Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[H-].[Na+].Br.Br[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:7]=1
Reactant: BrCc1cccnc1
Reactant: Nc1ncc2sc(=O)[nH]c2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=O)n(Cc3cccnc3)c2n1
Temperature: 30 °C

Procedure:
5-Amino-3H-thiazolo[4,5-d]pyrimidin-2-one (107 mg, 0.64 mmol) was dissolved in DMF (4 mL) at ambient temperature. Sodium hydride (30 mg, 1.32 mmol) was added and the mixture was heated to 30° C. Stirring was continued for 0.5 h before 3-bromomethyl-pyridine hydrobromide (179 mg, 0.71 mmol) was added. The mixture was then heated to 75° C. and allowed to stir for 4 h. Upon completion, the reaction was allowed to cool to room temperature, then concentrated. Water (12 mL) was added. The resulting mixture was diluted with H2O (12 mL), then extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (SiO2, 20-50% EtOAc—CH2Cl2) to generate 90 mg (54%) of 54 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.48 (d, J=3.6, 1H), 8.32 (s, 1H), 7.71 (d, J=8.4, 1H), 7.36 (m, 1H), 6.86 (s, 2H), 5.04 (s, 2H); [M+H]+ 260.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([OH:18])[C:10]=1[O:19][CH3:20])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](OS(OCC)(=O)=O)[CH3:32].C(#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:31][CH3:32])[C:10]=1[O:19][CH3:20])=[O:8]
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c(OC)c1O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
A mixture of 66B (1.15 g), potassium carbonate (1.0 g), diethylsulfate (0.54 g) and acetonitrile (20 ml) is heated to reflux for 3 hours. Upon cooling to room temperature water is added. The solid material is collected and the residue is re-crystallized from methanol yielding white crystals, 1.07 g (85.6% ), mp 131-132° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[CH2:22]([O:24][CH2:25][C:26]1[N:27]([CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C:28]2[C:33]([CH3:34])=[C:32]([CH3:35])[N:31]=[C:30]([NH2:36])[C:29]=2[N:37]=1)[CH3:23]>>[CH3:1][N:2]([CH3:3])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:43]3[CH2:44][CH2:45][CH:40]([CH2:39][CH2:38][N:27]4[C:28]5[C:33]([CH3:34])=[C:32]([CH3:35])[N:31]=[C:30]([NH2:36])[C:29]=5[N:37]=[C:26]4[CH2:25][O:24][CH2:22][CH3:23])[CH2:41][CH2:42]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(S(=O)(=O)c2ccc(N=Nc3ccc(N(C)C)cc3)cc2)CC1

Procedure:
Using the method of Examples 49-56, 4-dimethylaminoazobenzene4′-sulfonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 619.3185.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21]>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([NH:22][C:20](=[O:21])[C:19]([F:18])([F:29])[F:30])[CH2:24]2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(NC1CCCNC1)C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCCC(NC(=O)C(F)(F)F)C2)ncn1
Temperature: 170 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.149 g, 1.15 mmol) and diisopropylethylamine (0.446 g, 3.45 mmol) were suspended in n-butanol. 2,2,2-Trifluoro-N-piperidin-3-ylacetamide 9-3 (0.226 g, 1.15 mmol) was then added. The reaction was stirred at 170° C. for 24 hours. The butanol was then removed under reduced pressure and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). 1H-NMR (CD3OD): 8.06 ppm (s, 1H); 5.82 ppm (s, 1H); 4.27 ppm (d, 1H); 4.15 ppm (d, 1H); 3.85 ppm (m, 1H); 3.73 ppm (p, 3H); 3.23 ppm (q, 3H); 3.08 ppm (dd, 2H); 2.13 ppm (m, 1H); 1.85 ppm (m, 1H); 1.71 ppm (m, 1H); 1.62 ppm (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: CCOC(=O)CN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 24 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide. Yield: 24% of theory, Rf value: 0.56 (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:9]([O:16][NH:17][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCCCBr)NOCc1ccccc1
Reaction time: 18 h
Yield: 77.7 %

Procedure:
In an ice bath, 14 ml triethylamine was added to a suspension of 3.2 g (20 mmol) O-benzylhydroxylamine hydrochloride in 150 ml dichloromethane. Stirring was continued until the solution became clear. Then, 4.5 g (20 mmol) 8-bromo octanoic acid was added, followed by 5.6 g (22 mmol) bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. Stirring was continued at ambient temperature for 18 h. The solution was extracted twice with 150 ml each of 1M aqueous hydrochloric acid and twice with 150 ml each of 1M aqueous sodium bicarbonate. The organic solvent was removed i. vac. to give 5.1 g (78%) of 8-bromo-octanoic acid benzyloxyamide as a colorless oil. MS: 330 (M+H+)
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15].C(N(CC)CC)C.[CH2:24]([O:26][CH2:27][C:28](Cl)=[O:29])[CH3:25]>ClCCl>[CH2:24]([O:26][CH2:27][C:28]([NH:15][C:6]1[C:7]2[N:8]([N:12]=[N:13][N:14]=2)[C:9]([CH3:11])=[CH:10][C:5]=1[NH:4][CH2:3][CH:2]([CH3:16])[CH3:1])=[O:29])[CH3:25]
Reactant: Cc1cc(NCC(C)C)c(N)c2nnnn12
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)n2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of N7-(2-methylpropyl)-5-methyltetraazolo[1,5-α]pyridine-7,8-diamine (8.4 g, 38.1 mmol) in anhydrous dichloromethane (300 mL) was cooled to 0° C. under a nitrogen atmosphere, and triethylamine (5.3 mL, 38.1 mmol) was added. A solution of ethoxyacetyl chloride (4.7 g, 38.1 mmol) in dichloromethane (100 mL) was added dropwise over a period of five minutes, and a homogeneous solution resulted. After the solution was stirred for one hour, it was allowed to warm to room temperature, washed with water (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.2 g of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[1,5-α]pyridin-8-yl}acetamide as a light tan solid, m.p. 182-185° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C=O)C>[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:11])[CH3:12])[NH:9][C:33](=[O:32])[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([CH3:5])([CH3:4])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of L-valine tert-butyl ester hydrochloride (2.1 g, 10 mmole) in DMF (10 ml) was treated with DIEA (1.6 ml. 10 mmole) and benzyloxycarbonyl-L-alanine p-nitrophenyl ester (3.5 g, 10 mmole). After overnight at room temperature, the solution was filtered through a column of neutral Al2O3 (100 g) and eluted with DMF. The solvent was removed in vacuo and the residue filtered through a column of silica gel (50 g) eluted with CHCl3. The resulting oil (3.0 g, 79%) was homogeneous on tlc; Rf (CHCl3) 0.10; Rf (ether) 0.70; Rf (CHCl3 24, CH3OH 1) 0.55.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A solution of diethyl azodicarboxylate (40% toluene solution, 6.40 ml) in toluene (3.0 ml) was added dropwise at room temperature to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (10.0 g) obtained from Reference example 24(a), 4-fluorophenol (4.15 g) and triphenylphosphine (10.6 g) in toluene (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; dichloromethane/ethyl acetate=3/2) to afford the target compound (7.00 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[H][H]>[C].[Ru].C(O)(C)C>[F:1][C:2]([F:22])([F:23])[C:3]([CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([CH:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1)[C:4]([F:5])([F:7])[F:6]
Reactant: [H][H]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Ru]
Solvent: CC(C)O
Product: OC1CCC(C(C2CCC(O)CC2)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 130 °C
Yield: 56 %

Procedure:
Into a stainless steel autoclave were placed 500 g of 4,4'-(perfluoroisopropylidene)diphenol, 100 ml of isopropanol and 2 g of 5% ruthenium-carbon. The mixture was maintained at a temperature of 130° C. and a hydrogen pressure of 50 kg/cm2G for 40 minutes and then at 160° to 170° C. and a hydrogen pressure of 60 to 70 kg/cm2G for 40 minutes. After cooled to room temperature, the catalyst is filtered off and isopropanol was removed at a reduced pressure. The residue was recrystallized from toluene to obtain 290 g of 4,4'-(perfluoroisopropylidene)dicyclohexanol in the form of white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[CH3:28][C:29](=[CH2:32])[C:30]#[N:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:32]/[C:29](=[CH:28]\[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:24])([CH3:25])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1)/[C:30]#[N:31]
Reactant: C=C(C)C#N
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C/C(C#N)=C\c1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 228 and 2-methyl-acrylonitrile, followed by TBAF deprotection of the SEM group. The formation of about 20% of the (Z)-Isomer was also observed.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1.C[N:17](C=O)C>>[CH:3]1([C:6]2[N:7]([NH2:17])[C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: Fc1ccc2[nH]c(C3CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Product: Nn1c(C2CC2)cc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of NaH (1.9 g, 47 mmol, 60% in mineral oil) in DMF (20 mL) at 0° C. is treated with 2-cyclopropyl-5-fluoro-1H-indole (550 mg, 3.14 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (1.8 g, 15.7 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 5%-35% EtOAc in heptane to afford 2-cyclopropyl-5-fluoro-indol-1-ylamine (420 mg, 70%). MS: 191 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 7.11 (m, 1H), 6.92 (m, 1H), 5.90 (s, 1H), 4.57 (s, NH2, 2H), 2.07 (m, 1H), 1.02 (m, 2H), 0.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:53]=[CH:52][C:6]([C:7]([O:20][CH2:21][C@@H:22]([C@H:49]([CH3:51])[OH:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1CCCCC1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:20][CH2:21][C@@H:22]([C@H:49]([CH3:51])[OH:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:52][CH:53]=1
Reactant: COc1ccc(C(OC[C@H](NC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C)O)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H](NC(=O)CCCCCN)[C@H](C)O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
14 (9.1 g, 12.77 mmol) was dissolved in DMF (100 ml) containing piperidine (10 ml) and the reaction mixture was kept at RT for about 1 hour. The solvents were removed in vacuo and the residue purified by silica gel column chromatography using 1-10% gradient of methanol in dichloromethane to afford 15 as a syrup (4.46 g, 71%). 1H-NMR 7.48-6.92 (m, 14H, aromatic), 6.16 (d, J=8.8, 1H, NH), 4.17 (m, 1H, H3 Thr), 4.02 (m, 1H, H2 Thr), 3.86 (s, 3H, OCH3), 3.50 (dd, J=9.7, J=4.4, 1H, H1 Thr), 3.37 (dd, J=9.7, J=3.4, 1H, H1′ Thr), 2.78 (t, J=6.8, 2H, CH2CO Acp), 2.33 (t, J=7.6, 2H, CH2NH Acp), 1.76 (m, 2H, CH2 Acp), 1.56 (m, 2H, CH2 Acp), 1.50 (m, 2H, CH2 Acp), 1.21 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 491.5 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:28]([C:27]([F:26])([F:42])[F:41])[CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3,5-bis(trifluoromethyl)phenyl boronic acid. Mass spectrum (ESI) 528.3 (M+1).
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:14][C:3]2[S:2][C:6]3[CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:5]=3[N:4]=2)=[O:22])=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: I
Product: N#Cc1ccc(C(=O)Nc2nc3c(s2)Cc2ccccc2-3)cc1
Yield: 25.6 %

Procedure:
Acylation of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 4-cyanobenzoyl chloride (164 mg; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 26 mg of 4-Cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide 4. EI-HRMS m/e calcd for C18H14N2OS (M+) 306.0827, found 306.0827.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2ccnn2)C1
Yield: 46 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 6, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (142 mg, 46%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.76 (d, 2H), 7.40 (d, 2H), 7.11-6.83 (m, 9H), 5.31 (d, 1H), 5.15 (d, 1H), 4.77 (d, 1H), 3.71 (t, 1H), 3.30 (t, 1H), 3.02-2.91 (m, 1H), 2.82 (dd, 1H), 2.71 (dd, 1H), 2.57 (dd, 1H), 2.33 (s, 3H), 1.78-1.68 (m, 1H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Cl.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C:45](Cl)=[O:46]>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:45]([C@@H:41]4[CH2:42][CH2:43][CH2:44][NH:40]4)=[O:46])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Reactant: O=C(Cl)[C@@H]1CCCN1
Agent: Cl
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C(=O)[C@@H]2CCCN2)CC1

Procedure:
Prepared according to the method of Example 1 by replacing N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine with 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine and replacing 2-(dimethylamino)acetyl chloride hydrochloride with (S)-pyrrolidine-2-carbonyl chloride hydrochloride. Product was obtained. MS (ES+): 655.28 (M+1).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:19]1([CH3:51])[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[C:21]([O:20][C@:19]1([CH3:51])[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Compound 57 may be prepared according to Scheme 7, above. To a solution of uracil (4 g) in acetonitrile (120 ml) was added BSA (18 ml) and the mixture was stirred at 100° C. for 30 minutes. After cooling to room temperature, 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (10 g) in acetonitrile (120 ml) and 5 nCl4 (7 ml) were added. The reaction mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc and a saturated solution of NaHCO3 was added at 0° C. followed by filtration on celite. The filtrate was extracted with EtOAc and the organic layer was washed with a saturated solution of NaHCO3. After drying over Na2SO4 and filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0→20% EtOAc in dichloromethane to yield 2′,3′,5′-tri-O-benzoyl-2′-C-methyluridine (80%). 2′,3′,5′-tri-O-benzoyl-2′-C-methyluridine was characterized by the following spectroscopic data: MS (ESI, EI+) m/z=571.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[Cl:1])=[N:6][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc(F)cc1Cl
Product: NCc1c(N)nc(-c2ccc(F)cc2Cl)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=396.8 (M+), was prepared from 2-chlor-4-fluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.