Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([O:11][CH:12]3[CH2:15][O:14][CH2:13]3)[N:8]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:7]=2[CH:23]=1)#[CH:2].C([N-]C(C)C)(C)C.[Li+].[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38](=[O:40])[CH3:39].[Cl-].[NH4+]>C1COCC1>[NH2:22][C:18]1[N:17]=[C:16]([N:8]2[C:7]3[CH:23]=[C:3]([C:1]#[C:2][C:38]([C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:32]=4)([OH:40])[CH3:39])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[O:11][CH:12]2[CH2:13][O:14][CH2:15]2)[CH:21]=[CH:20][N:19]=1
Reactant: C#Cc1ccc2nc(OC3COC3)n(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2nc(OC3COC3)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-[6-ethynyl-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (270 mg, 0.88 mmol) in dry THF (5 mL) at −78° C. was introduced lithium diisopropylamide (1.10 mL of a 2M solution in THF, 2.20 mmol). After 15 minutes, 1-pyrimidin-2-yl-ethanone (107 mg, 0.88 mmol) was added and the reaction mixture maintained at −78° C. for 15 minutes. Following 2 hr at RT, saturated aqueous ammonium chloride (0.5 ml) was added and the solution concentrated in vacuo. The residue was dissolved in DCM (10 mL), washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography (Biotage, DCM containing a 0-12% gradient of methanol) furnished the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 4.78 (2H, dd, J=7.8, 4.9 Hz), 4.98 (2H, t, J=7.1 Hz), 5.87-5.80 (1H, m), 6.16 (1 H, s), 7.11 (1H, d, J=5.5 Hz), 7.14 (2H, s), 7.25 (1H, dd, J=8.2, 1.2 Hz), 7.45 (1H, d, J=8.2 Hz), 7.52 (1H, t, J=4.8 Hz), 8.16 (1H, s), 8.44 (1H, d, J=5.5 Hz), 8.91 (2H, d, J=4.8 Hz); LC-MS: m/z=+430.05 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:17][CH3:18])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]1[OH:16].[OH-].[Na+].[CH:21]1C=CC=CC=1.S(OC)(OC)(=O)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:21][O:16][CH:4]1[C:3]([O:17][CH3:18])([O:2][CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5]1
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Reactant: c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC1CN(Cc2ccccc2)CCC1(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 85 parts of 4,4-dimethoxy-1-(phenylmethyl)-3-piperidinol and 480 parts of sodium hydroxide solution 60% were added 288 parts of benzene and 0.5 parts of N,N,N-triethylbenzenemethanaminium chloride. Then there were added dropwise 49.2 parts of dimethyl sulfate at a temperature below 30° C. After stirring overnight at room temperature, there was added another portion of 13.3 parts of dimethyl sulfate and stirring was continued for 4 hours at room temperature. The reaction mixture was cooled, 640 parts of water were added and the layers were separated. The aqueous phase was extracted with benzene. The formed suspension was filtered and the filter-cake was set aside. The combined organic phases were washed with water, dried, filtered and evaporated. The oily residue was distilled (bp. 138° C. at 1 mm. pressure). The distillate was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized from ethanol, yielding 34.9 parts of 3,4,4-trimethoxy-1-(phenylmethyl)piperidine ethanediote; mp. 180.6° C. (intermediate 58).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Br)C1C=CC=CC=1>[CH2:22]([N:13]1[CH2:12][CH:11]=[C:10]([CH:8]([OH:9])[CH2:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[CH2:15][CH2:14]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccsc1CC(=O)c1ccncc1
Agent: BrCc1ccccc1
Product: Cc1ccsc1CC(O)C1=CCN(Cc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
After dissolving 2.72 g of 2-(3-methyl-2-thienyl)-1-(4-pyridyl)ethanone in 15 ml of toluene, 1.79 ml of benzyl bromide was added, the mixture was stirred for 7 hours at 110° C. and the precipitate was filtered out. The filtered substance was dissolved in 60 ml of methanol, 1.42 g of sodium borohydride was added in small portions at a time while cooling on ice, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.85 g, 73% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-amine (7-3, 0.500 g, 1.68 mmol) in THF (8.4 mL) was added triethylamine (0.510 g, 5.03 mmol) followed by isonicotinoyl chloride hydrochloride (0.750 g, 4.21 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in toluene to give N-{4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (0.17 g) as yellow solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J=6.0 Hz, 2 H), 8.42 (d, J=1.0 Hz, 1 H), 8.28 (d, J=1.0 Hz, 1 H), 8.13 (m, 1 H), 7.67 (d, J=6.0 Hz, 2 H), 6.84 (s, 1 H), 6.68 (s, 2 H), 1.98 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: COC(=O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 79 %

Procedure:
An 18-mL test tube was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (10 mg, 0.033 mmol, 1 eq. Synthesis of this compound was described in step 1 of EXAMPLE 1) and methyl 4-(4-aminophenyl)butanoate (17 mg, 0.088 mmol, 2.7 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by 5% of ethyl acetate in dichloromethane as eluent to give methyl 4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate (11 mg, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:21][CH2:22]2)[CH3:27])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)nn1
Reactant: CNC1CCN(C(=O)C2CC2)CC1
Product: CN(C(=O)COc1ccc(Cl)nn1)C1CCN(C(=O)C2CC2)CC1
Yield: 63 %

Procedure:
The title compound was synthesized from ethyl 2-(6-chloropyridazine-3-yloxy)acetate and cyclopropyl (4-(methylamino)piperidine-1-yl)methanone in the same manner as in Example 105 (63% yield, in 2 steps).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([CH3:15])C(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:23]1CCC[CH2:24]1>>[CH3:16][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH2:15][CH2:24][OH:23]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)c1cnccc1N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)c1ccncc1CCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the product of step (iv) (2.6 g) in tetrahydrofuran (100 ml) was added lithium aluminium hydride (1.2 g) and the resulting suspension stirred for 4 hours at ambient temperature. Excess reducing agent was destroyed by the sequential addition of ethyl acetate, water, and conc. HCl. The mixture was then basified and extracted sequentially with ethyl acetate and dichloromethane. The organic extracts were combined, dried (PS paper and MgSO4) and evaporated to yield 4-dimethylamino-3-(3-hydroxypropyl)pyridine as a pale yellow oil (2.2 g), essentially pure by Tlc NMR (d6DMSO) : δ 1.6-1.8 (2H,m); 2.65 (2H,t); 2.8 (6H,s); 3.5 (2H,t); 4.5 (1H,br.s); 6.7 (2H,d); 8.2 (2H,d); m/e 181 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C(N(CC)CC)C.[H][H].C(OCC)(=O)C>O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH3:8][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]2=[CH:2][N:7]=1
Reactant: Cc1nc(Cl)c2cn[nH]c2n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ncc2cn[nH]c2n1

Procedure:
4.464 g (approx. 24.28 mmol, purity 92%) of 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine were dissolved in 180 ml of dioxane, 2.948 g (29.14 mmol) of triethylamine and 5.629 g of 20% palladium hydroxide on carbon were added, and hydrogenation was effected with hydrogen at 3 bar and RT for 2 d. 100 ml of ethyl acetate, 2.948 g (29.14 mmol) of triethylamine and 2.000 g of 20% palladium hydroxide on carbon were added. The mixture was hydrogenated with hydrogen at 3 bar and RT for 3 h. The mixture was filtered through Celite and washed with a little dioxane/ethyl acetate, and the filtrate was concentrated on a rotary evaporator. 2.180 g (purity 73%, 49% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1>>[CH3:6][C:7]1[O:8][C:9]2[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2ccccc2o1
Product: Cc1nc2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 117.5 °C
Yield: 59.9 %

Procedure:
Chlorosulfonic acid (12.5 ml, 187.8 mmol) was cooled in an ice bath and 2-methylbenzoxazole (5.0 g, 37.5 mmol) was carefully added drop wise over a period of 15 min. The combined mixture was heated at 115-120° C. for 16 hours. After cooling, the mixture was added very slowly to ca. 100 ml ice/water mix. The white solid that separated was collected by filtration, washed with water until washings were neutral and dried to yield 5.2 g (59%) of Compound 8, whose structure is given below:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][NH:13][CH:12]2[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(C(C)C)CC)(C)C>C(O)CCCC>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:13]1[CH2:14][CH2:15][C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C@@H:12]1[CH3:16]
Reactant: CC1NCCC1c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: C[C@H]1[C@H](c2ccc(C(C)(C)C)cc2)CCN1c1ncccn1

Procedure:
1.4 g (0.0065 mol) of the substituted pyrrolidine prepared in (d), 0.74 (0.0065 mol) g of chloropyrimidine and 0.83 g (0.0065 mol) of diisopropylethylamine were mixed together in 40 mL pentanol and refluxed under nitrogen for six hours. The pentanol was distilled off under reduced pressure. The residue was taken up in dichloromethane and washed three times with water. The solution was dried over MgSO4 and filtered. The solvent was evaporated off under reduced pressure. Column chromatography using a toluene/ethylacetate mixture as the eluent afforded both the cis and trans isomers stereochemically pure in a 2:1 ratio in a yield of 1.36 g (70 percent of theoretical). Elemental analysis indicated the following:
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl.C(=O)(O)[O-].[Na+].Cl[C:22]1[C:27]2=[N:28][O:29][N:30]=[C:26]2[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1>C(C(C)=O)C.O>[CH3:14][CH:3]([CH2:2][S:1][C:22]1[C:27]2[C:26](=[N:30][O:29][N:28]=2)[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.03 h

Procedure:
3 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline was placed in a vial and dilute hydrochloric acid (0.1 N, 2 ml) added to dissolve same. 3 Ml of 0.1 M sodium bicarbonate solution was next added and the mixture was mixed in a vortex mixer. Thereafter, 3 ml of 1% (w/v) 4-chloro-7-nitrobenzofurazan in methyl ethyl ketone was added to the mixture, the vial was then closed and mixing was continued. The vial was held under running hot tap water, while shaking the vial, for about 2 minutes. The vial was then allowed to stand for 3 minutes, the organic (upper) layer was removed and was found to contain the title compound. The title compound was found to be fluorescent.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH3:32])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:33])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH2:31][CH3:32]
Reactant: CCCOc1c(-c2cccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]>C(O)C.[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:2][CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]
Reactant: COc1cccc(C(O)C2CCOC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CC2CCOC2=O)c1
Reaction time: 10 h
Yield: 86.2 %

Procedure:
A mixture of 3-[hydroxy(3-methoxyphenyl)methyl]-2-oxotetrahydrofuran (1.0 g) and 10% Pd/C (0.5 g) in ethanol (20 ml) was stirred under H2 for 10 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 3-(3-methoxybenzyl)-2-oxotetrahydrofuran (0.8 g).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(Br)c2ccccc21

Procedure:
1-Indanone (1 g) and NBS (1.4 g) was mixed with dry CCl4 (20 ml). A catalytic amount of AlBN was added and the mixture was refluxed for 30 minutes and excited with light using 250 W lamp. The mixture was cooled in an ice bath and filtered. The filtrate was concentrated in an evaporator and used without further purification for the next step. Yield was 1.5 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Example 39) was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine via General Procedure A. Purification on silica yielded the desired compound. NMR (400 MHz, CDCl3): 1.01-1.04 (2H, m, CH2), 1.20-1.25 (2H, m, CH2), 2.30 (1H, m, CH), 2.67-2.70 (4H, m, CH2), 3.39-3.41 (4H, m, CH2), 2.87-3.88 (4H, m, CH2), 3.90 (2H, s, CH2), 4.03-4.05 (4H, m, CH2), 4.08 (3H, s, CH3), 4.11 (3H, s, CH3), 7.36 (1H, s, ar), 8.95 (1H, s, ar).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:22]([CH2:25][CH3:26])[C:23]#[N:24])(=O)=O.[I-].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH:22]([CH2:25][CH3:26])[C:23]#[N:24]
Reactant: CCC(C#N)OS(C)(=O)=O
Reactant: O=Cc1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(C#N)Oc1cccc(C=O)c1Cl
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-3-hydroxy-benzaldehyde (1.0 g, 6.4 mmol) was dissolved in 10 ml N-methyl-pyrolidone at 20° C. The resultant yellow solution was degassed with argon. After addition of cesium carbonate (2.29 g, 7.0 mmol) the suspension was stirred for 20 minutes. 2-(methanesulfonyloxy)-butyronitrile (1.56 g, 9.6 mmol) and potassium iodide (0.05 g, 0.05 mmol) were then added and the reaction mixture was heated at 100° C. under microwave irradiation (Initiator™ Sixty, Biotage) for 3 minutes. After adding an additional portion of 2-(methanesulfonyloxy)-butyronitrile (0.52 g, 3.2 mmol) the reaction mixture was once again heated under microwave irradiation at 100° C. for 5 minutes. The reaction was monitored by TLC. On completion, the mixture was poured into water (0° C.) and extracted with ether. The organic layer was separated and washed with NaOH (1N), water and brine and dried with MgSO4. The crude material was purified on silicagel by flash chromatography (ethylacetate/cyclohexane) to give 2-(2-chloro-3-formyl-phenoxy)-butyronitrile as yellow oil; 1H-NMR (CDCl3) 1.25, t, 3H, 2.2 m, 2H, 4.81 dd, 1H, 7.4, m, 2H, 7.68 m, 1H, 10.5 s, 1H.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:15][CH2:16][OH:17])[N:5]=[C:6]([O:12][CH3:13])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[N:8]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:1][O:2][C:3]1[C@H:4]([C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:15][CH2:16][O:17][S:27]([CH3:26])(=[O:29])=[O:28])[N:5]=[C:6]([O:12][CH3:13])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@H](CCO)c1ccc(OC)cc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@H](CCOS(C)(=O)=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above oil 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanol (28) (17.7 g) was dissolved in 300 mL of dichloromethane. To the solution at −5° C. was added methane sulfonyl chloride (8.02 g, 5.42 mL, 70 mmol) followed by diisopropylethylamine (DIPEA, 12 mL, 70 mmol) dropwise over 10 min. The reaction was stirred at 0° C. for 2 hour. The light yellow solution was diluted with 2 L of ether and was washed with water (3×200 mL) and brine (2×200 mL). After it was dried over sodium sulfate, the solution was concentrated to a volume of 160 mL under vacuum at 20° C. TLC in EA/H (=1:1): Rf=0.74, as a major spot; Rf=0.21, as a minor spot.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26](C3CCCCO3)[N:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([CH2:20][CH2:19][C:16]3[CH:17]=[N:18][C:13]([NH:12][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([F:11])[F:10])=[C:2]([Cl:1])[CH:3]=4)=[N:14][CH:15]=3)=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: FC(F)Oc1ccc(Nc2ncc(CCc3ccc4c(cnn4C4CCCCO4)c3)cn2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)Oc1ccc(Nc2ncc(CCc3ccc4[nH]ncc4c3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To N-(3-chloro-4-(difluoromethoxy)phenyl)-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyrimidin-2-amine (0.075 g, 0.150 mmol) in DCM (5 mL) was added TFA (0.116 mL, 1.500 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the crude product purified by preparative HPLC on a Symmetry C18 column (19×300 mm, 7 μm) using 0-100% mobile phase B (ACN) in mobile phase A (10 mM ammonium acetate) to give 5-(2-(1H-indazol-5-yl)ethyl)-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine as an off white solid (0.012 g, 19% yield). 1HNMR 400 MHz, DMSO-d6: δ 2.85 (t, J=15.60 Hz, 2H), 2.99 (t, J=14.80 Hz, 2H), 6.95-7.31 (m, 3H), 7.46 (d, J=8.40 Hz, 1H), 7.54 (s, 1H), 7.65-7.68 (m, 1H), 7.98 (s, 1H), 8.08 (d, J=2.80 Hz, 1H), 8.36 (s, 2H), 9.76 (s, 1H), 12.95 (s, 1H). LCMS (ES-API), RT: 2.15 min, m/z 414 (M−H).
Reaction SMILES: [S:1]1CC(O)S[CH2:3][CH:2]1O.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].CO>O>[NH2:10][C:9]1[S:1][CH:2]=[CH:3][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(N)=O
Solvent: CO
Solvent: O
Product: NC(=O)c1ccsc1N
Temperature: 37.5 °C
Yield: 143 %

Procedure:
1,4-Dithiane-2,5-diol (50 g, 328 mmol), and cyanoacetamide (55.2 g, 657 mmol) were added to a mixture of MeOH (150 mL), water (9 mL) and TEA (6.5 g, 50 mmol). The resulting mixture was heated at about 35-40° C. for 30 minutes while stirring, and then heated to about 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to RT and poured into a mixture of ice (70 g)/water (200 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give (66.7 g) of the title compound. MS (ES+): 143 (M+H)+.