Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[NH2:10][CH2:11][CH2:12][C:13]1[CH:45]=[CH:44][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:15][CH:14]=1.[C:46]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:58]=1[OH:59])[C:53](O)=[O:54])([CH3:49])([CH3:48])[CH3:47].CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[ClH:8].[C:60]([C:57]1[CH:56]=[C:52]([CH:51]=[C:50]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:58]=1[OH:59])[C:53]([NH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:44][CH:45]=1)=[O:54])([CH3:63])([CH3:62])[CH3:61]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.4 %

Procedure:
A mixture of anhydrous triethylamine (0.106 g), 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), anhydrous N,N-dimethylformamide (10 ml), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.13 g) and 1-ethyl-3-[(3′-dimethylamino)propyl]carbodiimide hydrochloride (WSC.HCl, 0.13 g) was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by liquid chromatography on a silica gel column using ethyl acetate:n-hexane=4:1 as the eluant. To a solution of the glassy product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was crystallized in acetone to afford the title compound (0.17 g, pale yellow powder, mp 164-168° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(C)(C)C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(C)(C)C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2-(4-acetyl-phenyl)-2-methyl-propionic acid (Ex-77A) and 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. White foam. 1H-NMR (CCDl3) δ 8.11–7.86 (m, 5H), 7.62–7.46 (m, 3H), 7.42 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.3, 1H), 7.10–7.08 (m, 1H), 6.54 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). MS m/z=436 (M+, 55%), 405 ([M−OCH3]+, 100%).
Reaction SMILES: C[N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[F:10][C:11]([F:34])([F:33])[C:12]([F:32])([F:31])[C:13]([F:30])([F:29])[C:14](OC(=O)C(F)(F)C(F)(F)C(F)(F)F)=[O:15].[C:35]1(C)C=CC=CC=1>>[F:31][C:12]([F:32])([C:11]([F:34])([F:33])[F:10])[C:13]([F:30])([F:29])[C:14]([N:2]([CH3:3])[C:4]([N:6]([CH3:35])[C:7](=[NH:8])[NH2:9])=[NH:5])=[O:15]
Reactant: CN(C)C(=N)NC(=N)N
Reactant: Cc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(C(=N)N)C(=N)N(C)C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of metformin in dry toluene was slowly added heptafluorobutyric anhydride (1.2 equivalents) and stirred at ambient temperature for 4 hours. The reaction was terminated by addition of water and the reaction mixture was precipitated in acetone. The crude fluorinated metformin was chromatographed on silica gel, yielding N-heptafluorobutyryl N,N′-dimethylimidodicarbonimidic diamide.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][N:26]1[C:27](=[O:36])[C:28]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]2[C:30]1=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCOCc1ccccc1
Yield: 99.1 %

Procedure:
Diethyl azodicarboxylate (15.6 ml 99.4 mmol) added to a solution of 3-benzyloxy-1-propanol (15 g, 90.4 mmol), N-hydroxyphthalimide (14.7 g, 90.1 mmol) and triphenylphosphine (23.7 g, 90.4 mmol) in tetrahydrofuran (450 ml). After 16 hours at 20° C. the solvent was removed under reduced pressure and the residue chromatographed on silica gel (eluted with hexane:acetone, 3:1) to yield the title compound as a yellow oil (27.8 g, 99%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:20][CH3:21])[N:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:20][CH3:21])[N:3]=1)[NH2:24]
Reactant: CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Product: CNc1nc(NN)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R)-2-[2-chloro-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) (0.5 mmol), was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed under reduced pressure and the residue triturated with ether and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=4)[C:28]([NH:30][C@@H:31]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]([O:34]CC)=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>O1CCCC1.CO.O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=4)[C:28]([NH:30][C@@H:31]([CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]([OH:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of ethyl (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}-3-phenylpropionate (119 mg, 0.195 mmol) in tetrahydrofuran (4 ml) was added a solution of lithium hydroxide-water (16.4 mg, 0.390 mmol) in MeOH-water (1:1) (2.8 ml) at 5° C. The reaction mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 1N hydrochloric acid (0.5 ml) at 5° C. and extracted with EtOAc. The organic layer was washed with water and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo to give (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}-3-phenylpropionic acid (113.0 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9]([Li])[CH2:10][CH2:11]C.[CH2:14]([Si:17](Cl)(C)[CH3:18])C=C>C1COCC1>[CH2:9]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SiH:17]([CH3:18])[CH3:14])[CH:10]=[CH2:11]
Reactant: Brc1ccc(Br)cc1
Reactant: [Li]CCCC
Reactant: C=CC[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=CCc1ccc(Br)cc1[SiH](C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution 1,4-dibromobenzene (28.3 g, 120 mmol) in dried THF (300 mL) at −78° C. was added n-butyllithium (40.0 mL, 2.5 M solution in hexanes, 100 mmol) over a period of 20 min. After 30 min of further stirring at −78° C., allylchlorodimethylsilane (13.5 g, 100 mmol) in THF (50 mL) was added dropwise over a period of 20 min, and the reaction mixture was warmed to room temperature. After stirring for 1 h at room temperature the reaction mixture was concentrated, and the residue was extracted with ether and brine. The organic layer was dried (Na2SO4) and distilled under reduced pressure to provide colorless liquid (21.9 g, 82%, b.p. 72° C./0.1 mmHg); 1H NMR (300 MHz, CDCl3) δ 0.31 (s, 6 H), 1.77 (d, J=8.07 Hz, 2 H), 4.87 (m, 1 H), 4.92 (m, 1 H), 5.78 (ddt, J=17.55, 9.51, and 8.07 Hz, 1 H), 7.41 (d, J=8.28 Hz, 2 H), 7.52 (d, J=8.28 Hz, 2H); 13C NMR (75 MHz, CDCl3) −3.5 (2 C), 23.6, 113.8, 123.9, 130.9 (2 C), 134.2, 135.3 (2 C), 137.5; HRMS calcd for C11H15BrSi 254.0127 and 254.0107, found 254.0128 and 256.0109.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]4[C:36]([N+:37]([O-])=O)=[CH:35][CH:34]=[CH:33][C:28]=4[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]4[C:36]([NH2:37])=[CH:35][CH:34]=[CH:33][C:28]=4[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)=[CH:40][CH:41]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21a, 2.73 g, 4.96 mmol) and tin(II) chloride dihydrate (4.48 g, 19.9 mmol) in methanol (60 mL) was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and to the concentrated residue were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The mixture was stirred for 1 hr, and filtered, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and concentrated under reduced pressure. The concentrated solution was extracted with ethyl acetate. The ethyl acetate solution of the resultant product was dried magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column (hexane→hexane:AcOEt=4:1→2:1→3:2) to give methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate (compound 22a) (1.96 g, 70%) as a brown amorphous solid.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH2:20][O:21][CH3:22])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH2:20][O:21][CH3:22])=[C:7]([CH:2]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: COCc1oc(-c2ccc(F)cc2C)cc1C(Cl)CC(C)C
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccc(F)cc2C)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-(methoxymethyl)furan (487 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (45 mg, 6%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([Cl:19])[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:12]([Cl:19])[N:11]=1
Reactant: OCC1CCOCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tetrahydro-2H-pyran-4-ylmethanol (2.44 g) and 2,6-dichloropurine (1.97 g) was dissolved in dry THF (25 mL). To this solution was added triphenylphosphine (5.51 g), followed by diisopropyl azodicarboxylate (4.14 mL) added drop wise. The temperature of the reaction was kept below 43° C. (some cooling with a water bath was required). The reaction was stirred overnight at ambient temperature before being quenched with water (100 mL) and extracted into ethyl acetate (50 mL, twice). The separated and combined organic layer was then washed with water (100 mL). The organic layer was separated and then dried by passing through a hydrophobic frit before evaporation under reduced pressure to give pale yellow viscous oil. The material was partially purified by silica chromatography (ISCO) using 0-100% ethyl acetate: cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonate (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (13 g, 54.1 mmol). The mixture was stirred at 50 ° C. under argon for 16 hours. Poured into water (500 ml), extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[C:22]([F:24])[CH:23]=[C:18]3[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:37][CH:38]([F:40])[F:39])(=O)=O.[OH2:43]>CN(C=O)C>[F:39][CH:38]([F:40])[CH2:37][N:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([F:24])[CH:23]=2)[C:15]([C:12]2[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=2[OH:43])=[N:16]1
Reactant: Fc1cnc2c(-c3ccc(OCc4ccccc4)cc3)n[nH]c2c1
Reactant: O
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1nn(CC(F)F)c2cc(F)cnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-[4-(benzyloxy)phenyl]-6-fluoro-1H-pyrazolo[4,3-b]pyridine (100 mg) and Cs2CO3 (204 mg) in DMF (4 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (73.8 mg) at 0° C. The mixture was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (8 mL) and 10% Pd—C (50% wet, 100 mg) was added. The mixture was stirred at room temperature for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (47.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[N:11]=[C:10](C(OC)=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][Mg]Br.CC[O:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])[N:11]=[C:10]([C:33]([OH:32])([CH3:34])[CH3:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccccc2C(F)(F)F)n1
Reactant: C[Mg]Br
Reactant: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cc(-c2ccc(Br)cc2)n(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a suspension of methyl 5-(4-bromophenyl)-1-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (393 mg, 0.9 mmol) in dry toluene (9 mL) stirred at ambient temperature was added methylmagnesium bromide (1.4 mL of a 3.0M solution in ether, 4.2 mmol) dropwise. After 2¼ hours stirring at ambient temperature the reaction mixture was quenched by the addition of saturated ammonium chloride and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(5-(4-bromophenyl)-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol as an orange-yellow oil, which was carried on to the subsequent step. GC/MS (EI, =426 [M+]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33]C(OCC=C)=O)[C:28]=2[F:40])[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl.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>[NH2:33][C:29]1[C:28]([F:40])=[C:27]([C:9]2[N:10]=[C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (670 mg, 1.139 mmol) in dichloromethane (8 mL) were added tributylstannane (332 mg, 1.139 mmol), tetrakis (65.8 mg, 0.057 mmol) and water (66 μl, 3.66 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated and residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to obtain the title compound (482 mg). MS (ESI): 504.2 [M+1]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[CH:21]([NH:24][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4])([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Product: CC(C)NC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Yield: 24.3 %

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and isopropylamine (0.4 ml; 4.7 mmol). This gave the title compound as a white solid (0.021 g; 24%). LCMS: m/z=367 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[Li][CH2:15][CH2:16][CH2:17][CH3:18].Cl[Si:20](Cl)([CH3:22])[CH3:21].O>CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH:6]2[Si:20]([CH:15]1[C:6]2[C:18](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[CH:17]=[C:16]1[CH:8]([CH3:9])[CH3:7])([CH3:22])[CH3:21]
Reactant: [Li]CCCC
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)C1=Cc2c(Br)cccc2C1
Solvent: O
Solvent: CCOCC
Product: CC(C)C1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C(C)C)=Cc2c(Br)cccc21
Reaction time: 24 h

Procedure:
To a solution of 23.7 g (100 mmol) of 4-bromo-2-isopropyl-1H-indene in 600 ml of ether, 40.0 ml (100 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The mixture was stirred for 24 h at this temperature, and then 6.45 g (50.0 mmol) of dichlorodimethylsilane was added. The resulting mixture was stirred for 36 h at ambient temperature, and then 200 ml of water was added. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The product was isolated by MPLC on Silica Gel 60 (40-63 um, d 50 mm, l 500 mm; eluent—hexanes). Yield 16.6 g (63%) of a ca. 4:3 mixture of rac- and meso-products.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[C:21]([F:23])[N:20]=[CH:19][C:18]=4[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:28])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44]>C(O)CCC.C(OCC)(=O)C>[CH3:26][N:25]([CH2:24][C:18]1[C:17]([C:13]2[C:11]3[S:12][C:8]([C:6]4[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][N:39]5[CH2:43][CH2:42][NH:41][C:40]5=[O:44])[N:7]=4)=[CH:9][C:10]=3[CH:16]=[CH:15][CH:14]=2)=[CH:22][C:21]([F:23])=[N:20][CH:19]=1)[CH3:27]
Reactant: NCCN1CCNC1=O
Reactant: CN(C)Cc1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 120 °C
Yield: 63.2 %

Procedure:
Combine {4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-ylmethyl}-dimethyl-amine (0.25 g, 0.59 mmol) and triethylamine (0.25 mL, 1.78 mmol) in n-butanol (8.0 mL). Add 1-(2-aminoethyl) imidazolidin-2-one (0.23 g, 1.78 mmol). Heat the reaction mixture at 120° C. overnight (15 hours), then cool to room temperature. Dilute the reaction mixture with ethyl acetate, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from aqueous layer and dry over MgSO4. After filtration, remove the organic solvent to give a crude. Purify the crude by column chromatography (0.5% to 10% 2 N NH3 in methanol solution/dichloromethane) to afford the title compound (0.19 g, 63%). MS (ES) m/z 510 [M+1]+.