Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3(O)[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH:18]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(C)(C)CC(O)(c2ccccc2N2CCN(CC3CC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C=C(c2ccccc2N2CCN(CC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 91.6 %

Procedure:
A mixture of 1-[2-(4-cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol (250 mg, 0.675 mmol) produced in Example (108b), water (0.12 mL) and trifluoroacetic acid (1.04 mL, 13.5 mmol) was stirred for 21 hours at an external temperature of room temperature. Aqueous solution of potassium carbonate was added to the reaction mixture and then extraction was performed with ethyl acetate. Organic layer was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 218 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(OC([N:21]1[CH:26]([C:27]2[CH:32]=CC=C[CH:28]=2)[CH2:25][C:24]2[NH:33][N:34]=[CH:35][C:23]=2[CH2:22]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH:26]([CH:27]([CH3:32])[CH3:28])[CH2:25][C:24]3[NH:33][N:34]=[CH:35][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1Cc2[nH]ncc2CN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Benzyl 2-isopropyl-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[OH-].[K+].Br[CH2:13][CH2:14][CH3:15]>CS(C)=O.O>[CH2:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:14]=[CH2:13]
Reactant: CCCBr
Reactant: Cc1cccc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1c(C)cccc1C
Reaction time: 0.5 h

Procedure:
2,6-Dimethylphenol (1.22 g) is added to a mixture of powdered potassium hydroxide (2.24 g) in dimethylsulfoxide (20 ml). Then 3-bromopropane (2.42 g) is added at 20°-25° and stirred for 0.5 hr. The mixture is diluted with water (100 ml) and extracted with methylene chloride (3×). The organic extracts are washed with water (2×) and then with saline, dried over sodium sulfate and concentrated under reduced pressure to give 1-allyloxy-2,6-dimethylbenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[N:9]2[CH:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N+:29]([O-])=O)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.O.NN>[Ni].CCO>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([N:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]([CH3:13])([CH3:14])[O:11][C:10]2=[O:15])[CH2:17][CH2:18]1
Reactant: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3N)CC2)[C@H]1c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a flask charged with (S)-4-(4-fluorophenyl)-5,5-dimethyl-3-(4-((3-nitropyridin-4-yl)amino)cyclohexyl)oxazolidin-2-one (0.285 g, 0.665 mmol) was added EtOH (13.30 mL). Raney 3202 nickel (slurry in water) (0.733 mL, 111 mmol) was then added using a pipette. The flask was sealed, placed under nitrogen, and heated at 40° C. To the resulting yellow solution was added hydrazine hydrate solution (0.311 mL, 9.98 mmol) dropwise. The resulting mixture was stirred for 90 minutes at 40° C. LC-MS indicated complete conversion to the desired product. The mixture was cooled to room temperature, filtered through Celite® brand filter aid, and washed with MeOH. The filtrate was dried under reduced pressure and was then purified using a 5 g SCX-2 column washing with MeOH and then with 2 M NH3 in MeOH. The basic wash was dried under reduced pressure providing a brown oil which solidified after overnight under high vacuum to yield (S)-3-(4-((3-aminopyridin-4-yl)amino)cyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.213 g, 0.535 mmol, 80% yield) as a yellow solid. m/z (ESI) 399.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=[O:2].N1C=CC=CC=1>O>[OH:2][NH:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 50 parts of pyridine was stirred at 70° C for 1 hour and then poured into 500 parts of water to precipitate crystals. After cooled to 20°C, the crystals were recovered by filtration, washed with water and dried under reduced pressure to obtain 4.5 parts of 1-hydroxylaminoanthraquinone.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.B([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(O)O>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])[C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Clc1ncc2scc(Br)c2n1
Product: O=C(O)c1cccc(-c2csc3cnc(Cl)nc23)c1
Yield: 65.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzoic acid (380 mg, 65% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (500 mg, 2.0 mmol) and 3-boronobenzoic acid (332 mg, 2.0 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[O:22]1
Reactant: Cc1ccccc1N
Reactant: Cc1cccc(CBr)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1NCc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.09 g (19.5 mmol) of 2-methylaniline, 4.00 g (13.0 mmol) of 2-[2-(bromomethyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1.97 g (14.3 mmol) of K2CO3 in 75 ml of DMF was stirred for 12 h at the 80° C. The resulting mixture was poured into 300 ml of water. The product was extracted with 3×50 ml of ethyl acetate. The combined extract was dried over Na2SO4 and then evaporated to dryness. An excess of 2-methylaniline was distilled off using Kugelrohr apparatus. The residue was re-crystallized from 20 ml of hexane. Yield 2.60 g (59%) of light-yellow powder. Anal. calc. for C21H28BNO2: C, 74.79; H, 8.37; N, 4.15. Found: C, 74.95; H, 8.52; N, 3.95. 1H NMR (CDCl3): δ 7.22 (m, 1H, 3-H in 6-MeC6H3CH2), 7.16 (m, 1H, 3-H in 6-MeC6H3CH2), 7.12 (m, 1H, 5-H in 2-MeC6H4), 7.09 (m, 1H, 5-H in 6-MeC6H3CH2), 7.04 (m, 1H, 3-H in 2-MeC6H4), 6.71 (m, 1H, 6-H in 2-MeC6H4), 6.66 (m, 1H, 4-H in 2-MeC6H4), 4.34 (d, J=25.3 Hz, 1H, CHH′NH), 4.27 (d, J=25.3 Hz, 1H, CHH′NH), 3.85 (br.s, 1H, NH), 2.46 (s, 3H, Me in 6-MeC6H3CH2), 2.11 (s, 3H, Me in 2-MeC6H4), 1.25 (s, 12H, Bpin).
Reaction SMILES: CCN(CC)CC.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[N:9]1([C:18]([C:17]2[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:19])[CH2:12][CH2:11][CH2:10]1
Reactant: C1CNC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Et3N (2.00 mL, 14.3 mmol) and azetidine hydrochloride (462 mg, 4.94 mmol) were added to a solution of 4-bromobenzoyl chloride (1.07 g, 4.88 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 2 hr, diluted with CH2Cl2 (100 mL), and washed with 1N aqueous HCl (100 mL), H2O (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 and concentrated to give a colorless oil (1.10 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (ddd, J=17.43, 6.57, 2.27 Hz, 4 H) 4.21-4.32 (m, 4 H) 2.32-2.40 (m, 2 H); ); LCMS for C10H10BrNO m/z 241.00 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[N:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:19][N:18]=2)[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1
Yield: 95.1 %

Procedure:
Combine methyl-piperidin-4-yl-carbamic acid tert-butyl ester (75 g, 349 mmol), 1-chloro-4-(4-fluoro-phenyl)-phthalazine (75 g, 289 mmol), and potassium carbonate (80 g, 579 mmol) in dimethyl sulfoxide (500 mL) and heat the mixture to 110° C. for 3 h. Cool the reaction to ambient temperature and pour the slurry into water (1.0 L). Collect the solids by filtration and dry in a vacuum oven for 3 days to provide the title compound as a white solid (120 g, 95%). ES/MS m/z 437.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH2:62])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-benzyloxy-phenyl-acetic acid (39 mg, 0.16 mmol) and HATU (61 mg, 0.16 mmol) in DMF (3 mL) is added N-methylmorpholine (64 mg, 0.64 mmol) followed by a solution of ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate C) (64 mg, 0.16 mmol) in DMF (2 mL). The resulting mixture is stirred at RT for 17 h. The solvent is removed in vacuo to afford the title compound which is used in the next step without further purification. [M+H]+ 626.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22](=[O:36])[C@@H:23]3[CH2:27][C@H:26]([OH:28])[CH2:25][N:24]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22](=[O:36])[C@@H:23]3[CH2:27][C@H:26]([O:28][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:25][N:24]3[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ccc2c(c1)CCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)Nc3ccc4c(c3)CCC4)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
4-Dimethylaminopyridine (4.1 g) and p-toluenesulphonyl chloride (4.8 g) were added to a solution of cis-4-hydroxy-N-tert-butoxycarbonyl-L-proline 5-indanylamide (B, 5.8 g) in dichloromethane (85 mL) at 0° C. After stirring at room temperature for 6 hr, additional 4-dimethylaminopyridine (1.0 g) and p-toluenesulphonyl chloride (1.6 g) were added. The resulting solution was stirred at room temperature for 19 hr, and the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound (7.4 g) as a pale brown sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.6 (m, 9H), 2.10 (m, 2H), 2.2 (m, 1H), 2.39 (s, 3H), 2.5 (m, 1H), 2.88 (m, 4H), 3.68 (m, 2H), 4.3-4.4 (m, 1H), 5.17 (m, 1H), 7.15 (m, 2H), 7.31-7.35 (m, 3H), and 7.73 (d, J=7.8 Hz, 2H).
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:36](Cl)(=[O:40])/[CH:37]=[CH:38]/[CH3:39]>C(Cl)Cl>[C:36]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][N:8]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])(=[O:40])/[CH:37]=[CH:38]/[CH3:39]
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: C/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1cc(C)ccc1NC(=O)/C=C/C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
As described for Reference Examples 181 and 182, a mixture of 1.41 g (3.455 mmol) of methyl 3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate, 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to give 1.52 g of methyl 2-{[2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) amino}acrylate as a brown oil; Mass spectrum (ES) 459.4 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][CH:4]=1)#[CH:2].[N:17]([C:20]1[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:27]=1[O:41][CH3:42])=[O:24])=[N+:18]=[N-:19]>>[C:9]([C:6]1[N:7]([CH3:8])[C:3]([C:1]2[N:19]=[N:18][N:17]([C:20]3[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=3[CH3:46])[C:23]([NH:25][C:26]3[CH:31]=[C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:27]=3[O:41][CH3:42])=[O:24])[CH:2]=2)=[CH:4][N:5]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1cnc(C(=O)c2ccccc2)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C2(C)CC2)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(=O)c5ccccc5)n4C)nn3)c2)cc(C2(C)CC2)cc1NS(C)(=O)=O

Procedure:
Example 34 was prepared from (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone (Example 33) and 3-azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide (Example 33) in the same manner as Example 15. ESI MS m/z 640 [C33H33N7O5S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:17][C:16]2=[O:30])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:31](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[N:17]=[C:16]2[O:30][CH3:31])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: O=C([O-])O
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
A mixture of 9.2 g of crude isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-pentafluoroethyl -1(2H) -pyrimidinyl]-4-fluorobenzoate, 3.36 g of sodium bicarbonate and 3.78 g of dimethyl sulphate in 50 ml of anhydrous acetone is heated to reflux temperature for 3 hours. After cooling the solid constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is separated by chromatography on a silica gel column using n-hexane/diethyl ether (2:1). There is obtained isopropyl 2-chloro-4-fluoro-5-[5-fluoro-2-methoxy-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-benzoate, m.p. 75°-77° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:17])[N:13]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCC(CC)c1cc(C)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2cc(C)nc12
Temperature: 100 °C

Procedure:
Heat 850 mg (4.74 mmol) of 4-(1-ethyl-propyl)-6-methyl-pyridazin-3-ylamine and 0.415 ml (5.22 ml) of chloroacetone in 20 ml of ethanol in microwave at 110° C. for 35 minutes. Add 1.2 g (14.2 mmol) of sodium bicarbonate and heat in oil bath with reflux condensor at 100° C. overnight. Evaporate solvents, take up in ethyl acetate and wash 3 X's with brine. Dry over sodium sulfate, filter, and evaporate to a brown oil. Chromatograph using hexanes to 6:1 hex:ethyl acetate to ethyl acetate gradient. Collect title compound as oil weighing 3.69 g (17.0 mmol, 84.4%). 1H-NMR (DMSO-d6): δ 7.34 (s, 1H); 6.84 (s, 1H); 2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712 (t, J=7.49 Hz, 6H) ppm. MS/ES+=219 (100%, M+2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (100 mg, 0.224 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.224 mmol), potassium carbonate (155 mg, 1.121 mmol) and Pd(Ph3P)4 (26 mg, 0.022 mmol) was added Dioxane (1120 μl) and Water (374 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material will be used as is for subsequent reactions. m/z (ESI) 504.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: C#CCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCC#Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g) and 3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine (100 ml) was purged with nitrogen for 20 min under nitrogen. Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous iodide (800 mg) were added. The mixture was stirred for 18 h and then the solvent was removed in-vacuo. The residual oil was triturated with ethyl acetate (200 ml) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on Biotage (90 g) eluting with light petroleum 40-60°-diethyl ether (3:2) to give the title compound (21 g). LCMS RT=3.26 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18]O)[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.C(N(CC)CC)C.[F:36]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:36])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A solution of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.2 g, 5.44 mmol) in dry THF (40 mL) under nitrogen was cooled to 0° C. Triethylamine (4.55 mL, 32.6 mmol), triethylamine tri-hydrogen fluoride (1.77 mL, 10.9 mmol) and nonafluorobutanesulfonyl fluoride (1.95 mL, 10.9 mmol) were then added. The colourless solution was stirred at 0° C. for 10 minutes and then removed from the ice bath. After 120 minutes at RT, the reaction was quenched with saturated aqueous NaHCO3 (25 mL). The THF was removed in vacuo and then the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was treated with DCM (˜20 mL) to give a gelatinous precipitate. This mixture was filtered (washing with DCM). The filtrate was concentrated to ˜3 mL and loaded directly on to the column and purified by chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per mm, gradient 5% to 35% n-hexane in EtOAc) to give the title compound (1.45 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.97 (br. d, J=13.00 Hz, 1 H) 3.10-3.28 (m, 2 H) 4.02 (br. s., 1 H) 4.45-4.61 (m, 3 H) 4.62-4.71 (m, 1 H) 6.98-7.12 (m, 2 H) 7.40-7.51 (m, 2 H) 7.51-7.62 (m, 2 H) 8.03 (br. s., 2 H).