Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[N:10]([S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:8]>C1(C)C=CC=CC=1.C1COCC1.[NH4+].[Cl-]>[CH3:25][N:23]([CH3:24])[S:22]([N:10]1[C:9]([C:7](=[O:8])[CH3:1])=[CH:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:11]1)(=[O:26])=[O:27]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A 1.4M solution of methylmagnesium bromide in toluene and THF (3.88 mL, 5.43 mmol) was added to a solution of 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (1.54 g, 4.17 mmol) in THF (20 mL) at −78° C. and under nitrogen. The mixture was stirred at −78° C. for 1 hour and then at room temperature for 16 hours. Then, a second portion of methylmagnesium bromide in toluene and THF (3.58 mL, 5.01 mmol) was added at 0° C. and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (1.2 g, 89% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6](=O)[C:5]([NH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[O-]CC.[Na+]>>[C:13]([C:12]1[C:11](=[O:16])[NH:10][C:5]2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:8]=[CH:7][C:6]=12)(=[O:15])[CH3:14]
Reactant: CC(=O)CC(=O)Nc1ccc(Cl)ccc1=O
Agent: CC[O-]
Agent: [Na+]
Product: CC(=O)c1c2ccc(Cl)ccc-2[nH]c1=O

Procedure:
1-[(4-Chloro-7-oxo-1,3,5-cycloheptatrien-1-yl)amino]-1,3-butanedione (480 mg) was suspended in a solution of sodium ethoxide (prepared from 46 mg of sodium and 2 ml of anhydrous ethanol). The solution was heated at reflux for 3 hr. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness. The residue was dissolved in water. The solution was rendered acidic with 6 N aqueous HCl. The precipitate was collected and dried to give 3-acetyl-6-chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole, nmr (DMSO-d6) δ2.55 (s, 3H), 7.3-7.95 (m, 3H), 8.9 (d, 1H). The latter compound (5.8 g) was added to a stirred solution of sodium hydride (77 mg, 50% suspension in mineral oil) and DMF (10 ml), the solution having been stirred at 25° C. for 30 min prior to the addition. Thereafter, ethyl bromoacetate (400 mg) was added to the mixture. The mixture was heated at 100°-105° C. for 1.5 hr, cooled, diluted with water and extracted with chloroform. The residue was purified by chromatography on silica gel using methylene chloride-ethyl acetate (9:1) as the eluant. The pure fractions were pooled to give 3-acetyl-6-chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, nmr (CDCl3) δ1.3 (t, 3H), 2.7 (s, 3H), 4.2 (q, 2H), 4.85 (s, 2H), 7.6 (m, 4H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([N:41]1[C:45]([CH2:46][CH2:47][CH2:48]O)=[N:44][CH:43]=[N:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:48][CH2:47][CH2:46][C:45]1[N:41]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:42]=[CH:43][N:44]=1
Reactant: BrBr
Reactant: OCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Yield: 43.3 %

Procedure:
A solution of bromine (5.6 g) in dichloromethane (15 ml) was added dropwise to a stirred solution of triphenylphosphine (9.2 g) in dichloromethane (100 ml) cooled to -5° C. The mixture was stirred for a further ten minutes at 0° C., then treated portionwise with a solution of the above alcohol (6.9 g) and triethylamine (4.9 ml) in dichloromethane (30 ml) again maintaining the temperature below 0° C. The solution was stirred for a further ten minutes, filtered through a bed of silica, then chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give 1-bromo-3(1-trityl-1,2,4-triazol-5-yl)propane (3.5 g, m.p. 146-149° C.). NMR (CDCl3):δ 1.8(2H,m), 2.15(2H,t), 3.2(2H,t), 7.1-7.3(15H,m), 7.9(1H,s). 13C NMR was used to confirm the position of the trityl substituent.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:20]
Reactant: O=C=NCCCl
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (419 mg, 2.18 mmol) and 2-chloroethyl isocyanate (230 mg, 2.18 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled to room temperature and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient), dried and triturated with ethyl acetate/hexanes (1/9) to afford (1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (258 mg, 40%) as a yellow solid. MS M+H calculated 298.10; found 298.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH3:23])[C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH3:23])[C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1c(C)cc(Br)cc1C(=O)O
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 3-fluorophenylboronic acid (0.75 g, 5.39 mmol, 1.1 eq), 5-bromo-2-methoxy-3-methyl-benzoic acid (1.2 g, 4.90 mmol, 1.0 eq) and Na2CO3 (1.56 g, 14.69 mmol, 3 eq) in a mixture of EtOH (6 mL), DMF (24 mL) and H2O (6 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added, the reaction was filtered and the filtrate was extracted with EtOAc. The organic extract was discarded and the aqueous phase was acidified to pH 4-5 with 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to provide the title compound as a white solid (1.09 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH:24]([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CI.[Li+].[CH3:32][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:32])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C#N)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile (0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at −78° C. was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution in THF. The resulting mixture was stirred overnight, with the temperature slowly rising to ambient. The reaction mixture was quenched with brine (1 mL), diluted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep O18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.255 g (74%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile. LC-MS Method 1 tR=1.89 min, m/z 459, 461 (MH+); 1H NMR (400 MHz, CD3OD) δ7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83 (d, J=8.2 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 3.02-2.97 (m, 1H), 2.42-2.36 (m, 1H), 2.29-2.08 (m, 4H), 1.42 (d, J=7.0 Hz, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −116.50 (m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][NH:10]/[CH:11]=[C:12](\[CH3:18])/[C:13](OCC)=[O:14])[CH:4]=1)#[N:2].CC([O-])(C)C.[K+]>C(O)C>[OH:14][C:13]1[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC(=O)/C(C)=C/NNc1cc(C#N)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnn(-c2cc(C#N)ccn2)c1O
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a cooled mixture of ethyl(E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]-2-methylprop-2-enoate (415 mg, 1.69 mmol) in ethanol (18 mL) was added t-BuOK (568 mg, 5.06 mmol) slowly. After that, the mixture was stirred overnight, filtered, the solid was acidified with HCl (1N), filtered, collected the solid and dried to give 250 mg of the title compound (74%). 1H NMR (400 MHz, CDCl3): δ 1.93 (3H, s), 7.55 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.64 (1H, s), 8.64 (1H, d, J=4.8 Hz), 8.72 (1H, s). [M+H] Calc'd for C10H8N4O, 201; Found, 201.
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][N:11]1[C:15]([CH3:16])=[N:14][C:13]([CH2:17][N:18]([CH3:20])[CH3:19])=[N:12]1)C1C=CC=CC=1>CCO>[CH3:19][N:18]([CH2:17][C:13]1[N:14]=[C:15]([CH3:16])[N:11]([CH2:10][C:9]([OH:21])=[O:8])[N:12]=1)[CH3:20]
Reactant: Cc1nc(CN(C)C)nn1CC(=O)OCc1ccccc1
Solvent: CCO
Product: Cc1nc(CN(C)C)nn1CC(=O)O

Procedure:
The final compound was prepared using a method analogous to that of Example 14 step 14.2, (3-dimethylaminomethyl-5-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.15 min; [M+H]+: 199.16.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:18]Br>O.CC(O)=O>[CH2:11]([O:10][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([Br:18])[N:4]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1ncccc1N
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(Br)ccc1N
Yield: 69.2 %

Procedure:
A suspension of ethyl 3-aminopicolinate (Compound 6F, 4.15 g, 25.0 mmol) in H2O (30.0 mL) was treated with enough sulfuric acid to enable dissolution (˜1 mL). 2 mL of the total 10.7 mL of acetic acid to be used in this reaction was added in order to make the reaction mixture mostly homogeneous. A solution of bromine (1.29 mL, 25.0 mmol) in the remaining AcOH (8.7 mL) was added drop-wise to the vigorously stirring reaction mixture forming an orange precipitate. The mixture was allowed to stir for 15 min. The resulting thick yellow-orange suspension was filtered to collect a yellow precipitate. The filtrate was neutralized with saturated aqueous K2CO3 and the additional precipitate that formed was collected by filtration and combined with the previously collected precipitate. The combined precipitates were dried and re-crystallized in EtOH (overnight in the dark) to isolate 4.24 g of pale orange crystals. The mother liquor was purified on an ISCO Combiflash system eluting with 0-5% MeOH/DCM. To isolate a further 0.58 g of the desired product for a total of 4.82 g (79%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.1 Hz, 3H), 4.29 (q, J=7.1 Hz, 2H), 6.90 (br. s., 2H), 7.21 (d, J=8.6 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H). MS (ESI): m/z 244.94 (100), 246.92 (100) [M+H]+. HPLC: tR=3.45 min (ZQ3: polar—5 min).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5]Br)[CH3:2].[OH-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:30]3[NH:31][CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([C:30]3[N:31]([CH2:2][CH2:1][S:3][CH2:4][CH3:5])[CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:16]=1
Reactant: CCSCCBr
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCSCCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 89 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole obtained in the same manner as described in Reference Example 6 (1.81 g, 5 mmole), 2-bromoethyl ethyl sulfide (1.01 g, 6 mmole), and tetra-n-butylammonium bromide (0.16 g, 0.5 mmole) are refluxed in two phases of benzene (20 ml) and 50% aqueous sodium hydroxide (20 ml) for 4 hours. To the mixture are added water and benzene under ice-cooling, and the mixture is shaken. The benzene layer is taken, washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is subjected to silica gel column chromatography (solvent, ethyl acetate:cyclohexane=1:20) to give oily 4,5-bis(4-methoxyphenyl)-2-[1-(2-ethylthioethyl)pyrrol-2-yl]thiazole (2.01 g, yield: 89%).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([O:31][CH3:32])=[O:30])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.C(Cl)(=O)O[C@@H:52]1[CH:57]2[CH2:58][CH2:59][N:54]([CH2:55][CH2:56]2)[CH2:53]1>C(Cl)Cl.CCOC(C)=O.O>[C:36]1([C@H:9]([NH:8][C:6]([O:5][C@@H:52]2[CH:57]3[CH2:58][CH2:59][N:54]([CH2:55][CH2:56]3)[CH2:53]2)=[O:7])[C:10]2[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=2)[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][CH3:32])=[O:30])(=[O:22])=[O:23])=[CH:19][CH:20]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 197.6 %

Procedure:
To a mixture of (S)-methyl 1-((4-((3-((S)-((tert-butoxycarbonyl)amino)(phenyl)-methyl)-phenoxy)methyl)phenyl)-sulfonyl)pyrrolidine-2-carboxylate (I28, 636 mg, 1.1 mmol) in DCM (10 mL) was added TFA (3 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 min before being concentrated in vacuo. The residue was diluted in DCM (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic phase was passed through a hydrophobic frit and solvent was removed in vacuo. The residue (436 mg) was dissolved in pyridine (4 mL) and the reaction mixture was cooled to 0° C. (R)-quinuclidin-3-yl carbonochloridate hydrochloride (207 mg, 0.92 mmol, prepared as previously reported in 16, step 6) was added and the resulting mixture was stirred at room temperature for 16 h. Additional (R)-quinuclidin-3-yl carbonochloridate hydrochloride (104 mg, 0.46 mmol) was added at 0° C., the mixture was stirred for 2 h and then diluted with EtOAc (50 mL) and water (20 mL). The layers were separated and organic phase dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo to yield 576 mg of the crude title product as a thick oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
673 mg (corresponding to 2.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 25 mL of N,N-dimethylformamide, and 831 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 275 μL (corresponding to 3.0 mmol) of 1-bromo-3-fluoropropane, and then stirred at room temperature for 24 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform), and further by recycle preparative HPLC(HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 349 mg (corresponding to 0.881 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-5, Step 3).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].Cl.[O-:19][C:20]#[N:21].[K+]>O>[OH:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][C:20]([NH2:21])=[O:19]
Reactant: N#C[O-]
Reactant: CCCCCC(CCCN)OC1CCCCO1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCC(O)CCCNC(N)=O

Procedure:
To a stirred suspension of 4-(2-tetrahydropyranyloxy)-nonylamine (4.8 g., 0.02 mole) in water (75 ml.) is added just enough 10% hydrochloric acid to effect solution. Then potassium cyanate (1.62 g., 0.02 mole) is added and the reaction is heated gently on the steam bath for one hour, during which time an oil separates. The reaction mixture is cooled and extracted with ether (2 × 75 ml.). The ether is dried over sodium sulfate then concentrated in vacuo to give 4-hydroxynonylurea as a residual oil. The 4-hydroxynonylurea is taken up in pyridine (20 ml.) and acetic anhydride (2.0 g., 0.02 mole) is added. The reaction is stirred eight hours at room temperature then poured into water (100 ml.), and extracted with ether (2 × 100 ml.). The ether is washed with 5% hydrochloric acid, brine, and dried over sodium sulfate. Removal of the solvent in vacuo affords the subject compound as a residual oil.
Reaction SMILES: C(OC(N1CC(OC(=O)C)CC1C[C:21]1[C:29]2[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=O)C1C=CC=CC=1.[C:31](O)([C:33](F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[NH:23]1[C:31]2[C:33](=[CH:29][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:22]1[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)OC1CC(Cc2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCN2c1cc2ccccc2[nH]1
Temperature: 3 °C
Reaction time: 4.75 h

Procedure:
A solution containing 8 (2.9 g, 7.1 mmol) in EtOAc (ca. 5 mL) was cooled in an ice-bath and pre-cooled TFA (20.3 mL) was added in one portion. The resulting yellow-colored solution was stirred at 2-4° C. After 4.75 h, the cold reaction mixture was transferred (via canula) with stirring into a pre-cooled mixture of EtOAc (30 mL), and 25% aq. K2CO3 (80.7 g). The aqueous layer was separated and extracted with EtOAc (3×30 mL) and the combined organic extracts were washed with 10% aq. Na2CO3 (30 g). The organic solution was concentrated in vacuo and azeotropically dried using anhydrous EtOAc to afford 2.95 g of indolylindoline diastereomers as a yellow-colored foam which was used directly in the next reaction. Mass spectrum (ESI), m/z 821.3 [(M)+; calcd for C46H46F2N4O8: 820.9].
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:19]([Mg]Br)[CH:20]=[CH2:21].[Cl-].[NH4+]>C1COCC1>[CH2:6]([O:5][P:4]([CH:9]([C:17]#[N:18])[CH:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:21][CH:20]=[CH2:19])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=CC[Mg]Br
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(C1CCCCC1)C(C#N)P(=O)(OCC)OCC
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of the oil isolated in Step A (17.5 g, 65 mmol), and cuprous iodide (0.75 g) in THF (100 mL) at 0° C., a solution of allylmagnesium bromide in THF (2 M, 42 mL, 84 mmol) was added slowly while the temperature was maintained at about 5-10° C. The reaction mixture then was stirred at room temperature overnight. Aqueous saturated ammonium chloride solution (100 mL) was then added. The reaction mixture was stirred 30 min at room temperature and then extracted with ethyl acetate (200 mL). The organic solution washed with saturated ammonium chloride solution three times and with brine one time, and then was dried over sodium sulfate. The reaction mixture was then filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield a colorless oil (GC showed it contained 20% starting material, but the oil was used as is without further purification).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32](=[O:45])[N:33]([CH3:44])[N:34]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([C:32](=[O:45])[N:33]([CH3:44])[N:34]4[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
300 mg (796 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 231 mg (876 μmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 229 mg (46% of theory)