Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]#[C:6][C:7]1[C:12]([NH2:13])=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:9][N:8]=1)[CH3:2].CC(C)([O-])C.[K+].O>CN1CCCC1=O.O1CCCC1>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[NH:13][C:12]2[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)[CH3:23]
Reactant: CCOC(C#Cc1ncnc(Oc2ccccc2)c1N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(OCC)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
4-(3,3-Diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine (2.30 g) was dissolved in 1-methyl-2-pyrrolidone (7.5 mL), and the mixture was cooled to 0° C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 M tetrahydrofuran was added dropwise to this solution, and the mixture was stirred at 0° C. for 30 min. and at room temperature for 1.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→50:50) to give the title compound (1.34 g) as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13])=[CH:3][Cl:4].O.[NH3:17]>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:3][Cl:4]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(Cl)=CCl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 6 h

Procedure:
A solution of 17.5 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-chloride in 150 ml of methylenechloride is added slowly to a mixture of 30 ml of methylene chloride, 50 ml of water and 50 ml of 30% aqueous ammonia. The reaction mixture is stirred for 6 hours at a temperature of 20°-25° C. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of 40 ml. The crystallised 2-(1,2-dichlorovinyloxy)phenylsulfonamide is separated and dried. Yield: 12.5 g, m.p. 147°-149° C.
Reaction SMILES: [Mg].[CH2:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH2:3][CH3:4].[C:12](=[S:14])=[S:13].Cl>C1COCC1>[CH2:2]([C:5]1[CH:10]=[CH:9][C:8]([C:12]([SH:14])=[S:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: S=C=S
Reactant: CCCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(C(=S)S)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a 1000 ml three neck flask provided with a stirrer, thermometer, dropping funnel, and nitrogen gas introducing tube were added 9.4 g (386.8 mmol) of magnesium turnings and 20 ml of THF under nitrogen gas atmosphere, and 200 ml solution of 70.0 g (351.6 mmol) of 4-propylbromobenzene in THF was added dropwise while being stirred in 1 hour while the reaction temperature being adjusted at 45 to 55° C. After finishing of the dropping, it was stirred at 55° C. for 2 hours. The reaction mixture thus obtained was cooled down to a temperature lower than 10° C., 133.8 g (1.75 mol) of carbon disulfide was added dropwise thereto in 50 minutes. After finishing of the dropping, it was further stirred at room temperature for 14 hours. The reaction mixture was cooled down to a temperature lower than 5° C., and then 100 ml of 6N hydrochloric acid was added dropwise thereto to terminate the reaction. It was extracted with 300 ml of diethyl ether, and the extract was washed with water (200 ml) thrice, dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 64.2 g of purplish red oily 4-propyldithiobenzoic acid. 1H-NMR (δ ppm): 0.95 (3H, t, J=7.4 Hz), 1.65 (2H, m), 2.63 (2H, t, J=7.8 Hz), 6.0-6.5 (1H, bs), 7.18 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=8.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[C:35][C:36]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][CH:37]=1>CN(C=O)C.[NH4+].[Cl-].CCOC(C)=O>[I:42][C:39]1[CH:40]=[CH:41][C:36]([C:35]#[C:34][CH2:33][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:8]2)=[CH:37][CH:38]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Reactant: BrCC#Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(I)cc3)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a stirred suspension of (6-methoxy-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methanone (0.69 g, 0.5 mmol) and K2CO3 in anhydrous DMF (2 ml) was added the solution of 1-(3-bromoprop-1-ynyl)-4-iodobenzene (0.150 g, 0.47 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at 50° C. for 2 h, diluted with saturated solution of NH4Cl (5 ml) and diluted to 30 ml with EtOAc. The organic layer was washed with H2O and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2), to give the desired product (0.079 g; 32%), as light yellow paste. 1H-NMR (CDCl3) 3.84 (s, 6H); 3.89 (s, 3H); 3.91 (s, 3H); 5.06 (s, 2H); 6.94 (d, 1H, J=2.06 Hz); 7.00 (dd, 1H, J=2.22, 7.1 (s, 2H); 8.75 Hz); 7.1 (d, 2H, J=8.27 Hz); 7.65 (d, 2H, J=8.42 Hz); 7.72 (s, 1H); 8.25 (d, 1H, J=8.78 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.[CH3:13][C:14]1([CH3:29])[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17][CH2:16][CH:15]1[C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:17][CH2:16][CH:15]([C:25]([O:27][CH3:28])=[O:26])[C:14]([CH3:29])([CH3:13])[CH2:19]2)[CH:12]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCC(n2cc(Br)cn2)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (2.93 g, 9 mmol) and 4-bromopyrazole (482 mg, 3.3 mmol) were added to a solution of methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.79 g, 3 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate. MS ESI calc'd. for C13H20BrN2O2 [M+H]+ 315 and 317. found 315 and 317. 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 7.22 (s, 1H), 4.53-4.50 (m, 1H), 3.69 (s, 3H), 2.26-2.18 (m, 1H), 2.06-1.78 (m, 4H), 1.36-1.28 (m, 2H), 1.06 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:5])[CH3:2].[IH:30].CO>C(OCC)C>[IH:30].[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)Cn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.405 g, 1.00 mmol), aqueous hydriodic acid (0.29 mL, 57%), and methanol (15 mL). Heat to reflux. After 2 hour, cool to ambient temperature and add diethyl ether (100 mL) and stir to give a solid. After 1 hour, collect the solid by filtration, dissolve in methanol and add diethyl ether (100 mL) to give a solid. Collect the solid by filtration and dry in vacuo to give the title compound.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4].CCN(C(C)C)C(C)C.[CH:29]1[CH:34]=[C:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]([Cl:40])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:37]([O:36][CH2:35][C:33]3[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:40])=[O:38])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc(Cn2cc(N)cn2)cs1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(4-amino-pyrazol-1-ylmethyl)-thiazole-2-carboxylic acid ethyl ester (1.43 g, 5.65 mmol) in CH2Cl2 (56.0 mL) was treated with DIPEA (1.15 mL, 8.47 mmol) followed by 2-chlorobenzylchloroformate (1.04 mL, 6.78 mmol). The reaction mixture was stirred at rt for 1 h before being quenched with water (50 mL), extracted with CH2Cl2 (3×40 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (96:4 CH2Cl2-MeOH) gave the title compound as a pink foam. TLC: rf (96:4 CH2Cl2-MeOH)=0.28. LC-MS-conditions 02: tR=0.99 min; [M+H]+=421.14.
Reaction SMILES: CC(C)(O[N:5]([C@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:16]=[C:15]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH2:35][C:36]#[CH:37])[C:31]([Br:38])=[CH:30][N:29]=2)[CH:14]=1)=[O:11])C(=O)[O-])C.S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:5][C@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:16]=[C:15]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH2:35][C:36]#[CH:37])[C:31]([Br:38])=[CH:30][N:29]=2)[CH:14]=1)=[O:11]
Reactant: C#CCOc1nc(Nc2cc(NC(=O)[C@@H](Cc3ccccc3)N(OC(C)(C)C)C(=O)[O-])cc(NC(=O)N3CCCC3)c2)ncc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: C#CCOc1nc(Nc2cc(NC(=O)[C@H](N)Cc3ccccc3)cc(NC(=O)N3CCCC3)c2)ncc1Br
Yield: 86.8 %

Procedure:
1,1-Dimethylethoxy[(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl]amino]-2-oxo-1(phenylmethyl)ethyl]carbamate (105 mg) and sulfuric acid (0.5 ml; 2 n) were stirred in dioxane (5 ml) at 85° C. for 3.5 h. After cooling and dilution with water saturated NaHCO3-solution was added and the resulting precipitate collected by filtration yielding the title compound (76 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A mixture of 0.722 g 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine, 3.5 mL triethylamine, 0.025 g copper iodide, 0.037 g dichlorobis(triphenyl)phosphine palladium II and 0.289 g 1-chloro-4-ethynylbenzene was stirred under nitrogen at room temperature for 18 hours. The dark brown mixture was evaporated in vacuo at a bath temperature of 30–35° C. The beige residue was partitioned between dichloromethane and water. The organic phase was washed twice with water, dried over sodium sulfate, filtered and evaporated to yield 1.0 g of a caramel colored film. The residue was dissolved in 1:1 dichloromethane/hexanes and purified by column chromatography on silica gel, eluting successively with 1:1 dichloromethane/hexanes, dichloromethane and ethyl acetate. The product was recovered from the latter two eluates by evaporation to yield 0.7 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneaminopyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[CH:7]=1)#[N:2].[NH2:27][OH:28].Cl.CCN(CC)CC>CCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[C:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:6]4[CH:7]=[C:3]([C:1]([NH2:2])=[N:27][OH:28])[CH:4]=[N:5]4)[C:12]=3[CH:19]=[N:18]2)=[CH:25][CH:24]=1
Reactant: NO
Reactant: N#Cc1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
A mixture of 2-(4-cyanopyrazol-1-yl)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.175 g, 0.50 mmol), NH2OH—HCl (0.500 g, 7.2 mmol) and NEt3 (1.00 mL, 7.1 mmol) in EtOH (3 mL) was heated at 90° C. for 5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to obtain 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 60%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[Br:17].[OH-].[Li+].Cl>CO.O>[Br:17][C:6]1[CH:7]=[C:8]([O:15][CH3:16])[C:9]([O:11][CH:12]([F:14])[F:13])=[CH:10][C:5]=1[CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)Cc1cc(OC(F)F)c(OC)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(Br)c(CC(=O)O)cc1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid methyl ester (400 mg) was dissolved in 5 ml methanol and treated with 150 mg lithium hydroxide in 1 ml of water. The mixture was stirred at room temperature for 18 hours, acidified with 10% aqueous hydrochloric acid, filtered and dried to yield 350 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[CH2:8][O:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[N:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3)=O.[Cl-].[Li+].C(OCC)(=O)C>CO.[Pd]>[CH3:22][O:21][C:16]1[N:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]1[O:9][CH2:8][CH:7]([CH2:5][OH:4])[CH2:20][C:19]2=1
Reactant: COC(=O)C1=Cc2c(cnc3ccc(OC)nc23)OC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)CC(CO)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
Sodium borohydride (417 mg, 11.03 mmol, 5.0 eq) is added at 0° C. to a stirred suspension of 6-methoxy-2H-1-oxa-5,9-diaza-phenanthrene-3-carboxylic acid methyl ester (600 mg, 2.20 mmol, 1.0 eq) in methanol (60 mL), followed by lithium chloride (467 mg, 11.03 mmol, 5.0 eq). After 3 hours stirring at room temperature, solvent is removed and the residue is dissolved in methanol (60 mL) and treated with 10% palladium on activated carbon (100 mg, 0.09 mmol, 0.05 eq). The resulting mixture is stirred under hydrogen flow (3 bars) at room temperature for 3 hours. The catalyst is then removed by filtration and the solution is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 4:1 to 3:1, v/v) to afford (6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthren-3-yl)-methanol as a white solid (400 mg, 74% yield).
Reaction SMILES: [CH2:1]([Mg]Cl)CC.C(OC(N[C@@H](CC1C=CC=CC=1)[C@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C.[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)[C@@H:43](OS(C)(=O)=O)/[CH:44]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(OCC)(=O)C>CCCCCC>[C:34]([O:38][C:39]([NH:41][C@H:42](/[CH:43]=[CH:44]/[C@@H:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH3:1])[CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCC[Mg]Cl
Reactant: CCOC(=O)/C=C/[C@H](OS(C)(=O)=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@@H](C)/C=C/[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 6 %

Procedure:
Using the procedure of Example 8 but replacing benzylmagnesium chloride with n-propylmagnesium chloride and replacing the resultant compound of Example 7 with the resultant compound of Example 27 provided, after silica gel chromatography using 15% ethyl acetate in hexane, the desired compound (Rf 0.35, 4:1 hexane:ethyl acetate) in 6% yield. 1H NMR (CDCl3) δ 0.8-1.0 (m, 2 H), 0.90 (t, J=7 Hz, 3 H), 1.1-1.8 (br envelope, 15 H), 1.43 (s, 9 H), 2.97 (q, J=8 Hz, 1 H), 4.12 (q, J=7 Hz, 2 H), 4.33 (m, H), 5.43 (br d, 1 H), 5.56 (dd, J=16, 9 Hz, 1 H). 13C NMR (CDCl3, ppm) 13.77, 14.22, 20.24, 26.25, 26.30, 26.53, 28.38 (3 C), 33.16, 34.19, 34.65, 43.31, 48.72, 49.46, 49.50, 60.43, 127.89, 133.83, 174.33 . Mass spectrum: (M+H)+ =382.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[S:8]2)=[O:4].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:25](=[O:26])[C:24]1[CH:23]=[C:22]([O:21][CH3:20])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=1)[S:8]2)=[O:4]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cn2cc(-c3ccccc3N)sc2n1
Solvent: c1ccncc1
Product: COC(=O)c1cn2cc(-c3ccccc3NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2n1
Temperature: 25 °C
Yield: 243.2 %

Procedure:
2-(2-Amino-phenyl)-imidazo[2,1-b]thiazole-6-carboxylic acid methyl ester (27 mg, 0.095 mmol) was mixed with 1 mL of pyridine along with 22 mg of 3,4,5-trimethoxybenzoyl chloride. The reaction mixture was reacted in a microwave reactor at 160° C. for 10 minutes. It was then cooled to room temperature and concentrated. The resulting crude product was purified by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA to afford 108 mg of 2-[2-(3,4,5-trimethoxybenzoylamino)-phenyl]-imidazo[2,1-b]thiazole-6-carboxylic acid methyl ester (MS, M++H=468).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][N:18]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: FC(F)Oc1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(OC(F)F)cc2)C1
Yield: 63.3 %

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.088 g, 0.30 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979) (0.115 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.079 mL, 0.45 mmol) to obtain 0.085 g of title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([F:28])=[C:30]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 35.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.048 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.06 (s, 2H), 7.24 (s, 1H), 7.51 (t, J=9.6 Hz, 1H), 7.84 (m, 1H), 8.30 (d, J=4.2 Hz, 1H), 8.45 (s, 2H), 9.84 (s, 1H), 11.99 (br s, 1H), 11.53 (br s, 1H); MS [M+H]+: 554.54.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@H:11]([C:20]([O:22]C)=[O:21])[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@H:11]([C:20]([OH:22])=[O:21])[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(I)cc2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a solution of 1.3 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-iodophenyl)-5-oxazolidinecarboxylate in 25 cm3 of ethanol is added, at a temperature in the region of 25° C., a solution of 0.35 g of lithium hydroxide hydrate in 8 cm3 of distilled water. The reaction medium is stirred for 30 minutes at a temperature in the region of 25° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The evaporation residue is dissolved in 20 cm3 of distilled water and the solution obtained is washed with twice 15 cm3 of diethyl ether, acidified to a pH in the region of 2 by addition of aqueous 1N hydrochloric acid solution and extracted with twice 40 cm3 of ethyl acetate. The organic phases are combined, washed with twice 10 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.3 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-iodophenyl)-5-oxazolidinecarboxylic acid are thus obtained in the form of a yellow oil.