Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (500 mg, 1.887 mmol) in DCM (10 mL) was added 3,4-dihydro-2h-pyran (0.517 mL, 5.66 mmol) and p-toluenesulfonic acid monohydrate (35.9 mg, 0.189 mmol). The solution was stirred for 1 h. The solution was diluted with DCM, washed with saturated NaHCO3 and concentrated. The residue was purified by flash chromatography on silica gel with eluting with 10% EtOAc/Hexane to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazole as a colorless oil (610 mg, 93%). 1NMR: 400 MHz, CDCl3: δ ppm 1.69-1.75 (m, 7H), 2.12-2.17 (m, 2H), 2.48-2.51 (m, 1H), 3.61 (d, J=85.20 Hz, 3H), 3.72-3.78 (m, 2H), 3.87-3.99 (m, 3H), 4.56 (s, 1H), 5.77 (dd, J=4.00, 8.00 Hz, 1H), 7.52-7.60 (m, 2H), 7.96 (t, J=24.40 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[Cl-:9].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Product: [Cl-]
Yield: 60.1 %

Procedure:
A solution of 11.8 grams (0.05 mole) of 4-fluoro-3-phenoxyphenylmethyl chloride (prepared in Example 2, Step B) and 13.1 grams (0.05 mole) of triphenylphosphine in 150 mL of dry tetrahydrofuran was stirred for about 60 hours. After this time the reaction mixture was concentrated under reduced pressure to a solid residue. The solid was stirred with diethyl ether and was collected by filtration, yielding 15 grams of (4-fluoro-3-phenoxyphenyl)methyltriphenylphosphonium chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.C([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=O.[C:23]([O-])([O-])=[O:24].[Na+].[Na+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[CH:23]=[O:24])=[O:11]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccccc2)ccc1C=O
Yield: 71.6 %

Procedure:
A mixture if 2.0 g (9.3. mmol.) methyl-3-bromobenzoate, 1.5 g (10.2 mmol.) 4-formylbenzeneboronic acid and 537 mg (0.47 mmol.) tetrakis(triphenylphosphine)-palladium in 14 mL (27.9 mmol.) 2M Na2CO3 and 15 mL dimethoxyethane was heated at 80° C. for 4 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined then washed successively with 1N NaOH, 1N HCl, water, brine then dried (MgSO4) and concentrated in vacuo to give an oil. Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:5) gave 1.6 g 4-formyl-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=2[Cl:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:35]=3[CH:34]=2)=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:35]=3[C:34]=2[C:15]([C:14]2[CH:18]=[CH:19][C:11]([O:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:12]([Cl:20])[CH:13]=2)=[O:17])=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.6 g(8.12 mmol) of 4-[2-(1-piperidinyl)ethoxy]-3-chlorobenzoic acid hydrochloride was dissolved in 25 mL of dichloromethane and 50 mL of SOCl2 with three drops of DMF. The reaction was reluxed for sixteen hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, then re-dissolved in 50 mL of dichloromethane. 2.2 g (8.12 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene was added to the solution and cooled to 0° C. 7.6 g (56.8 mmol) of AlCl3 was added in three portions to the reaction mixture and allowed to proceed for 1.5 hours. The reaction was quenched by pouring into ice. The organic layer was separated and washed with Na2CO3 solution and with water. The organic layer was dried by filtration through Na2SO4 and evaporated to dryness. The crude material was chromatographed on a silica gel column (HPLC) with a linear gradient beginning with CHCl3 and ending with MeOH-CHCl3 (1:9). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 1.3 g of the title compound as a yellow amorphous foam. PMR: Consistent with the proposed structure
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N+]=[N-]>[Pd].C(O)C>[NH3:1].[NH2:1][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Product: N

Procedure:
10% Palladium on charcoal (750 mg) was added to a solution of tert-butyl (2R)-2-(azidomethyl)-1-pyrrolidinecarboxylate (preperation 51) (5.74 g, 25.39 mmol) in ethanol (100 ml). The reaction mixture was hydrogenated @15 psi for 2.5 hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.5) as the eluant, to afford the title compound and some starting material. The mixture was dissolved in ethanol (100 ml) and 10% palladium on charcoal (500 mg) was added, the mixture was hydrogenated at 30 psi for 18 hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure to afford the title compound as a clear oil, 4.32 g, (85%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13](=O)[CH:14]([CH3:16])[CH3:15].[O:18]1CCC[CH2:19]1>>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([CH:19]([OH:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][CH:4]=1)[CH3:10]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)C=O
Product: CCOC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-iodobenzoate (140 g, 507 mmol) in tetrahydrofuran at −40° C. was added Isopropylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran, 429 mL, 558 mmol) dropwise at a rate to maintain the internal temperature below −30° C. The mixture was stirred for 30 minutes at which point isobutyraldehyde (61 g, 710 mmol) was added dropwise while maintaining the temperature below −35° C. The mixture was stirred at this temperature for 15 minutes and then slowly warmed to room temperature. The reaction was quenched with 1N HCl (3 L) and the mixture extracted with ethyl acetate (2 L×2). The combined organics were washed with brine (1 L) and water (1 L), and then dried over anhydrous Na2SO4. This was concentrated in vacuo to give (+/−)-4-(1-hydroxy-3-methyl-butyl)-benzoic acid ethyl ester (120 g, 100%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.4 Hz, 2 H), 7.47 (s, J=7.2 Hz, 2 H), 4.76-4.73 (m, 1 H), 4.33-4.28 (m, 2 H), 1.71-1.60 (m, 2 H), 1.46-1.41 (m, 1 H), 1.39-1.31 (m, 3 H), 0.92-0.87 (m, 6 H).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:17](I)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].C(#N)C>CCOCC>[CH2:1]([N:4]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH2:17][CH2:18][CH3:19])[CH:2]=[CH2:3]
Reactant: CCCI
Reactant: C=CCNC1COc2cccc(OC)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: C=CCN(CCC)C1COc2cccc(OC)c2C1
Temperature: 47 °C
Reaction time: 120 h
Yield: 80.4 %

Procedure:
3-(N-Allylamino)-5-methoxychroman (1.3 g, 5.9 mmol) prepared analogous to example 26, n-propyl iodide (2.1 mL, 21 mmol), anhyrous K2CO3 (3.0 g, 21 mmol) and acetonitrile (5.5 mL) were stirred under N2 at 47° C. (oilbath temp) for five days until GC indicated complete reaction. Ether (40 mL) was added, the salts were filtered off by suction and the clear filtrate was concentrated in vacuo to afford 3-(N-allyl-N-n-propylamino)-5-methoxy chroman (1.24 g, 81% yield) as an oil. The base was precipitated from an ether solution by adding a slight excess of HCl (approx. 3M in ether). Crystallization of the crude HCl salt afforded colourless needles. Mp 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCN(C)C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a cooled (−78° C.) solution of 6-chloro-1,3-dihydro-indol-2-one (4.0 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) was slowly added BuLi (2.2 M solution in cyclohexane, 22 mL, 48 mmol). The solution was stirred for 30 minutes at the same temperature and then iodomethane (2.2 mL, 36 mmol) was slowly added. The reaction was stirred at −20° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Chromatography (SiO2, EtOAc/Petrol 2:8) gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.
Reaction SMILES: CC(C)=CC[C@@H](O)[C:6]1[C:16](=[O:17])[C:15]2[C:14](O)=[CH:13][CH:12]=[C:11](O)[C:10]=2[C:8](=[O:9])C=1.CC(C)=CCC(OC(C=C(C)C)=O)C1C(=O)C2C(=C(O)C=CC=2O)C(=[O:30])C=1>C(O)C>[CH2:15]([OH:30])[CH:16]([OH:17])[CH3:6].[CH2:8]([OH:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CC(C)=CCC(OC(=O)C=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Solvent: CCO
Product: CC(O)CO
Product: OCc1ccccc1

Procedure:
Manufacture the injection solution of the above described 7 Shikonin compounds according to the methods known to those skilled in the art. Under the aseptic operation conditions, take 0.5 g β,β-dimethylacrylshikonin obtained in Preparation example 1 or Preparation example 2, 400 ml propylene glycol, 100 ml ethanol, 20 ml tween-80 and 15 ml benzyl alcohol, dissolve the compounds completely and then add water to 1,000 ml. After thoroughly mixing, bottle them as the injection solution.
Reaction SMILES: NC1C=CC(SC2C=CC(N)=CC=2)=CC=1.[C:16]1([C:22]#[C:23]C2C=C(C=CC=2)C=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH3:23][CH2:22][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(C#Cc2ccccc2)c1
Agent: Nc1ccc(Sc2ccc(N)cc2)cc1
Solvent: CCO
Product: CCCCCCC
Product: Cc1ccccc1
Yield: 93.8 %

Procedure:
Using a procedure similar to that described in Example 5, 3.4 g (0.016 mol) of 4-aminophenylsulfide was reacted with 6.6 g (0.032 mol) of 3-phenylethynylbenzaldehyde in 75 ml of ethanol. The product precipitates as a yellow solid which was recrystallized from heptane/toluene (8.9 g, 0.015 mol, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][C:9]=2[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[C:14]([F:37])[CH:13]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:42][C:39]1[CH:40]=[CH:41][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH:38]=1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=3[N:19]=2)=[C:14]([F:37])[CH:13]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 83 %

Procedure:
Methyl 2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (1.9 g) obtained in Example 337 was suspended in ethanol (40 ml), and tin(II) chloride dihydrate (3.5 g) was added, which was followed by refluxing under heating for 30 min. The reaction mixture was concentrated under reduced pressure, 4N sodium hydroxide was added and the mixture was extracted with chloroform. The organic layer was washed with 2N sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (1.5 g, yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]3[C:27]([O:36][CH3:37])=[CH:28][CH:29]=[C:30]4[C:35]=3[N:34]=[CH:33][CH:32]=[CH:31]4)[CH2:21][CH2:20]2)[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:37][O:36][C:27]1[C:26]([N:22]2[CH2:23][CH2:24][CH2:25][N:19]([CH:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:15][C:16](=[O:18])[NH:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:20][CH2:21]2)=[C:35]2[C:30]([CH:31]=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
(±)-3-[(tert-Butoxycarbonyl)piperidin-4-yl]-3-[4-(7-methoxyquinolin-8-yl)-[1,4]-diazepan-1-yl]propanoic acid (800 mg, 1.56 mmol), and 2-(pyrrolidin-1-yl)ethanamine (250 mg, 2.19 mmol) were suspended in anhydrous DMF (6 mL). N,N-Diisopropylethylamine (0.5 mL, 2.88 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (761 mg, 2.00 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated complete reaction (LC/MS [M+H]+609.7). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel flash column chromatograph using 2 to 5% MeOH in DCM with 0.5% aqueous NH4OH to afford the title compound as a light yellow oil (480 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 8.81 (dd, 1H, J=1.6 and 4 Hz), 8.03 (dd, 2H, J=1.6 and 8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.22 (dd, 1H, J=4 and 8 Hz), 4.12 (br s, 2H), 3.96 (s, 3H), 3.51 (m, 4H), 3.38 (m, 3H), 3.20-2.80 (m, 4H), 2.70-2.40 (m, 5H), 2.24 (m, 1H), 1.98 (br, 1H), 1.80-1.55 (m, 11H), 1.46 (s, 9H), 1.34-1.16 (m, 3H). MS (ES) m/z 609.7 (M+H+).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:12]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: ClCc1cccs1
Product: O=C(c1ccc(OCc2cccs2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 2-chloromethyl-thiophene [CAS 765-50-4], and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 389.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH2:15][N:14]4[CH2:16][CH2:17][CH:11]3[CH2:12][CH2:13]4)[O:8][C:5]2=[N:6][CH:7]=1.O.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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.CCO>[O:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:3]=[C:4]2[CH2:10][C@:9]21[CH2:15][N:14]1[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)o1
Temperature: 65 °C
Yield: 91.9 %

Procedure:
To a solution of (2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine] (6 g, 20.3 mmol) in 400 mL of a DME:H2O:EtOH mixture (7:3:2) was added 5-formyl-2-furanboronic acid (5.67 g, 40.5 mmol). The reaction mixture was purged with N2 (directly into the solvent) and stirred for ten minutes until homogeneous. Solid Na2CO3 (8.6 g, 81.0 mmol) was added to the reaction mixture followed by Pd(PPh3)2Cl2 (711 mg, 1.0 mmol). The reaction mixture was again purged with N2 for 10 min, then heated at 65° C. for 6 h. The reaction mixture was stirred at rt overnight, then concentrated via rotary evaporator. The resulting residue was diluted with CHCl3 and filtered through diatomaceous earth. The CHCl3 filtrate was concentrated and the resulting residue was diluted with 1N HCl and extracted with EtOAc (3×150 mL). The acidic aqueous layer was made basic with the addition of 2N aqueous NaOH (to pH˜12) and the basic aqueous solution was extracted with CHCl3 (3×150 mL). The combined CHCl3 layer was washed with brine, dried (Na2SO4), filtered and concentrated to a solid (5.79 g, 92% yield). This material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.46-1.53 (m, 1H), 1.68-1.71 (m, 2H), 2.03-2.04 (m, 1H), 2.22-2.26 (m, 1H), 2.78-2.94 (m, 3H), 2.97 (d, J=14.7 Hz, 1H), 3.00-3.04 (m, 1H), 3.07 (d, J=16.5 Hz, 1H), 3.40 (d, J=14.7 Hz, 1H), 3.47 (d, J=16.5 Hz, 1H), 6.74 (d, J=3.7 Hz, 1H), 7.30 (d, J=3.7 Hz, 1H), 7.89 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H) MS ES+, m/z=311 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@H:7]([NH:10][S@](C(C)(C)C)=O)[CH2:8][CH3:9].[ClH:17].O>CO.O1CCOCC1>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@H:7]([NH2:10])[CH2:8][CH3:9]
Reactant: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-pyrimidin-2-yl-propyl)-amide (Comp. No. 14b) (2.6 g, 10.8 mmol) in methanol was added 4 M hydrogen chloride in dioxane (4.35 ml) and the mixture was stirred for 1 h at 25° C. Water (100 ml) was added and the aqueous phase was washed with methyl tert-butyl ether. The aqueous layer was freeze-dried to give 1.7 g (75%) of (R)-1-pyrimidin-2-yl-propylamine hydrochloride. LC/MS (method 5): Rt=0.68 min; m/z=138.15 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][NH:34][CH3:35].N=C=N.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1>ClCCCl>[CH3:32][O:33][N:34]([CH3:35])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([S:15](=[O:17])(=[O:16])[NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1)=[O:30]
Reactant: CNOC
Reactant: O=C(O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid 34 (212 mg, 0.5 mmol) in DCE (5 mL), was added O,N-dimethyl-hydroxylamine hydrochloride (59 ul, 0.6 mmol), PS-carbodiimide (1.9 g, 2.5 mmol), triethyl amine (140 uL, 1 mmol) and HOAt (102 mg, 0.75 mmol). After stirring at 50° C. overnight, the resultant solution was filtered and concentrated in vacuo to give the crude product 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35. LCMS showed m/z: 468 (M+H)+. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19].CCOCC.O>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [2-(4-bromobenzoyl)-4-chlorophenyl]carbamate (10 g, 25 mmol) in MeOH (50 mL) at 25° C. was added 2 M HCl-MeOH (100 ml), and the reaction mixture stirred for 4 h. The organic layer was evaporated, then the residue was partitioned between CH2Cl2 (300 ml) and water (200 ml). The organic layer was washed with 10% Na2CO3 (to pH=9) and brine, dried over Na2SO4 and evaporated to give 7.5 g (98% yield) (2-amino-5-chlorophenyl)(4-bromophenyl)methanone. To a solution of (2-amino-5-chlorophenyl)(4-bromophenyl)methanone (13 g, 42 mmol) in 500 ml CH2Cl2 was added solid carbonyldiimidazole (15.7 g, 96 mmol) portionwise. The resulting yellow solution was allowed to stir at 40° C. for 16 hrs, concentrated to give a yellow foam. The foam was treated with 30 ml of ether and 20 ml of water with vigorous stirring resulting in a solid precipitate. After filtration, the cake was recrystallized from CH2Cl2/Ether (1:5) to give N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide as a yellow solid. 1HNMR: (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (dd, J=8.4, 1.6 Hz, 1H), 7.33 (s, 1H), 6.98˜7.10 (m, 5H), 6.71 (d, J=2.0 Hz, 1H).