Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.C([O-])=[O:19].[K+]>ClCCl>[CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH2:12][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)NCc1ccccc1
Reactant: O=C[O-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CO)CC(=O)NCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (compound A 50 g, 261 mmol) in dichloromethane (350 ml) was added bromine (14.82 ml, 288 mmol) at 0-5° C., then stirred at 20-25° C. for 3 hours (bromine colour disappeared). Water (300 ml) was added to the mixture with stirring, stirred for 10 min. Organic phase was separated, washed with sodium bicarbonate solution, dried, evaporated to dryness (compound B). The solid residue (compound B) dissolved in methanol (900 ml), added potassium formate (44.0 g, 523 mmol) and the mixture was heated under reflux for 2 hours. Methanol was removed on a rotavap, the residue was taken up into ethyl acetate (EA) (500 ml) under reflux, filtered hot, the filter cake washed with warm EA (100 ml). The combined filtrate was cooled to 5-10° C., aged for 1.5 hours. The precipitate was collected, washed with cold EA (50 ml), dried to give 25 g (46.1%) of crude product, light beige. Re-crystallised from water (300 ml), with active carbon (1 g). Filtered hot on celite, cooled in ice, aged for 1 hour, crystals collected, washed with cold water (20 ml), dried on air overnight to give N-benzyl-4-hydroxy-3-oxobutanamide (21 g, 101 mmol, 38.8% yield).
Reaction SMILES: [F:1][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[F:1][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CCNCC3)c21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 2.155 mmol) was dissolved in dioxane (5 mL) and cooled to 0° C. A solution of HCl in dioxane (13.47 mL, 53.88 mmol; 4M) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. A white precipitate had formed after about 8 hours. The reaction mixture was concentrated in vacuo, re-suspended in MeOH, and re-concentrated (3×). The residue was dissolved in MeOH (about 2 to 3 mL) and added dropwise to a rapidly stirring flask containing ether (80 mL). The white solid was filtered under a blanket of nitrogen gas and dried under nitrogen gas to give (5R,7S)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride a white solid (555 mg, 83%). LCMS (ESI+) m/z 237.2 [M+H]+; Rf: 1.70 min.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#C
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1
Reaction time: 3 h
Yield: 3.6 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of H2PtCl6. Into the same apparatus as described in Example 1 were placed 125 μl of a 0.1 M H2PtCl6 /IPA solution under a dry nitrogen atmosphere and the IPA removed under vacuum. Into the flask were added 3.01 g of bis(dichlorosilyl)methane and 20 ml of dried benzene. The flask content was heated to reflux temperature and acetylene gas was blown into the content at a rate of 90 ml/min for 3 hours. The reaction products were vacuum distilled at 67 Pa to yield a mixture comprising 1.99 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC area 3.6%); 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 47.4%); 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane (TCD-GC area 17.2%); and 1,1,3,3,6,6,8,8,11,11,13,13-dodecachloro-1,3,6,8,11,13-hexasilatridecane (TCD-GC area 8.6%). 1,1,3,3-Tetrachloro-1,3-disilacyclopent-4-ene=1H-NMR (CDCl3, ppm): 1.14 (s, 2H, SiCH2Si), 7.36 (s, 2H, CH=CH); 1,1,3,3 -tetrachloro-1,3-disilacyclopentane =1H-NMR (CDCl3, ppm): 1.12 (s, 2H, SiCH2Si), 1.50 (s, 4H, CH2CH2); and 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane=1H-NMR (CDCl3, ppm): 1.41-150 (m, 8H, SiCH2SiCH2CH2SiCH2Si), 5.71 (s, 2H, SiH).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1)C.[C:23]1([C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][C:26]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) and 4-phenylphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce the title compound. MS(ES) for C28H28O4[M+NH4]+: 446.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C[Al](C)C.[C:18]([O:22][C:23]([N:25]([CH3:48])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:38]([C:39](OCC)=[O:40])=[CH:37][C:36]([C:44]([F:47])([F:46])[F:45])=[N:35]2)[CH2:30][CH2:29]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:48][N:25]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:38]([C:39](=[O:40])[NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:12])([F:13])[F:1])=[CH:37][C:36]([C:44]([F:45])([F:47])[F:46])=[N:35]2)[CH2:30][CH2:29]1)[C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Reactant: NCc1ccccc1OC(F)(F)F
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC(F)(F)F)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-(Trifluoromethoxy)benzylamine (58.6 mg, 0.307 mmol) in toluene (1.239 mL) at 0° C. was added trimethylaluminium (2M in toluene, 0.557 mL, 1.115 mmol) dropwise. The mixture was stirred for 5 min at 0° C., then a solution of 95 (125 mg, 0.279 mmol) in toluene (0.620 mL) was added dropwise. The mixture was stirred at room temperature for 1 h, then at 55° C. for 1 h, and at 95° C. for 1.5 h till the reaction was complete. Saturated NaHCO3 was added to the reaction mixture followed by extraction with EtOAc. The organic extracts were dried over MgSO4, filtrated and concentrated and the residue was purified via Biotage (5% to 20% MeOH/CH2Cl2; 12M column) to give 99 as yellow oil. LRMS (ESI): calc.593.6; found 594.3 (MH)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]([CH3:20])=[O:21]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 147.4 g of dibenzothiophene in 1.6 liters of carbon tetrachloride, cooled in an ice bath, was added a filtered solution of 122.7 g of anhydrous aluminum chloride in 425 ml of dichloromethane and 65.4 ml of acetyl chloride at 10° C., over 45 minutes. The mixture was stirred for 20 minutes, then a mixture of 2.5 liters of crushed ice and 500 ml of concentrated hydrochloric acid was added in one portion. This mixture was stirred vigorously until the yellow color disappeared. The aqueous layer was separated and washed in 100 ml of carbon tetrachloride. The wash was combined with the organic layer, washed with two 2 liter portions of water, dried and evaporated. The residue was crystallized from 250 ml of toluene and 750 ml of ether, giving 85.9 g of the desired product as colorless crystals, mp 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[C:16]([NH2:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][C:10]2[N:25]=[C:16]([OH:24])[C:17]3[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:19]=2)[CH2:14][C:13]([OH:12])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: NC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: O=C(O)CC(Cc1nc(O)c2ccccc2n1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
The solution of 3-(4-chlorophenyl)glutaric anhydride (449 mg) and anthranilamide (272 mg) in toluene (8 ml) was heated to reflux for 4 h. After removal of the solvent the residue was dried in vacuo. The off-white solid was dissolved in 2M sodium hydroxide (3 ml) and stirred under reflux for 2 h. After cooling to room temperature acetic acid (0.5 ml) was added with stirring. The precipitate formed was isolated by suction filtration, washed, and dried in vacuo to give 3-(4-chlorophenyl)-4-(4-hydroxy-2-quinazolinyl)butanoic acid (0.57 g) as colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:49]2[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccncc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), pyridine-4-boronic acid (81.0 mg, 0.659 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (40 min gradient of 0-80% CH3CN in 0.05% aqueous formic acid) yielded the product (15.6 mg, 17%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.O.O.[Cu:7].[Cu+2].[C:9]([OH:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>O>[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cu+2:7]
Reactant: CC(C)(C)C(=O)O
Reactant: [Cu]
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)(C)C(=O)[O-]
Yield: 44.4 %

Procedure:
To a suspension of 13.6 g of CuCO3.Cu(OH)2 in 50 ml of water is added, dropwise at rt, a solution of 18.6 g of pivalic acid in 100 ml of hot water, and the mixture is stirred until the evolution of gas has ceased. The reaction mixture is filtered by suction and the precipitate is washed four times with water. The precipitate is taken up in 300 ml of THF, the insoluble material is filtered off and the filtrate is concentrated under vacuum. 7.2 g of the expected product are obtained after drying under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH:10]=[O:11])[CH:3]=1.S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:10]2[O:11][CH:24]=[N:23][CH:22]=2)[N:5]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(Cl)c(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1cc(-c2cnco2)nc(Cl)c1Cl
Temperature: 50 °C
Yield: 85 %

Procedure:
A mixture of 4,5,6-trichloropyridine-2-carbaldehyde (1.66 g, 8 mmol), tosylmethyl isocyanide (1.54 g, 8 mmol) and potassium carbonate (1.09 g, 8 mmol) in methanol (20 mL) was heated at 50° C. for 30 min and then heated at 80° C. for 5 min. The solvent was removed by rotary evaporation and the residue was suspended in water (200 mL) and stirred vigorously. The precipitate was collected by suction filtration, washed with water and air-dried to provide of 2,3,4-trichloro-6-(5-oxazolyl)pyridine (1.7 g, 6.8 mmol), mp 128-130° C.
Reaction SMILES: O[CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.COCCN(CCOC)S(F)(F)[F:19].C(O)C>>[F:19][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1
Reactant: C=C1CC(C#N)(CO)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: C=C1CC(C#N)(CF)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.252 g, 0.00205 mol) in methylene chloride (20 mL, 0.3 mol) in a plastic bottle was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (1.13 mL, 0.00614 mol) followed by ethanol (20 μL, 0.0004 mol). The reaction was stirred at rt overnight, then quenched with aq. sodium bicarbonate, and extracted with dichloromethane. The extracts were combined and washed with water, brine, and dried over magnesium sulfate, and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:8])([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:10]1[C:11](=O)[CH2:12][CH2:13][C:14]=1[O:15]C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C)C=O>[CH3:2][C:3]([C:4]1[NH:5][C:11]2[CH2:12][CH2:13][C:14](=[O:15])[C:10]=2[N:6]=1)([CH3:8])[CH3:7]
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c([nH]1)CCC2=O
Temperature: 80 °C
Yield: 73.4 %

Procedure:
A mixture of 2,2-dimethylpropanimidamide hydrochloride (0.858 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.53 g) in N,N-dimethylformamide (15 mL) were heated at 80° C. for 20 h. The reaction mixture was cooled down to room temperature and DCM (20 mL) was added. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using Acetonitrile Water with an ammonium carbonate modifier gradient (5-40%). The desired fractions were combined and concentrated under vacuum to yield 685 mg of the title compound. LC/MS MH+ 179, Rt 1.48 min (5 minute run).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]3[O:25]C(C)(C)C(C)(C)[O:18]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.O>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]([OH:25])[OH:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(B(O)O)ccc21
Reaction time: 48 h
Yield: 67.5 %

Procedure:
To N-Boc-indazole-5-boronic acid pinacol ester (S46) (390 mg, 1.13 mmol, 1.00 equiv) in acetone/H2O (5.0 mL/5.0 mL) at 23° C. was added NH4OAc (436 mg, 5.65 mmol, 5.00 equiv) and NaIO4 (1.21 g, 5.65 mmol, 5.00 equiv). After stiffing for 48 hr at 23° C., the reaction mixture was concentrated in vacuo to remove acetone. To the residual solution was added EtOAc (5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×5 mL). The combined organic phases are washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford 200 mg of the title compound as a colorless solid (68% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccc3)c2c1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of (R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (298 mg, 0.83 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (200 mg, 0.83 mmol) and DIPEA (700 μL, 4.2 mmol) in n-butanol (5 mL) was heated at 90° C. in a sealed vial for 48 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a colourless oil (256 mg, 64%). LCMS (Method B): RT 3.26 min [M+H]+ 480.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[C:5]=1[OH:13].Br[CH2:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:7]1[C:6]2[O:12][CH2:16][CH2:17][CH2:18][O:13][C:5]=2[C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCCCO2
Reaction time: 7 h

Procedure:
A mixture of 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled and filtered. The solvent was evaporated. HCl (aqueous solution of 0.5 N, 1000 ml)) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:hexane/ethyl acetate/DCM 70/30/15). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding methyl 3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate 7).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][CH2:15][C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:20].[Ce+4].S([O-])([O-])(=O)=O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Reactant: O=S(=O)([O-])[O-]
Agent: [Ce+4]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2=O
Yield: 29.9 %

Procedure:
To a suspension of 2-Acetylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (140 g) in acetic acid (1.5 L) and water (1.5 L) was added gradually cerium (IV) sulfate 4 hydrate (900 g) with vigorously stirring. After the solution was stirred overnight, the solid was removed by filtration and the filtrate was concentrated. The solution was then neutralized with aqueous ammonia and extracted 3 times with ethyl acetate-tetrahydrofuran (=4:1). The organic layers were combined and evaporated in vacuo. The resulting solid was washed with tetrahydrofuran to provide the title compound (44 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](O)([CH3:16])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[CH:10]([CH3:13])[CH2:9][CH2:8][CH2:7]2)([CH3:16])[CH3:15]
Reactant: COc1cc2c(cc1C(C)(C)O)CCCC2C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)C)CCCC2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a stirred solution of 2-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-2-ol (5.38 g, 22.96 mmol) in methylene chloride (100 mL) at room temperature under nitrogen atmosphere, was added triethyl silane (36.6 mL, 229.6 mmol) followed by trifluoroacetic acid (17.7 mL, 229.6 mmol). The reaction mixture was stirred for five hours at room temperature, then was concentrated under reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous potassium carbonate solution. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with flash chromatography on silica (10:0.1 hexanes/dichloromethane) to give 3.06 g of 6-isopropyl-7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[CH3:28][NH:29][CH3:30]>CN(C)C=O.CCOC(C)=O>[Cl:26][C:22]1[C:21]([CH3:27])=[C:20]([CH2:19][N:5]([C:6]2[N:7]=[C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:9][C:10]=2[C:11]#[N:12])[C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])[CH:25]=[CH:24][CH:23]=1
Reactant: CNC
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN(C)C)c1nc(N2CCOCC2)sc1C#N
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (100 mg, 0.235 mmol) (prepared according to the procedures of example 111) in N,N-Dimethylformamide (DMF) (2 mL) was added dimethyl amine (0.588 mL, 1.176 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The resultant mixture was diluted in EtOAc (100 mL) and washed with H2O (100 ml×2). The organic layer was concentrated to afford the crude product, which was use in next step without further purification. (88%)
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)[CH:4]([C:10]([Cl:13])([CH3:12])[CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15](=O)(O)[O-:16].[Na+]>CO>[Cl:13][C:10]([CH3:12])([CH3:11])[CH:4]([CH:3]([O:16][CH3:15])[O:2][CH3:1])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C(Cl)OC)C(C)(C)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C(OC)OC)C(C)(C)Cl
Reaction time: 3 h

Procedure:
The solution of Step A of Example 1 was added to methanol at a low temperature and the mixture was stirred at 5°-10° C. for 3 hours and was poured into aqueous sodium bicarbonate solution. The mixture was filtered and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with aqueous sodium bicarbonate solution and evaporated to dryness under reduced pressure to obtan 11 g of residue. The latter was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=40°-70° C.)-ethyl acetate mixture to obtain 8.66 g of methyl 4-chloro-4-methyl-3-dimethoxymethyl-pentanoate with a boiling point of 62° C. at 0.05 mm Hg which was identical to the product of Step A of Example 3.