Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=CC=C([Cl:20])C=1OC.[Li]CCCC.COB(OC)OC>>[Cl:20][C:4]1[C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1c(Cl)cccc1Br
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1c(Cl)cccc1B(O)O
Yield: 91 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-6-chloroanisole (0.71 g, 3.2 mmol), n-BuLi (2.5 M hexanes; 1.28 mL, 3.2 mmol), and trimethylborate (1.09 mL, 9.6 mmol) to afford 0.55 g (91%) of 3-chloro-2-methoxyphenylboronic acid which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:45])=[O:46])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
A solution of triphenylphosphine (194 mg, 0.74 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (132 mg, 0.74 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (200 mg, 0.57 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (143 mg, 1.43 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) to afford pure 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide (178 mg, 72%) as a light yellow foam: mp 61–64° C. (foam to gel); EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0790.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][O:19]C(=O)C2C=CC=CC=2)=C(Cl)N=1>C(O)(C)C>[OH:19][CH2:18][CH2:17][O:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:2](=[S:3])[NH:1][C:6]([NH2:5])=[N:14][C:13]1=2
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: Nc1nc2c(ncn2COCCO)c(=S)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Thiourea (0.28g) was added to a refluxing solution of 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (1.27g) in isopropanol (40ml). The reaction mixture was heated at reflux for 11/2 hours and then chilled. 9-(2-benzoyloxyethoxymethyl)thioguanine (0.58g, m.p. 199°-202° C.) was removed by filtration. This was added to 40ml of aqueous ammonia (about 7N) and the mixture heated on a stream bath for 10 minutes and then stirred overnight at room temperature. The water and ammonia were removed in vacuo and the residue triturated with acetone and then with ether to remove benzamide. The remaining solid was recrystallized twice from water to give yellow flakes of 9-(2-hydroxyethoxymethyl)thioguanine (0.26g., m.p. 251°-254° C.).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([F:25])[CH:3]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:31][CH2:32][CH:27]([NH:26][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[C:2]([F:1])=[CH:3][C:4]([F:25])=[CH:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:28][CH2:29]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(F)cc(F)c56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 115) and amine 14.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([NH:39][CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][NH:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: CNc1ccc(N)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in step 1.1) and 0.216 g (1.67 mmol) of 3-amino-6-(methylamino)pyridine (WO2005/028452) in 10 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.471 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[OH:26][N:25]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)=[CH:22][CH:23]=1)[NH2:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(N)=NO)cc2)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl 4-[(4-cyanophenoxy)methyl]piperidine-1-carboxylate (Step 1, 1.47 g, 4.22 mmol, purity 91%), hydroxylamine hydrochloride (646 mg, 9.30 mmol) and triethylamine (1.30 mL, 9.30 mmol) in ethanol (24 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in tert-butyl methyl ether. The solid was filtered off and dried in vacuo to give the title compound (1.16 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 6.89 (d, 2H), 4.82 (s, 2H), 4.22-4.08 (broad m, 2H), 3.81 (d, 2H), 2.81-2.66 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.78 (d, 2H), 1.46 (s, 9H), 1.35-1.18 (m, 2H); ES-MS m/z 350, HPLC RT (Method D) 1.56 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[F:31][C:32]1([F:45])[CH2:37][CH2:36][C@H:35]([OH:38])[C@@H:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH2:33]1.[H-].[Na+]>CN(C=O)C>[F:45][C:32]1([F:31])[CH2:37][CH2:36][C@H:35]([O:38][C:13]2[CH:14]=[C:15]([F:16])[C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:3]=3[O:2][CH3:1])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:8])=[O:9])=[C:11]([F:18])[CH:12]=2)[C@@H:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH2:33]1
Reactant: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 48.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.34 mmol) prepared in Example 27a, the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (61.6 mg, 0.28 mmol) prepared in Example 88 g, sodium hydride (63%; 21.7 mg, 0.57 mmol) and DMF (2.0 mL), to yield the title compound (85.9 mg, 47%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1[O:55][N:54]=[CH:53][C:52]=1[C:56](O)=[O:57]>CN(C=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([C:56]([C:52]3[CH:53]=[N:54][O:55][C:51]=3[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:57])[CH2:9][CH:8]2[CH2:12][OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1ccccn1)N1CC(CO)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (6 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O3: 349.1426, found 349.1427.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1>CC(N(C)C)=O>[F:15][C:14]([F:17])([F:16])[S:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25](=[O:32])[O:24]4)[CH2:20][CH2:19]3)=[N:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(c1ccc2[nH]c(Cl)nc2c1)C(F)(F)F
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CC(=O)N(C)C
Product: O=C1OC2(CCN(c3nc4cc(S(=O)(=O)C(F)(F)F)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Stir 2-chloro-5-trifluoromethylsulfonyl-1H-benzimidazole (185 mg) and spiro[isobenzofuran-1,4′-piperidin]-3-one (263 mg) in dimethylacetamide (6 mL) at 195° C. for 1 hour. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify the residue by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-trifluoromethylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])=[O:5].C[Li].[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])(=[O:5])[CH3:27]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CON(C)C(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 4 h
Yield: 16 %

Procedure:
A solution of N-methoxy-N-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (160 mg) in anhydrous tetrahydrofuran (10 mL) was cooled to −70° C. under nitrogen atmosphere. A solution (1.8 mL) of 1.2M-methyllithium in diethyl ether was added dropwise. The temperature of the solution was gradually raised from −70° C. to 0° C., and the mixture was stirred for 4 hr. The reaction mixture was poured into aqueous citric acid solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-3:7), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (22 mg, yield 16%) as colorless crystals. melting point 241-243° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0.0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 0° C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 3.14 g (92.6%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.ClCCl>[CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoic acid and 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF were added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:9].[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37].C[N+]([O-])=O>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:20]([F:31])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:6]=3[F:5])[CH:12]=2)[NH:17][CH:18]=1)=[O:37]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)c4ccc(Cl)c(Cl)c4)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 21.4 %

Procedure:
A slurry of aluminum trichloride (0.078 g, 0.59 mmol) was added to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.029 g, 0.074 mmol) in DCM (1.2 mL) at 0° C., and the reaction mixture was allowed to stir at 0° C. for 40 minutes. 3,4-Dichlorobenzoyl chloride (0.023 g, 0.11 mmol) was added, and the mixture was allowed to slowly warm to room temperature overnight. CH3NO2 (300 μL) was added, and the reaction mixture was sonicated for 2 minutes. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was quenched with ice and then partitioned between aqueous sodium bicarbonate and EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residual solids were triturated with 5% MeOH/EtOAc to provide N-(3-(3,4-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (9 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.98-8.99 (m, 1H), 8.66-8.68 (m, 1H), 8.09 (s, 1H), 7.63-7.79 (m, 3H), 7.13-7.17 (m, 1H), 3.11-3.15 (m, 2H), 1.85-1.91 (m, 2H), 1.05-1.09 (m, 3H); m/z (APCI-pos) M+1=567.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([F:25])=[O:16])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonylisoleucine (0.482 g, 2 mmol) and pyridine (0.16 ml) in methylene chloride (5 ml) is dropped cyanuric fluoride (0.9 ml) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylisoleucine fluoride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:28][CH3:29])=[C:24]([Cl:27])[CH:25]=2)[N:20]=[C:19]([CH3:30])[C:18]=1[CH3:31]>>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:28][CH3:29])=[C:24]([Cl:27])[CH:25]=4)[N:20]=[C:19]([CH3:30])[C:18]=3[CH3:31])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1cc2nc(C)c(C)c(Cl)c2cc1Cl
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Product: COc1cc2nc(C)c(C)c(N3CC4(CCOCC4)c4ccc(Br)cc43)c2cc1Cl

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (0.3 g, 1.12 mmol) and 4,6-dichloro-7-methoxy-2,3-dimethylquinoline (0.3152 g, 1.23 mmol) to give 6-bromo-1-(6-chloro-7-methoxy-2,3-dimethyl-4-quinolinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.65 (1H, s), 7.58 (1H, s), 7.21 (1H, d, J=8.1 Hz), 6.82 (1H, dd, J=7.8, 1.7 Hz), 5.90 (1H, d, J=1.7 Hz), 3.96-4.05 (4H, m), 3.82-3.92 (3H, m), 3.41-3.53 (2H, m), 2.66 (3H, s), 2.17 (3H, s), 1.95-2.06 (2H, m), 1.85 (1H, dd, J=13.4, 1.7 Hz), 1.72 (1H, dd, J=13.3, 1.8 Hz); Mass Spectrum (ESI) m/e=487.0 [M+1 (79Br)] and 489.1 [M+1 (81Br)].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(C1C=CC(CN2C(CCl)=CN=C2)=CC=1)#N.Cl.[C:47]([C:49]1[CH:63]=[CH:62][C:52]([CH2:53][N:54]2[C:58](CCl)=[CH:57][N:56]=[C:55]2[CH3:61])=[CH:51][CH:50]=1)#[N:48]>>[C:47]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]2[C:58]([CH2:6][N:8]3[CH2:9][CH2:10][C:11]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:57][N:56]=[C:55]2[CH3:61])=[CH:62][CH:63]=1)#[N:48]
Reactant: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Agent: Cl
Agent: N#Cc1ccc(Cn2cncc2CCl)cc1
Product: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step B-C substituting methyl N-tert-butoxycarbonyl-4-(3-methylbenzyl)piperidine-4-carboxylate with ethyl N-tert-butoxycarbonyl-4-(3-nitrobenzyl)piperidine-4-carboxylate in Step B, and 1-(4-cyano-benzyl)-5-chloromethylimidazole hydrochloride salt with 1-(4-cyano-benzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B) in Step C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Reactant: C[C@@H](N)CO
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@@H](C)O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((R)2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (R)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 350 mg 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=181.5-184.4° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:26][CH:27](Br)[C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[Br:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: O=S1(=O)Nc2ccccc2N1c1cccc(F)c1F
Reactant: Cc1ccccc1C(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(Cc2ccccc2CBr)c2ccccc2N1c1cccc(F)c1F

Procedure:
In an analogous manner to general procedure IV, 1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 75 mg, 0.27 mmol) was treated with cesium carbonate (132 mg, 0.4 mmol) and α,α-dibromo-ortho-xylene (346 mg, 1.32 mmol) to give 68 mg of 1-[2-(bromomethyl)benzyl]-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.