Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:54].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>C(#N)C.O.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]>[CH3:24][N:25]1[C:26](=[O:54])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: O=Cc1c(Br)cncc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)nc2)CC1
Temperature: 100 °C
Yield: 43 %

Procedure:
A sealed tube was charged with 3-bromo-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)isonicotinaldehyde 101f (200 mg, 0.53 mmol), 1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one 102a (225 mg, 0.53 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (210 mg, 1 mmol), and NaOAc (85 mg, 1 mmol) in acetonitrile/H2O (8 mL/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column eluting with 20:1 DCM/MeOH to afford 102b (135 mg, 43%). LCMS: [M+H]+ 593.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:20]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cc(Oc2cncnc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Cl)cc(Oc2cncnc2)c1
Temperature: 75 °C
Yield: 84 %

Procedure:
3-Chloro-5-(pyrimidin-5-yloxy)benzoic acid (464 mg, 1.85 mmol, 1 eq) was dissolved in methanol (9.3 mL) in a microwave vial and H2SO4 (0.93 mL) was added dropwise. The vial was capped and heated at 75° C. for 3 h. The reaction was cooled to rt and neutralized with 1N NaOH. The reaction was extracted with EtOAc (2×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 414 mg (84%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.74 (s, 2H), 7.75 (t, J=1.7 Hz, 1H), 7.65 (t, J=2.2 Hz, 1H), 7.54 (dd, J=1.4, 1.0 Hz, 1H), 3.84 (s, 3H); [M+1]+: 265.1.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:11]=23)[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].[OH-].[Na+]>CN(C)C(=O)C.O.C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:10]3[C:11]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=4[N:13]=[CH:14][C:15]=3[C:16](=[O:17])[NH:18][C:39]2=[O:40])[CH2:5][CH2:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N[C@H]3CC[C@H](CO)CC3)c(C(N)=O)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n([C@H]3CC[C@H](CO)CC3)c12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
4-{[trans-4-(Hydroxymethyl)cyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (270 mg, 0.645 mmol) in N,N-dimethylacetamide (3 mL) was mixed with N,N-diisopropylethylamine (3 mL) and 1,1′-carbonyldiimidazole (1.04 g, 6.45 mmol) and stirred at 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and stirred with 1M aqueous sodium hydroxide (3 mL) and acetonitrile (3 mL) for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=9/1 (v/v)) to give the title compound as a colorless solid (206 mg, yield 73%).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]1([NH:16][C:17]2[N:22]=[C:21]([C:23]3[N:27]4[CH:28]=[CH:29][N:30]=[C:31]([CH3:32])[C:26]4=[N:25][C:24]=3[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:20]1[C:21]([C:23]2[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([CH3:32])[C:26]3=[N:25][C:24]=2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:22][C:17]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[N:18][CH:19]=1
Reactant: Cc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nccn2c(-c3nc(NC4CC4)ncc3Cl)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Trichloroisocyanuric acid (0.001 g, 0.04 mmol) was added portion-wise to a refluxing mixture of cyclopropyl-4-[2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamine (Example #A.2.1, 0.050 g, 0.14 mmol) in CHCl3 (2.5 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature, diluted with DCM and washed with a saturated aqueous solution of Na2CO3. The organic phase was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel chromatography using a gradient of heptane/EtOAc (50:50 to 0:100) to afford 0.015 g (27%) of the title compound. LC/MS (Table 1, Method g) Rt=2.71 min; MS m/z: 393.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:16][OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[Cl:19][CH2:20][CH2:21][NH2:22].[OH-].[K+]>CN(C)C=O>[ClH:19].[NH2:22][CH2:21][CH2:20][O:17][N:16]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:11][O:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCOCC(=NO)c1ccc([N+](=O)[O-])cc1
Reactant: NCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCOCC(=NOCCN)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C

Procedure:
10 Mmol of 4'-nitro-2-propoxyacetophenone oxime, 10.4 mmol of 2-chloroethyl amine hydrochloride and 1.4 g of powdered potassium hydroxide were added to 25 ml of dimethyl formamide while stirring at 10° C. After stirring for two days at room temperature the dimethyl formamide was evaporated in vacuo, the residue was brought in water and then 2 N hydrochloric acid was added until pH 3. The remaining oxime was removed by means of ether, after which 30 ml of 2 N sodium hydroxide solution were added. Then three extractions with ether were carried out. The collected ether layers were washed twice with a 5% sodium bicarbonate solution and then dried on sodium sulphate. After removing the ether in vacuo the residue was dissolved in absolute ethanol and converted into the little compound by means of alcoholic hydrochloric acid. After recrystallization from alcohol/ether the melting point was 128°-130° C.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:5]([O:7]C)=[O:6])=[N+:2]=[N-:3].[OH-].[Li+]>C1COCC1>[N:1]([CH:4]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(N=[N+]=[N-])c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(C(=O)O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in THF/H20 (2.6:1) cooled to 0° C. was added 1.7 eq. of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory funnel. The mixture was extracted into water and washed with ether. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:19](=[O:25])[CH:18]([CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:17]2.C([O-])(=O)C.[Na+].C(=O)C1C=CC=CC=1>[Pd].CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:17][CH:18]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:11][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:29][CH2:28]3)[C:19](=[O:25])[C:20]2=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 10 h
Yield: 370.4 %

Procedure:
0.22 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt, and 0.10 g of sodium acetate were added to 60 mL of anhydrous methanol. 100 milligrams of 10% Pd/C were also added. The reaction mixture was stirred at room temperature with H2 being supplied at 1 atmosphere for 10 hours. 55 milligrams of benzaldehyde were added in equal portions at 0 hrs, 2 hrs, 4 hrs, 6 hrs and 8 hrs. Solids were filtered off. The filtrate was concentrated. 30 mL of 5% aqueous Na2CO3 solution were added, and the resulting mixture was extracted with 3×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of aqueous Na2CO3 solution and 15 mL of aqueous NaCl solution, and dried over anhydrous MgSO4. After solids were filtered off, solvent was removed in vacuo to afford 0.67 g of product as oil. Purification on silica gel column chromatography afforded 0.11 g of title compound in 62% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([NH2:30])[CH3:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:30][CH:28]([CH3:29])[CH3:27])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), propan-2-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 211 (34), 139 (4), 98 (5), 70 (7), 58 (bp).
Reaction SMILES: [Na].[O:2]=[C:3]1[O:9][C@H:8]([C@H:10]([CH2:12][OH:13])[OH:11])[C:6]([OH:7])=[C:4]1[OH:5].Br[C:15]1[CH:16]=[C:17]([C@:21]23[CH2:29][O:28][CH2:27][C@H:26]2[CH2:25][S:24][C:23]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:22]3)[CH:18]=[CH:19][CH:20]=1.C1(N)CCCCC1N.[N-:47]=[N+:48]=[N-:49].[Na+]>O.C(O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[O:2]=[C:3]1[O:9][C@H:8]([C@H:10]([CH2:12][OH:13])[OH:11])[C:6]([OH:7])=[C:4]1[OH:5].[N:47]([C:15]1[CH:16]=[C:17]([C@:21]23[CH2:29][O:28][CH2:27][C@H:26]2[CH2:25][S:24][C:23]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:22]3)[CH:18]=[CH:19][CH:20]=1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NC1=N[C@@]2(c3cccc(Br)c3)COC[C@H]2CS1)c1ccccc1
Agent: [Cu+2]
Agent: NC1CCCCC1N
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1cccc([C@]23COC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
A 0.66 M solution of L-ascorbic acid is prepared by dissolving L-ascorbic acid sodium salt (0.79 g, 2.0 mmol) in water (6 mL). N-((4aS,7aS)-7a-(3-bromophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (1.40 g, 3.35 mmol) and 1,2-cyclohexanediamine, N,N′-dimethyl-, trans (+/−) (162 mg, 1.11 mmol) are dissolved in ethanol (13.4 mL). Sodium azide (0.661 g, 10.1 mmol) is added. The 0.66 M aqueous L-ascorbic acid sodium salt (2.24 mL) and water (2.58 mL) are added. The reaction flask is fitted with a reflux condenser and the mixture is degassed and evacuated with nitrogen. Copper (II) sulfate pentahydrate (0.184 g, 0.738 mmol) is added and the reaction flask is heated to 80° C. and stirred for 1.5 h. The reaction mixture is cooled to room temperature and ice water is added. The reaction mixture is extracted three times with ethyl acetate. The combined organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give a residue that is purified on silica gel with 50% ethyl acetate in hexanes to give the title compound (0.620 g, 49%). Further elution of the flash column with 100% ethyl acetate yields more title compound (0.488 g, 41%). ES/MS m/e: 380 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>CO>[ClH:18].[NH:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCC1(CO)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1-tert-butoxycarbonylpiperidine-4,4-diyl)dimethanol, 4M HCl-dioxane solution, and MeOH was stirred at ambient temperature for 2 hours to yield (piperidine-4,4-diyl)dimethanol hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.[OH-].[Na+]>>[C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cc(Nc2cccc(-c3ccccc3)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58. The mixture was basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was collected by filtration, washed with excess water:ethanol (1:1) and isolated as a light brown solid (64 mg, 85%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.75 (d, J=5.4 Hz, 2H), 7.68 (s, 1H), 7.63–7.37 (m, 10H), 6.98 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H:40]([O:43]CCC)[CH2:39][CH2:38]2)CCCCC1.C1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCC1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([O:43][CH2:40][CH2:39][CH3:38])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: O=C1CCCCC1
Solvent: CCCBr
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,2-Dimethylpropionic acid [8-chloro-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (600 mg) and potassium carbonate (630 mg) were suspended in N,N-dimethylformamide (10 ml), and 4-bromo-2-methyl-2-butene (183 μl) was added to the suspension at room temperature. After the reaction mixture was stirred at room temperature for 24 hours, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 470 mg of the title compound from the elution fraction of hexane-ethyl acetate (3:1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3ccc(O)c(Cl)c3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.28 (d, 1H), 8.17 (s, 2H), 7.66 (m, 2H), 7.17 (d, 1H), 6.97 (d, 1H), 6.78 (d, 1H), 4.48 (s, 2H), 3.59 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.79 (t, 2H), 2.06 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; mp. 195.1° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:16]1([Na])[CH:20]=[CH:19][CH:18]=[CH:17]1>CCOCC>[CH:19]1([CH2:2][C:3]2[C:15]3[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:20]1
Reactant: [Na]C1C=CC=C1
Reactant: BrCc1cccc2c1Cc1ccccc1-2
Solvent: CCOCC
Product: C1=CC(Cc2cccc3c2Cc2ccccc2-3)C=C1
Reaction time: 2 h
Yield: 70 %

Procedure:
The ligand (cyclopentadienyl)(fluorenyl)methane was prepared as follows. To 0.4 mole dibromomethane dissolved in 200 mL pentane was added 0.2 mole fluorenyllithium powder. After the addition was complete, the reaction mixture was stirred for two hours. The reaction mixture was filtered and the filtrate washed with 100 mL of distilled water. The organic phase was dried with Na2SO4 and the solvent was stripped under vacuum. The residue was washed with 150 mL pentane to remove unreacted fluorene and dried under vacuum to yield pale yellow colored (bromo)(fluorenyl)methane. The yield was 80%. The (bromo)(fluorenyl)methane was dissolved in 20 mL ether and 19 mL (2 M in THF) cyclopentadienylsodium was added at a rate of 0.15 mL/min. The reaction mixture was stirred for two hours and washed with 50 mL distilled water. The organic phase was dried over Na2SO4 and the solvent removed under vacuum to yield pale yellow (cyclopentadienyl)(fluorenyl)methane. The yield was 70%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].CC([O-])=O.[Na+].[CH3:21][NH2:22]>CS(C)=O>[CH3:21][NH:22][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1ccc(NS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a stirred solution of N-(4-fluoro-3-nitrophenyl) methane sulfonamide (0.5 g, 0.0021 mol) in DMSO (10 ml) was added NaOAc (1.75 ml, 0.0021 mol) and methyl amine (0.65 g, 0.0021 mol) portion wise with constant stirring. The reaction mixture was allowed to stir at 120° C. for 10 h. The reaction mixture was concentrated and diluted with water (10 ml) and extracted with DCM (3×15 nil). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo to afford the desired product N-(4-(methyl amino)-3-nitrophenyl)methane sulfonamide (21) as a red color solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.4 (s, 1H), 8.16 (bs, 1H), 7.93 (s, 1H), 7.46-7.43 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.04-7.01 (d, J=9.2 Hz, 1H), 2.95-2.94 (d, J=4.8 Hz, 3H), 2.92 (s, 3H). LCMS (ES) m/e MS (M−1=244). Purity: 94%.
Reaction SMILES: [C@H:1]12[NH:8][CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.C([O-])([O-])=O.[Na+].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[C@H:1]12[N:8]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)[C@@H]2C1
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.4 g, 6.8 mmol) in THF (35 mL) and H2O (35 mL) was added Na2CO3 (1.4 g. 13.6 mmol) and CbzCl (1.1 mL, 7.5 mmol). After 18 h, the reaction mix was diluted with H2O and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) to give 2.4 g of the title compound as a clear oil that was used without further purification.