dimethoxyphenyl)ethynyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydro-3H-purin-3-yl}methyl pivalate as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (300 mg, 0.51 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-ethyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-propionic acid ethyl ester.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][O:3]1>CO.C(O)(=O)C.O>[CH3:15][C:13]1([CH3:16])[O:12][C@@H:10]2[C@@H:9]([C@@H:8]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:7]([C@H:5]([OH:6])[CH2:4][OH:3])[O:11]2)[O:14]1
Reactant: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC1(C)O[C@H]2O[C@H]([C@H](O)CO)[C@H](OCc3ccccc3)[C@H]2O1
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Crude 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (6) (23.5 g, 75.6 mmol) was dissolved in a 1:1:1 mixture of methanol, acetic acid and water (200 ml) and stood at 50° C. for 16 hours. The solvents were evaporated and the crude syrup purified by flash chromatography (ethyl acetate-hexane 3:2) to give 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose (18.1 g, 87%) as a clear oil, [α]20D -49.9° (c, 1.08 in chloroform) [lit.44 -50.8° (c, 1.24 in chloroform)]; 1H NMR δ 1.33, 1.49 (6H, 2×s, acetonide); 2.17 (2H, bs, 2×OH); 3.69, 3.81 (2H, 2×dd, H-6,6', J6,6' 11.4 Hz, J5,6 5.5 Hz, J5,6' 3.4 Hz); 4.00-4.15 (3H, m, H-3, H-4, H-5); 4.56, 4.73 (2H, 2×d, CH2Ph, JH,H' 11.7 Hz); 4.63 (1H, d, H-2); 5.94 (1H, d, 1-H,J1,2 3.7 Hz); 7.31-7.38 (5H, m, H-Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:14]([Cl:18])(=O)(=[O:16])[OH:15].O=S(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([C:9](=[O:11])[CH3:10])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:14]([Cl:18])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)C(C)(C)c1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 3-(3-chlorophenyl)-3-methylbutan-2-one (15 g, 76 mmol) in CHCl3 (100 mL) was added chlorosulfuric acid (101 mL, 20 eq) at 0° C. over 2 h. Next SOCl2 (20 mL) was added dropwise to the reaction mixture over 30 min under nitrogen. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was slowly added to ice-water and then extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography (silica, Hex/EtOAc=9:1 to 4:1) to give 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzene-1-sulfonyl chloride as a yellow solid (9.8 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 2.03 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:20][C:21]4[NH:22][CH:23]=[CH:24][N:25]=4)[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]3)=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1.[H-].[Na+].[CH3:31]I>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:20][C:21]4[NH:25][CH:24]=[CH:23][N:22]=4)[O:17][CH:16]([CH2:18][O:19][CH3:31])[CH2:15][O:14]3)=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: CI
Reactant: Cc1cc(Cl)ccc1Oc1ccc(C2(Cc3ncc[nH]3)OCC(CO)O2)cc1
Agent: [H-]
Agent: [Na+]
Product: COCC1COC(Cc2ncc[nH]2)(c2ccc(Oc3ccc(Cl)cc3C)cc2)O1
Temperature: 25 °C

Procedure:
16 parts of 2-[p-(4-chloro-2-methylphenoxy)phenyl]-2-(1-imidazolylmethyl)-4-hydroxymethyl-1,3-dioxolane are dissolved in 150 ml of N,,N-dimethyl formamide and then 1.9 parts of 55% sodium hydride dispersion are stirred in while introducing nitrogen. The mixture is heated for 2 hours to 80° C., then cooled to room temperature, treated dropwise, with stirring, with 6.3 parts of methyl iodide over 1 hour, then heated for 2 hours to 60° C., diluted with 800 ml of ice-water and extracted with three 300 ml portions of ethyl acetate. The combined extracts are washed with two 50 ml portions of water, dried over sodium sulfate, filtered, and the solvent is removed by evaporation. The residue is purified by column chromatography over silica gel with acetone/ethyl acetate (1:1). The eluant is then removed by evaporation and the mixture of diastereoisomers is crystallised by treatment with tiexane, giving beige-coloured crystals with a melting point of 92°-106° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:6]=[N:5][CH:4]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(Cl)Cl.CO>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:6]=[N:5][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COc1ccccc1CCn1cncc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1CCn1cncc1CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
248 mg(1.09 mmol) of 5-hydroxymethyl-1-(2-methoxyphenethyl)-1H-imidazole prepared according to the same procedure as Preparation 9-1) was dissolved in 3 ml of dimethylformamide and 170 mg(1.13 mmol) of t-butyldimethylsilylchloride was added thereto. After stirring for 1 hour, the solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: methylene dichloride/methanol=95/5, v/v) to give 248 mg(0.72 mmol, Yield 66%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([CH3:18])[CH3:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.[CH:34](O)(CC)C>>[Br:1][C:2]1[C:3]([CH:34]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([CH3:18])[CH3:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CC1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4(C)C)c23)C1
Yield: 46.5 %

Procedure:
N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide (500 mg, 1.53 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (921 mg, 4.60 mmol) in s-BuOH (10 mL) were stirred at 130° C. for 18 hours. The reaction was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 90/10->0/100, 30 CV) to yield tert-butyl (1R)-3-(5-bromo-3-(2,2-dimethylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohexylcarbamate (360 mg, 46.5% yield) as a solid.
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O-:17])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=O.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].Cl.CN(C)[CH2:27][CH2:28]CN=C=NCC>ClCCl>[CH3:18][N:19]([CH2:20][CH2:21][NH:22][C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:27][CH3:28])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3])[CH3:23]
Reactant: O=C([O-])C1=Cc2cccc(C(=O)O)c2OCC1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)CCN
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cccc(C(=O)NCCN(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (0.39 g), N,N-dimethylethylenediamine (0.163 ml), and 1-hydroxybenzotriaole hydrate (0.22 g) in dichloromethane (8 ml) was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.31 g). The reaction mixture was stirred for 4.5 hours at ambient temperature and evaporated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a solid of ethyl 2,3-dihydro-9-[2-(N,N-dimethylamino)-ethylaminocarbonyl]-1-benzoxepin-4-carboxylate (0.39 g),
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[N:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][O:25][CH3:26].Cl>>[CH3:26][O:25][N:24]=[CH:1][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[CH:18][CH:19]=[CH:20][N:21]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Yield: 83.3 %

Procedure:
was synthesized as described in Example 22 but using (68) (210 mg, 0.70 mmol) instead of (55) and NH2OMe.HCl (300 mg, 3.6 mmol) instead of NH2OH.HCl. The reaction gave (69) (192 mg, 83%). Mp. 158-159° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[I:14]I.N.CO.C(Cl)Cl>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([I:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2cc(N)ccc21
Reactant: II
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(I)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) and Hg(OAc)2 (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution of I2 in ACOH until it produces a precipitation; The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.3 mmol, 35%) of the product.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[C:20]([Cl:21])=[N:19][CH:18]=[CH:17][N:16]=2)[C@@H:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>>[ClH:21].[Cl:21][C:20]1[C:15]([N:11]2[C@H:10]([CH3:22])[CH2:9][NH:8][CH2:13][C@@H:12]2[CH3:14])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1c1nccnc1Cl
Agent: CC(Cl)OC(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1c1nccnc1Cl
Product: Cl

Procedure:
The title compound was prepared by treating the product obtained in Step 2 with 1-chloroethyl chloroformate according to the procedure described in Example 1 78, Step 3. The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5.0.2, followed by 90:10:0.5) as eluent to give 0.50 g(8% over two steps) of the free base of the title compound as a colorless oil. An analytical sample was precipitated as its HCl salt with HCl/ether: mp 199-200° C. Anal. (C10H15ClN4.HCl) C, H, N
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]([C:32]2([C:35](=[O:44])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:34][CH2:33]2)=[O:31])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]2[CH:13]=[C:12]([C:14](O)=[O:15])[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=2[N:8]=[CH:9][N:10]=1.[N:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>C(OCC)(=O)C>[F:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:35]([C:32]2([C:30]([NH:29][C:27]3[CH:26]=[CH:25][C:3]([O:4][C:5]4[C:6]5[CH:13]=[C:12]([C:14](=[O:15])[NH:53][CH2:52][CH2:51][N:45]6[CH2:50][CH2:49][O:48][CH2:47][CH2:46]6)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:7]=5[N:8]=[CH:9][N:10]=4)=[C:2]([F:1])[CH:28]=3)=[O:31])[CH2:33][CH2:34]2)=[O:44])=[CH:38][CH:39]=1
Reactant: NCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)O)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(C(=O)NCCN2CCOCC2)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.05 g, 0.08 mmol, 1.0 eq.), 2-Morpholin-4-yl-ethylamine (0.016 ml, 0.12 mmol, 1.5 eq), HATU (0.076 g, 0.2 mmol, 2.5 eq), TEA (0.033 ml, 0.24 mmol, 3.0 eq), and dry DMF (5 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with (2×) H2O (50 ml), sat'd NaHCO3 (2×), 5% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo, giving cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-(2-morpholin-4-yl-ethylcarbamoyl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide as a cream solid (0.049 g, 83% yield). MS (ESI) for C36H43F2N7O6Si: 736 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].Br[CH2:12][C:13]([CH3:15])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:14][C:13](=[CH2:12])[CH2:15][O:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1]
Reactant: Cc1cc(Br)cc(Br)c1O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1c(C)cc(Br)cc1Br
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 2,4-dibromo-6-methylphenol (2.0 g, 7.5 mmol), 3-bromo-2-methylprop-1-ene (1.5 g, 11.3 mmol), K2CO3 (3.12 g, 22.6 mmol) in DMF (15 mL) was heated at 70° C. 2 hours. The reaction was then cooled to room temperature and was diluted with water and hexanes. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 0-10% EtOAc/hexanes to give the title intermediate (1.05 g) as colorless liquid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)C.O.[NH2:15][NH2:16].C(OCC)C>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[C:4]([NH:15][NH2:16])=[O:3]
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NNC(=O)c1ccc(Cl)c(Cl)c1
Yield: 57 %

Procedure:
17.5g (0.08 mol) of 3,4-dichlorobenzoic ethyl ester and 4.3g (0.086 mol) of 100%-hydrazine hydrate in 30 ml of ethanol were refluxed under heat for 6.5 hours. Upon cooled, the sedimented white crystals were added with ethyl ether and the reaction mixture was enough agitated and pulverized. The thus resulted products were filtered and enough washed with ethyl ether to provide 9.3g of 3,4-dichlorobenzoic hydrazide in white crystals. m.p.: 168°-170° C. Yield: 57%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN1CCCC1=O>[C:19]([O:22][CH2:23][CH2:24][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1)(=[O:21])[CH3:20]
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)OCCON=C1Oc2ccccc2C1=O
Reaction time: 2 h
Yield: 63 %

Procedure:
1.63 g (0.01 mol) of benzofuran-2,3-dione 2-oxime (XI-1) in 5 ml of N-methyl-2-pyrrolidinone are stirred with 1.14 g (0.0108 mol) of sodium carbonate at 20° C. for 30 minutes. After the addition of 1.7 g (0.0102 mol) of 2-bromoethyl acetate, stirring is continued at 70° C. for 2 hours. The mixture is poured into 30 ml of water and the product is filtered off. The product is dried to afford 1.57 g (63% of theory) of crystalline 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV-1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])#[N:2].Cl.C(OCC)(=O)C>C(O)C.ClCCl.[Fe]>[NH2:17][C:16]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cc(C(=O)c2ccccc2)ccc1N
Yield: 15.9 %

Procedure:
To a stirred refluxing mixture of 3-cyano-4-nitrobenzophenone (Method 6) (1.50 g) and iron powder (3.64 g) in ethanol (50 ml) was added dropwise over 0.5 hour a solution of concentrated hydrochloric acid (0.35 ml) in ethanol (14 ml) and reflux was maintained overnight. The hot mixture was filtered through diatomaceous earth and the reaction flask and diatomaceous earth pad was washed with three 50 ml portions of ethanol. The combined filtrate was evaporated to yield a tan solid. Chromatography (eluent 10% to 40% ethyl acetate gradient in dichloromethane) gave the title compound (0.21 g) as a tan solid. M.p. 158-160° C.;
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:24])([CH3:23])[C:10]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1)=[O:11].[F:25][CH:26]([F:37])[C:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([F:35])[N:29]([CH3:36])[N:28]=1.O>ClCCl>[Cl:18][C:17]1[C:12]([C:10](=[O:11])[C:9]([NH:8][C:32]([C:31]2[C:27]([CH:26]([F:37])[F:25])=[N:28][N:29]([CH3:36])[C:30]=2[F:35])=[O:33])([CH3:24])[CH3:23])=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:16]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(C)(N)C(=O)c1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)F)c(C(=O)NC(C)(C)C(=O)c2ncc(C(F)(F)F)cc2Cl)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.7 %

Procedure:
In a 13 ml Chemspeed™ vial is weighted 73 mg (0.726 mmol) of triethylamine. 3 ml of a 0.23 molar solution of 2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-methylpropan-1-one (0.594 mmole) in dichloromethane is added followed by 3 ml of a 0.26 molar solution of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.66 mmole) in dichloro-methane and stirred at ambient temperature for 15 hrs. 1 ml of water is then added and the mixture is deposited on a basic alumina cartridge (2 g) and eluted twice by 8 ml of dichloromethane. The solvents are removed to yield 57 mg (19%) of pure N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-methyl-1-oxopropan-2-yl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as an oil (M+H=443).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[CH3:58][N:59]([CH3:64])[CH2:60][C:61](O)=[O:62]>C(Cl)Cl.O>[Cl:35][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:33])[CH3:34])[C:24]([NH:23][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:61](=[O:62])[CH2:60][N:59]([CH3:64])[CH3:58])=[O:36]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)CN(C)C)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCl (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Sc2ccccc2)cc1
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Sc2ccc(OC3CCCC3)cc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution was prepared by combining 11.3 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 8.2 g of bromocyclopentane, 7.6 g of potassium carbonate, and 40 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 100 g of 5 wt % dilute hydrochloric acid was added to quench the reaction. To the solution, 150 g of toluene was added for extraction. The organic layer was separated and washed with water. It was combined with 5 wt % sodium hydroxide aqueous solution. The organic layer was separated and washed with water again. On subsequent concentration in vacuum, 13.8 g of the target compound, 4-cyclopentyloxyphenyl phenyl sulfide was obtained as oily matter. Yield 100%.