Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OC2C=CC(C[O:7][C:8](=O)[C@H:9]([N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]4[O:39][CH2:40][O:41][C:35]=4[CH:34]=3)[S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=CC=2O1.[CH2:47]([O:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(OCC)(=O)C.[Pd].C(O)C.O1CCCC1>[CH2:47]([O:54][NH:55][C:8](=[O:7])[C@H:9]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31])(=[O:20])=[O:21])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Reactant: NOCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (3.26 g, 4.57 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd—C (2 g) and the resulting reaction mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon, the slurry was filtered over Celite, and the Celite pad was washed with ample 80% ethanol-methylene chloride. The filtrate was concentrated and azeotroped with tetrahydrofuran (200 mL) and the residue was dissolved in dimethylformamide (25 mL). O-Benzyl hydroxylamine (1.78 g,14.5 mmol), HOBT (0.71 g, 5.2 mmol), and EDAC (2.75 g) were added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and was washed with 2.4 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The mixture was then dried over magnesium sulfate and concentrated in vacuo to afford crude N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)-propionamide (2.8 g,) which was taken directly into the next reaction without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CNC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](N)[C@H](CNC(=O)OC(C)(C)C)C1

Procedure:
A sample of the product from Step 5 was dissolved in MeOH (100 ml). Palladium on carbon (0.185 g, 1.743 mmol) was added to the solution and the reaction mixture was stirred under 50 psi hydrogen for 2 h. The reaction mixture was filtered through Celite with EtOAc. The resulting solution was concentrated in vacuo to yield tert-butyl ((1S,2S,5R)-2-amino-5-methoxycyclohexyl)methylcarbamate as a clear oil which was used without any further purification. A quantitative yield was assumed. LC/MS found [M+H]+=259.41.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (31%). MS (ESI): m/z=560.08 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][C:15]([C:14]1[CH:19]=[CH:20][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)COc2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure given in Example 13a 2,4-dichlorophenol was interacted with an equimolar quantity of 4-methylphenacyl chloride in the presence of potassium carbonate to give w-(2,4-dichlorophenoxy)-p-methylacetophenone. Recrystallized from 2-ethoxyethanol, this product melted at 96.5°-98.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:13]#[N:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Product: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Temperature: 165 °C

Procedure:
A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile and 9 g (43.2 mmol) of phosphorous pentachloride was heated at 165° C. for 2 hours. The mixture was diluted with hexanes and the solid was collected. The solid was dissolved in 700 ml ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel giving 5.2 g of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile as a tan solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[C:28]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)[CH:23]=[CH:24][C:25]=1[O:31][CH3:32]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(Br)cc1OC
Agent: Cl
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1OC
Yield: 31.9 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-1,2-dimethoxybenzene (326 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 131 mg (yield 32%).
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(OCC)(=O)C>[CH3:1][C:2]1([C:5]2[O:6][C:9](=[O:10])[NH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C(=O)NN)CC1
Solvent: CCOC(C)=O
Product: CC1(c2n[nH]c(=O)o2)CC1
Yield: 103.8 %

Procedure:
A solution containing 54.0 g (0.385 mol) of 1-methylcyclopropanecarboxylic acid hydrazide (m.p. 72°-74°) and 90 g (0.9 mol) of phosgene in 1000 ml of ethyl acetate was refluxed for 2 hours. The reaction mixture was concentrated on a rotary evaporator. The residual solid crystallized from ether-hexane (1:5) to give 56.0 g (85%) of product as a white crystalline solid; m.p. 77°-78°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:19]1([NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:44])=[C:29]([NH:31][C:32]([C:34]3[CH:35]=[N:36][C:37](S(C)(=O)=O)=[N:38][CH:39]=3)=[O:33])[CH:30]=2)=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:44])=[C:29]([NH:31][C:32]([C:34]3[CH:35]=[N:36][C:37]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:38][CH:39]=3)=[O:33])[CH:30]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2ccccn2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a solution of 2-pyridinylmethanol (258 μl, 2.67 mmol) in THF (50 mL) cooled in ice bath to 0° C. was added dropwise lithium hexamethyldisilazide (1M solution in THF, 2.67 mL, 2.67 mmol) and the resulting mixture stirred for 30 minutes at 0° C. N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (1 g, 2.67 mmol) was added and the resulting mixture stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and DCM. Concentration of the organic phase under reduced pressure and crystallisation from acetonitrile gave the title compound as a colourless solid (132 mg, 12%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 5.61 (s, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.66 (m, 1H), 7.85 (m, 2H), 8.38 (m, 1H), 8.58 (m, 1H), 9.16 (s, 2H), 10.16 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]=[C:6](C(O)=O)[CH:5]=1.CCN(CC)CC.[CH:32]([O:35]C(Cl)=O)(C)C.[BH4-].[Na+]>C1COCC1.CN1CCCC1=O.C(OCC)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:5]=[CH:6][CH2:10][C:11]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])([CH2:32][OH:35])[CH:12]=1
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1=CC(CO)(NC(=O)OCc2ccccc2)CC=C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Benzyloxycarbonylamino-isophthalic acid monomethyl ester (10 g, 30.1 mmol, 1 eq) and Et3N (5 ml, 36.1 mmol, 1.2 eq) are suspended in a mixture of THF (200 ml) and N-methylpyrrolidone (200 ml). Isopropylchloroformate (42 ml, 1 N in toluene, 42 mmol, 1.4 eq) is added, and the reaction mixture is stirred for 30 min at 0° C. and then diluted with diethyl ether and water. The organic layer is washed with 0.1 N HCl and brine. NaBH4 (3.82 g, 101 mmol, 3.36 eq) is dissolved in H2O (100 ml), and the solution is added to the reaction mixture, which is then stirred for 1 h. Diethyl ether and H2O are added, and the organic layer is separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography using EtOAc/hexane in a ratio of 1 to 2 to give the product.
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCOCC[O:3][CH2:2]1.FC(F)(F)COP(CC(OC)=O)(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:56]1[C:61]([CH:62]=O)=[C:60]([O:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:59]=[C:58]([S:71][CH3:72])[N:57]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOCC>[Cl:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[N:55]1[C:56]2[N:57]=[C:58]([S:71][CH3:72])[N:59]=[C:60]([O:64][C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[C:61]=2[CH:62]=[CH:1][C:2]1=[O:3]
Reactant: CSc1nc(Nc2ccccc2Cl)c(C=O)c(Oc2ccccc2)n1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1nc(Oc2ccccc2)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (81 μL, 0.38 mmol, 1.2 eq) in anhyd THF (20 mL) was cooled to −78°. To this solution was added potassium bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene. This solution was stirred for additional 30 min at −78° and 4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbaldehyde (119 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was then stirred for 8 h at −78° and warmed to 23° and stirred 16 h. Saturated aq NH4Cl (5 mL), followed by Et2O (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to give 100 mg (91% yield) of pure 8-(2-chloro-phenyl)-2-methylsulfanyl-4-phenoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 1.89 (s, 3H), 6.55 (d, 1H, J=9.9 Hz), 7.18 (m, 4H), 7.28 (m, 4H), 7.44 (m, 1H), 7.98 (d, 1H, J=9.9 Hz). LC MS (m/e)=396 (MH+). Rt=2.68 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:41]([O:43][CH3:44])=[O:42].CN1CCOCC1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl.O>[C:31]([O:30][C:28]([NH:27][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16](=[O:17])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:41]([O:43][CH3:44])=[O:42])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](CCCCN)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](CCCCNC(=O)[C@@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A stirred solution of acid 8 (1.95 g, 4.00 mmol) and amine 14 (1.04 g, 4.00 mmol) in CH2Cl2 (60 mL) was charged with NMM (2.64 mL, 24.0 mmol) and EEDQ (1.97 g, 8.00 mmol). The resulting mixture was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture and extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography (silica gel, 20% to 40% EtOAc in hexanes) to afford amide 15 (2.15 g, 73% over two steps) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.10-4.02 (m, 1H), 4.01-3.92 (m, 1H), 3.70 (s, 3H), 3.35 (t, J=6.8 Hz, 2H), 3.24-3.10 (m, 2H), 1.83-1.67 (m, 2H), 1.66-1.55 (m, 4H), 1.52 (s, 9H), 1.46 (s, 9H), 1.45-1.35 (m, 6H), 1.438 (s, 9H), 1.431 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C@:13]12[CH2:22][O:21][C@@H:20]([CH2:23]O)[CH2:19][C@H:18]1[CH2:17][S:16][C:15]([NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:14]2>C1(C)C=CC=CC=1>[Cl:3][CH2:23][C@@H:20]1[O:21][CH2:22][C@:13]2([C:7]3[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=3[F:5])[N:14]=[C:15]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:16][CH2:17][C@@H:18]2[CH2:19]1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CCl)C[C@H]2CS1)c1ccccc1
Temperature: 80 °C

Procedure:
Thionyl chloride (10.4 mL, 143 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (2.0 g, 4.8 mmol) in toluene (68 mL), and the reaction mixture was heated at 80° C. for 18 hours. After cooling to room temperature, it was concentrated in vacuo and azeotroped three times with dichloromethane. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Two purifications using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as an off-white solid. Yield: 1.88 g, 4.30 mmol, 90%. LCMS m/z 437.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.08-8.12 (m, 2H), 7.59-7.65 (m, 1H), 7.46-7.55 (m, 3H), 7.05-7.17 (m, 2H), 4.18 (dd, J=12.2, 1.3 Hz, 1H), 4.01 (d, J=12.3 Hz, 1H), 3.91-3.98 (m, 1H), 3.61-3.69 (m, 2H), 3.26-3.3 (m, 1H, assumed; partially obscured by solvent peak), 3.07 (br dd, J=13.3, 3.7 Hz, 1H), 2.91 (br dd, J=13.3, 2.5 Hz, 1H), 1.86-1.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[N+:11]([O-])([OH:13])=[O:12]>ClCCl.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: O=[N+]([O-])O
Reactant: N#CCc1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#CCc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-phenyl-acetonitrile (15.0 g, 99.0 mmol) in the dichloromethane (50 mL) and H2SO4 (40 mL) is slowly added a mixture of H2SO4 (14 mL) and HNO3 (5.5 mL) at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, warmed to room temperature for 30 minutes and then concentrated to remove organic solvent. The solution is poured into a beaker containing ice-water (400 mL) to give a crystalline precipitate, which is collected by vacuum filtration and washed with water to give the title intermediate (13.4 g, 69.0%).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].I[C:19]1[CH:24]=[CH:23][C:22]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)=[CH:21][CH:20]=1.[NH4+].[Cl-]>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].II.C1COCC1>[Si:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:19]1[CH:24]=[CH:23][C:22]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(I)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: II
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CCCCCCO[Si](C)(C)C(C)(C)C)cc2)OC1(C)C
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 72.7 %

Procedure:
To a suspension of zinc powder (5.0 g, 76.46 mmol) in anhydrous DMA (30 ml) is added iodine (0.5 g, 2 mmol). This mixture is stirred until the red color of I2 disappeared (ca. 2 min), followed by the addition of (6-bromohexyloxy)-tert-butyl-dimethylsilane (15.0 g, 50.79 mmol) and the mixture is stirred at 85° C. for 4.5 h, then cooled to room temperature and excess zinc allowed to settle. In another flask charged with anhydrous THF (30 ml) is added 2-(4-iodophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (15.0 g, 45.46 mmol) and Pd(dppf)Cl2 (0.85 g, 0.10 mmol). This mixture is stirred for 10 min, then the solution of organozinc reagent is transferred by cannula into the flask. The reaction mixture is stirred overnight (˜16 h) at room temperature. Sat. aq. NH4Cl solution is added and the mixture is extracted with ethyl acetate (3×70 ml). The extracts are dried (Na2SO4) and evaporated under reduced pressure. The residue is purified by column chromatography, eluting with petrol/ethyl acetate (10:0 to 4:1), to give a brown oil (13.83 g, 73%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.70 (d, J=7.9 Hz, 2H, Ar—H), 7.14 (d, J=7.9 Hz, 2H, Ar—H), 3.54 (t, J=6.6 Hz, 2H, OCH2), 2.56 (t, J=7.3 Hz, 2H, ArCH2), 1.27-1.65 (m, 20H, CH2 and CH3), 0.85 (s, 9H, CH3), 0.05 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ(ppm) 146.3 (quat.), 134.9 (CH), 127.9 (CH), 83.6 (2×quat.), 63.3 (CH2), 36.2 (CH2), 32.9 (CH2), 31.4 (CH2), 29.1 (CH2), 26.1 (3×CH3), 25.8 (CH2), 24.9 (4×CH3), 18.4 (quat.), −5.2 (2×CH3).
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[Br:16]Br>C(O)(=O)C>[Br:16][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][C:7](=[O:15])[O:6][C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
To a solution of glacial acetic acid (1500 ml) was added sodium acetate (222 g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was cooled to 15° C. bromine (118 ml, 2.29 mole) added dropwise over 1 h and the mixture stirred for 12 h at ambient temperature. The solids were then filtered, washed with H2O (3×500 ml) and dried under vacuum to give the title compound as a white solid (374 g, 89.7%): mp 186.0-187.0° C.: 1H NMR (DMSO-d6) δ 11.8 (s, 1 H), 7.6 (s, 1 H), 7.3 (d, J=8.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](OC(C3C=CC=CC=3)C)=[N:8][C:7]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[N:6][C:5]=2[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:9]1[C:10]2[C:2]([Cl:1])=[CH:3][NH:4][C:5]=2[N:6]=[C:7]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[N:8]=1
Reactant: CC(Oc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Temperature: 70 °C
Yield: 22 %

Procedure:
5-chloro-N-(1-methyl-1H-pyrazol-4-yl)-4-(1-phenylethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (1.65 g, 4.47 mmol) was suspended in POCl3 (9 mL) and the reaction was heated to 70° C. for 40 min, then further heated to 100° C. for 0.5 hr. The reaction mixture was cooled, concentrated in vacuo and diluted with water (50 mL). NH4OH was added to adjusted the pH 8 and the mixture was extracted with EtOAc (three×75 mL), and concentrated under reduced pressure. A precipitate was formed upon concentrating that was filtered off, and the filtrate was concentrated and the resulting residue was purified by flash chromatography eluting with a gradient of 30% 100% EtOAc in heptanes to afford the title compound (282 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br. s., 1H) 9.58 (br. s., 1H) 7.87 (s, 1H) 7.52 (s, 1H) 7.37 (s, 1H) 3.81 (s, 3H). m/z (APCI+) for C10H8Cl2N6 283.15 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCOc1ccccc1
Product: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1

Procedure:
2,6-Dichloroquinoline (1.0 g, 5.1 mmol) and 2-phenoxyethylamine (1.5 g, 11 mmol) were microwaved at 120° C. for 1 h. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->70:30 gradient). (6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine was obtained as a light yellow solid (1.1 g, 73%), MS: m/e=299.3 (M+H+).