Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12](O)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:31]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12]([Cl:31])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)C(F)(F)C3
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)C(F)(F)C3
Temperature: 70 °C

Procedure:
To a stirred solution of the product from step (a) (25 mg) in SOCl2 (1 ml) was added pyridine (1 ml). The mixture was heated to 70° C. for 30 minutes after which LCMS indicates no starting material. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and washed with 1 M citric acid, saturated NaHCO3, brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound (21 mg) as a colorless oil which was used as obtained in the next step. MS: ESI (positive): 330 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][NH:7][C:6](=[O:9])[NH:5]1)[CH3:3].Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][CH:2]([C@H:4]1[CH2:8][N:7]([C:11]2[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[C:6](=[O:9])[NH:5]1)[CH3:3]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CC(C)[C@H]1CNC(=O)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1CN(c2ncc(C(F)(F)F)cn2)C(=O)N1
Yield: 22 %

Procedure:
A solution of (4S)-4-(propan-2-yl)imidazolidin-2-one (100 mg), 2-chloro-5-trifluoromethylpyrimidine (142 mg), Pd2(dba)3 (40 mg), Xantphos (45 mg) and sodium tert-butoxide (70 mg) in toluene (2 mL) was stirred at 100° C. for 1 hr. The reaction mixture was purified by column chromatography (NH silica gel cartridge and silica gel cartridge, hexane/ethyl acetate) to afford the title compound (47 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: COc1cc(Br)c(O)cc1F
Reactant: BrCC1CC1
Product: COc1cc(Br)c(OCC2CC2)cc1F

Procedure:
Starting from 2-bromo-5-fluoro-4-methoxy-phenol (example B.e1) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:30][C:29]3[C:24](=[C:25]([O:37]C)[C:26]([O:35][CH3:36])=[C:27]([O:33][CH3:34])[C:28]=3[O:31]C)[CH2:23]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)(O)[O-].[Na+]>O.C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:23][C:24]3[C:25](=[O:37])[C:26]([O:35][CH3:36])=[C:27]([O:33][CH3:34])[C:28](=[O:31])[C:29]=3[CH2:30]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(Cc3ccccc3)CC1)(c1ccccc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCN3CCN(Cc4ccccc4)CC3)(c3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a mixture of 4-benzyl-1-[8-(4,5,6,7-tetramethoxy-2-phenylindan-2-yl)octyl]piperazine (713 mg), 2,6-pyridinedicarboxylic acid (597 mg), THF (14 ml), and water (7 ml) was dropwise added a solution of CAN (2.59 g) in water (7 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate 8:1) and then with recrystallization from hexane-diethyl ether to yield the entitled compound (310 mg) as crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
Palladium (II) acetate (0. 15 g, 0.67 mmol) was added to a stirred solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6g, 30 mmol) and 4-iodo-N-2-pyridinylbenzenesulfonamide (10.8 g, 30 mmol) in dimethylacetamide (40ml) and tributylamine (10 ml, 42 mmol) at 95° C. After 100 min. the solution was filtered and evaporated at 50°-60° C. (bath temp.) until solid material appeared. The mixture was diluted with isopropanol (0.5 l) and chilled in a freezer. The product was filtered off to yield 7.1 g (52%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[N:7]=[C:2]([NH:32][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(N)=O)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)n2)nc1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
To a resealable vial was added (4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.200 g, 0.535 mmol), 5-cyanopicolinamide (0.118 g, 0.802 mmol), 1,4-dioxane (4 mL), and cesium carbonate (Strem Chemicals; 0.435 g, 1.337 mmol). The reaction vessel was carefully evacuated and backfilled with N2. This was repeated twice. To the solution was added tris(dibenzylideneacetone)dipalladium (0) (Aldrich; 0.049 g, 0.053 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich; 0.062 g, 0.107 mmol). The reaction vessel was carefully evacuated and backfilled with N2. This was repeated twice. The solution was stirred and heated at 100° C. for 3 h. The reaction mixture was allowed to cool to rt and poured into sat NaHCO3 (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (100 mL) and brine (50 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient; 0.0 to 10% MeOH/CH2Cl2, Silicycle HP column, 40 g) followed by further purification by reverse phase preparative-HPLC afforded N-(6-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide (0.0675 g, 0.153 mmol, 28.7% yield) as a white solid. MS m/z=440.9 [M+H]+. Calculated for C18H13F5N6O2: 440.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[O:9]2)[CH3:2].C(OC([N:36](C(OC(C)(C)C)=O)[CH2:37][C:38](O)=[O:39])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:63]>ClCCl.C(OCC)(=O)C>[ClH:63].[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:38](=[O:39])[CH2:37][NH2:36])=[CH:23][CH:22]=1)[O:9]2)[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c12
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 11.35 g of 5-ethoxy-2-(4-hydroxyphenylthio)-7-isopropoxy-6-methoxychromone obtained in Example 18, 5.43 g of N-t-butoxycarbonyl(Boc)glycine, and 6.40 g of dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 11.28 g of 5-ethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxy-6-methoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[C:10](Cl)(Cl)=[S:11]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][O:7][C:10](=[S:11])[O:5][CH2:4]1)[CH3:2]
Reactant: CCC(CC)(CO)CO
Reactant: S=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCC1(CC)COC(=S)OC1
Temperature: 25 °C

Procedure:
The thiocarbonate 1 was prepared by a variation of the thiocarbonylation procedure developed by Corey and Hopkins. To a three-necked round-bottomed flask, equipped with a mechanical stirrer and an additional funnel, was placed 2,2-diethyl-1,3-propanediol (15.86 g, 120 mmol), 4-dimethylaminopyridine (DMAP, 29.32 g, 240 mmol) and 120 mL of toluene under an atmosphere of nitrogen. The mixture was allowed to stir at room temperature until a homogeneous solution was reached. The mixture was cooled to 0-5° C. and then a solution of thiophosgene (9.43 mL, 120 mmol) in 90 mL of toluene was added dropwise via the additional funnel over a period of 90 min. This resulted in the formation of a bright orange DMAP-thiophosgene complex. After the completion of addition, the reaction mixture was allowed to stir for an hour at 0-5° C. and then slowly warmed to room temperature. The reaction mixture was allowed to stir at room temperature for an additional hour and then the precipitated DMAP-HCl salt was removed by filtration. The filtrate was concentrated under reduced pressure using a rotary evaporator. The crude material was purified by recrystallization (the crude material was dissolved in refluxing ether, allowed to cool to room temperature and slowly evaporated) or by column chromatography (silica gel, 2:1 methylene chloride/hexanes). The desired thiocarbonate 1 was obtained as white crystalline in 70% yield. Mp (DSC) 64.4° C. 1H-NMR (CDCl3, 300 MHz) δ4.17 (s, 4H), 1.51-1.43 (q, 4H, J=7.5 Hz), 0.92-0.87 (t, 6H, J=7.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ189.53, 76.08, 33.67, 23.09, 6.97; IR (KBr pellet) (cm−1) 2960, 2920, 1455, 1395, 1380, 1290, 1240, 1200, 1180, 1060, 990, 930, 720.
Reaction SMILES: C([Si](C(C)(C)C)(C1C=CC=CC=1)[O:6][CH2:7][CH:8]([CH3:39])[O:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].CO>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:7][CH:8]([CH3:39])[O:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:31][CH:30]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2
Reactant: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
2-(2-{7-(2-{[Di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl)acetamide (262 mg) was dissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (0.5 mL) was added, and the mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate=0:100 to 10:90, volume ratio) to give the title compound (144 mg, yield 81%) as a white solid. The obtained white solid was recrystallized from ethyl acetate-hexane to give colorless crystals. melting point 137-142° C. MS 504 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COCCOCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
5 g of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 5.0 g of 3-nitroaniline is added, and it is stirred for another 15 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation and, after purification by chromatography on silica gel, 7.5 g of the title compound is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:25]1([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24]1
Reactant: c1ccc2occc2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Yield: 23.9 %

Procedure:
A solution of benzo[b]furan (1.50 g, 12.7 mmol) in dry THF (50 ml) was cooled to −8° C. under a stream of argon. Tert-butyllithium (15.2 mmol, 10.2 ml of a 1.5 molar pentane solution) was added dropwise in such a way that a reaction temperature of −5° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2½ hours at −5° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (2.76 g, 12.7 mmol) in dry THF (15 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 4 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 1.02 g 1-benzofuran-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 134–137° C. were obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14](OC)[CH2:15][C:16]#[N:17].Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC(CC#N)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 400 mg, 10 mmol) was charged and washed with hexane twice. Into this flask, N,N-dimethylformamide (15 ml) was added and a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and. 3,3-dimethoxypropionitrile (1.15 g, 10 mmol) in N,N-dimethylformamide (5 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 4 hours, the reaction mixture was poured into water (50 ml). This mixture was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1 to 1/1) to obtain 251 mg (yield 13.2%) of title compound (IIa) having a low polarity and 372 mg (yield 19.8%) of title compound (IIb) having a high polarity.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12](=O)[NH:11][C:9]1=[O:10])[CH2:3][OH:4].C[Si](C)(C)[NH:18][Si](C)(C)C.C(N)=O>CO>[OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12]([NH2:18])=[N:11][C:9]1=[O:10])[CH2:3][OH:4]
Reactant: O=c1ccn(C2CC2C(O)CO)c(=O)[nH]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: NC=O
Solvent: CO
Product: Nc1ccn(C2CC2C(O)CO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 85.8 mg (0.42 mmol) of 1-(2'-(1",2"-dihydroxyethyl) cyclopropyl)uracil, the product of Step B of Example 9, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[C:4]([F:20])[C:3]=1[NH:21][C:22]1[CH:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[NH:24][N:23]=1.[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([N:21]3[C:3]4[C:4]([F:20])=[C:5]([NH:9][C@H:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[CH2:11][OH:12])[C:6]([F:8])=[CH:7][C:2]=4[N:1]=[CH:30]3)[CH:26]=2)[CH2:29][CH2:28]1
Reactant: Nc1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@H](Nc1c(F)cc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1

Procedure:
(R)-2-(4-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluorophenylamino)-2-(4-fluorophenyl)ethanol (Method 104, 0.230 g, 0.57 mmol) and formamidine acetate (0.119 g, 1.14 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organic layer was separated, washed with brine (3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (Hex-EtOAc=1:1) to give the title compound as off white solid (0.070 g, 30%). 1H NMR (400 MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.8 Hz, 2H), 6.14 (s, 1H), 5.14 (d, J=9.6 Hz, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.62 (m, 1H), 3.64-3.74 (m, 2H), 1.97 (m, 1H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 413; Found: [M+H]+ 414.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6]O)[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:43]I>O1CCOCC1.CO>[I:43][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Temperature: 21 °C
Reaction time: 7 h
Yield: 57.3 %

Procedure:
To a suspension of thymidine (0.968 g, 4.0 mM) in dioxane (20 mL) containing pyridine (0.65 mL, 8.0 mM) was added triphenylphosphine (1.57 g, 6.0 mM) and iodine (1.52 g, 6.0 mM). After stirring the mixture for 7 hours at 21° C., methanol (1.0 mL) was added, followed by removal of the solvent by evaporation. A solution of the residue in ethyl acetate (150 mL) was extracted successively with water (30 mL), 10% aqueous sodium thiosulfate solution (30 mL), and brine (30 mL). The ethyl acetate phase was concentrated in vacuo to a sirup which was taken up in hot ethanol (50 mL) and filtered. The filtrate was concentrated to a volume of 15 mL. On cooling, 5'-deoxy-5'-iodothymidine crystallized out. The crystals were filtered, rinsed with ethyl acetate, and dried, affording 5'-deoxy-5'-iodothymidine (0.806 g), a compound according to Formula 2.