Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14].I[CH2:22]C>>[CH2:1]([C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14])[CH3:22]
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Reactant: CCI
Product: CCOC(=O)CC1(CC)C(=O)Nc2cccc([N+](=O)[O-])c21

Procedure:
Essentially following the procedures described for Intermediate 17, but using iodoethane in place of iodomethane, the title compound was prepared. MS: m/z=293 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@@H:6]1[C@@H:13]([OH:14])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9]C)[CH2:7]1)=[O:4].[N+](=[CH2:20])=[N-].B(F)(F)F>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:20][O:14][C@H:13]1[C@H:12]([CH3:15])[O:11][CH:8]([OH:9])[CH2:7][C@@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:17])([F:16])[F:1]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@@H](O)[C@H](C)O1
Reactant: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Yield: 98 %

Procedure:
Treatment of 2.57 g; 10 mmoles of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-arabino-hexopyranoside (III-A) in methylene dichloride with diazomethane/boron-trifluoride, as described in Example I gave the corresponding 4-O-methylderivative (III-B, 1.7 g., 63%): m.p. 185°; [α]D23° =-101° (c=1, in CHCl3); mass spectrum m/e 271 (H+); pmr spectrum (CDCl3); 1.31 (d, CH3 --C--5), 3.30 and 3.43 (two s, OCH3) and 4.70δ (broad s, C--1--H). Acid hydrolysis of compound III-B as in Example I (1.63 g., 6 mmoles) gave 2,3,6-trideoxy-4-O-methyl-3-trifluoroacetamido-L-arabino-hexopyranose (III-C, 1.51 g., 98%): m.p. 201°; [α]D23° =-12.7° (c=0.48, in CHCl3); mass spectrum m/e 257 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH:28]1(O)[CH2:32]CC[CH2:29]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:32][CH2:28][CH2:29][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 70 mg of powdered potassium cyanide in 10 ml of cyclopentanol are stirred at the boiling point overnight, the excess cyclopentanol is removed in vacuo, the residue is taken up in chloroform, filtered and evaporated. By recrystallization from ethyl acetate/hexane there is obtained cyclopentyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 210.5°-212°.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C([O-])(=O)C.[Na+]>C(O)=O>[CH3:22][O:23][C:24]([CH2:25][N:26]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH2:7][CH2:6][N:5]1[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]2[C:1]1=[O:20])=[O:27]
Reactant: COC(=O)CN
Reactant: CC(=O)CCC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cn1c(C)ccc1CCN1C(=O)c2ccccc2C1=O

Procedure:
82 g (0.03 mol) of 7-phthalimido-2,5-heptanedione, 5.0 g (0.04 mol) of glycine methyl ester hydrochloride and 3.3 g (0.04 mol) of sodium acetate are stirred in 150 ml of formic acid at 60° C. for 4 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[C:19]([C@:11]([NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)(=[O:8])=[O:9])([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])([CH3:21])([CH3:20])[CH3:18]
Reactant: C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CN)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N[C@@](CN)(C(=O)O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Acid 14-3 (5.0 g, 19.4 mmol) was suspended in dioxane (100 ml) in a 1-L pressure bottle. The bottle was cooled to -15° and isobutylene (100 ml) was condenced into the dioxane. Concentrated H2SO4 (5 ml) was added and the bottle sealed and stirred at room temperature for 36 h. The bottle was opened and the excess isobutylene carefully vented. The solution was diluted with ethyl acetate (200 ml) and washed with 1N NaOH (200 ml). The organic layer was dried (Na2SO4), filtered and evaporated to give 14-4 as a white crystaline solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][N:10]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: BrC1CCCC1
Reactant: CCc1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in 0.5 g portions to a 10° C. solution of 13.17 g (58.5 mmol, 1.0 equiv) 6-bromo-3-ethyl-1H-indazole in 500 mL anhydrous DMF. The mixture was stirred at room temperature for 20 minutes, then a solution of 8.8 mL (81.9 mmol, 1.4 equiv)cyclopentyl bromide in 10 mL anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2 L H2O and extracted 2×1L ethyl acetate. The organic extracts were combined, washed 2×750 mL H2O, 1×500 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 20.7 g of crude product, which was purified on a silica gel column (1.1 kg silica gel, 3% ethyl acetate/hexanes) to give 10.6 g (62%) of an amber liquid: IR (CHCl3)2972, 2875, 1606, 1501, 1048 cm−1; 1H NMR (300 MHz, CDCl3) d 7.56 (d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=1.5, 8.5 Hz), 4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J =7.7 Hz); MS (thermospray, NH4OAc) m/z 295/293 (M+H+, base); Anal. calcd for C14H17N2Br: C, 57:35; H, 5.84; N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([O:15]C)=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncn(-c2ccc(I)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ncn(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Methyl 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylate (830 mg, 2.5 mmol) was dissolved in MeOH (20 mL) and THF (10 mL). 1 M NaOH (2.5 mL, 2.5 mmol) was added and the mixture stirred at room temperature for 2 h. Additional 1 M NaOH was added (2.5 mL, 2.5 mmol) and the reaction was heated to 50° C. for 30 minutes. After cooling to room temperature, the pH was adjusted to 4 by the addition of 6 M HCl, MeOH and THF were removed under reduced pressure and the resulting white precipitate was collected by filtration and dried in vacuo to obtain 680 mg (86% yield) of 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27](O)=[O:28])([CH3:23])[CH3:22]>>[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27]([N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:11]([S:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH2:18]1)=[O:28])([CH3:23])[CH3:22]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(c2)CNCC3)CC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (CA [741674-53-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 536.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-[2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid(12.3 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 12.5 g (80%) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [CH2:1]([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:19][C:14]1[CH:13]=[N:12][N:11]2[C:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:7][C:8]([C:15]([F:16])([F:17])[F:18])=[N:9][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCc1cc(C(F)(F)F)nc2ccnn12
Solvent: ClC(Cl)Cl
Product: CC(C)CCc1cc(C(F)(F)F)nc2c(Br)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 4.0 gm (0.0155 mol) of 7-isopentyl-5-trifluoromethylpyrazolo[1,5-a]pyrimidine in 50 ml chloroform was cooled to 15° and 2.73 gm. (0.0155 mol) of N-bromosuccinimide was added. The solution was stirred for 30 minutes at ambient temperature, then poured on ice (50 gm, crushed). The chloroform layer was washed with sat. K2CO3 solution and then dried (Na2SO4) and chromatographed on neutral alumina (Woelm, grade I). Elution of the compound with chloroform, followed by evaporation of the solvent and distillation, afforded 4.0 gm (58%) of the product as an amber oil, b.p. 123°-126° /0.5 mm.
Reaction SMILES: [F:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl-].[Li+].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>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.C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([CH2:17][CH:16]=[CH2:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)c(I)cc1C#N
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(C#N)c(OC)cc1F
Temperature: 115 °C

Procedure:
To a mixture of 4-fluoro-5-iodo-2-methoxybenzonitrile (2.5 g, 9.0 mmol), Pd(Ph3P)4 (1.0 g, 0.90 mmol) and lithium chloride (0.96 g, 23 mmol) under nitrogen was added anhydrous toluene (50 mL) and the mixture was flushed (3×) with nitrogen. Allyltributyltin (4.15 mL, 14 mmol) was added and the mixture was flushed again with nitrogen. The reaction was heated under nitrogen at 115° C. for 2.5 hours and then let cool to room temperature. TLC (10% ethyl acetate/Hexanes) showed several spots with a strongly charring product spot right above the starting material. The reaction was diluted with hexanes and filtered to remove insoluble material. The mother liquor was concentrated and the residue was purified on a Biotage 65+M column with a gradient elution from 0 to 40% ethyl acetate in hexanes to afford the title product which had some residual tributylstanane by-product contaminant by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.327 (d, J=6.5 Hz, 2H), 3.902 (s, 3H), 5.102 (2 d, J=10.0 and 17 Hz, 2H), 5.868 (m, 1H), 6.668 (d, J=11.1 Hz, 1H), 7.390 (d, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:40])[CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 85.5 %

Procedure:
Using 7-(2,5-difluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.094 mmol) obtained in step 5 and acetic acid (0.027 mL, 0.471 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.046 g, 84%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH:7]([CH2:14][CH2:15][CH3:16])[CH2:6]2.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[OH:13]
Reactant: BrBr
Reactant: CCCC1CC(=O)c2ccc(OC)cc2C1
Solvent: ClC(Cl)Cl
Product: CCCc1cc2cc(OC)ccc2c(O)c1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-Methoxy-3-propyl-3,4-dihydro-2H-naphthalen-1-one (93) (1.6 g, 7.33 mmol) in dry chloroform (65 mL) was added dropwise via an addition funnel bromine (2.35 g, 14.7 mmol) in chloroform (20 mL). The reaction mixture was stirred at ambient temperature for 20 h. The reaction mixture was concentrated to afford the title compound as oil, 2.76 g. The crude material (2.76 g, 7.33 mmol) in dry acetonitrile (64 mL) was cooled to −10° C., 1,8-diazabicyclo[5.4.0]undec-7-ene (1.64 mL, 10.99 mmol) in dry acetonitrile (8 mL) was added dropwise via an addition funnel. The reaction mixture was quenched with 1 N HCl (50 mL) after stirring for 1 h at 6° C. The aqueous layer was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified with 1:9 EtOAc:hexanes over 40 min to obtain 1.41 g (65%) of the title compound (94). 1H NMR (400 MHz, d-CDCl3): δ 1.01 (t, J=7.3 Hz, 3H), 1.68-1.74 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 3.90 (s, 3H), 6.06 (s, 1H), 7.00-7.01 (m, 1H), 7.08 (dd, J1=2.6 Hz, J2=9.1 Hz, 1H), 7.17 (s, 1H), 8.07 (d, J=9.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCCC2)C1
Reaction time: 1 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-cyclopentyl]-(3-hydroxymethyl-piperidin-1-yl)-methanone (0.5 g, 1.55 mmol) in dichloromethane (9.5 mL) at room temperature was added iPr2NEt (0.5 g, 3.9 mmol) followed by MsCl (0.214 g, 1.86 mmol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (gradient 2.5-100% EtOAc in hexane). The desired compound was obtained as an oil (0.345 g, 56%). 13C (100 MHz, CDCl3, partial) δ 174.0, 144.0, 131.8, 128.8, 126.5, 70.8, 58.1, 35.3, 26.5, 24.9. 1H (300 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 7.13-7.10 (m, 2H), 4.61-1.86 (m, 19H), 1.67 (s, 3H).
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:19]3[C:20]([F:40])=[C:21]([N:25](COC)[S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O.O>>[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:19]3[C:20]([F:40])=[C:21]([NH:25][S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CCn1cc(-c2ccnc(NC(C)(C)C)c2)c(-c2cccc(N(COC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2ccnc(N)c2)c(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 37.8 %

Procedure:
N-{3-[4-(2-tert-Butylamino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (250 mg, 0.436 mmol) was treated with TFA/H2O 9:1 (3 mL) at 70° C. for 4.5 h. The reaction mixture was then evaporated to dryness, taken up with AcOEt and washed with sat, aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (DCM/MeOH/NH3 7M in MeOH 90:8:2) and then treated with ethyl ether, filtered and dried to give 78 mg of N-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-benzene-sulfonamide as a white solid. HPLC (254 nm): Rt: 5.13 min; 1H NMR (DMSO-d6) Shift: 10.75 (br. s., 1H), 8.13 (s, 1H), 7.67 (dd, J=0.5, 5.4 Hz, 1H), 7.50-7.59 (m, 1H), 7.41-7.50 (m, 2H), 7.30 (td, J=24, 7.4 Hz, 1H), 7.12-7.26 (m, 2H), 6.27 (d, J=0.7 Hz, 1H), 6.08 (dd, J=14, 5.4 Hz, 1H), 5.82 (br. s., 2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H); HRMS (ESI) calcd for C22H19F3N5O2S [M+H]+ 474.1206. found 474.1184.
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[Li].P(=O)([O-])O[CH2:24][C:25](=[O:36])[C:26](C)(C)[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[O:36]=[C:25]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:24]=[CH:1]/[C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2
Reactant: CC(C)(Oc1ccccc1)C(=O)CO[PH](=O)[O-]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1
Yield: 87.5 %

Procedure:
A solution of 548 mg. of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [J. Amer. Chem. Soc. 96: 5865 (1974)] in 20 ml. of absolute tetrahydrofuran is combined with 581 mg. of the lithium salt of dimethyl-2-oxo-3-phenoxypropyl phosphonate, and the mixture is agitated for 1.5 hours at room temperature under argon. The mixture is then combined with 0.3 ml. of glacial acetic acid, concentrated under vacuum, mixed with 100 ml. of methylene chloride, and extracted with 10 ml. of 5% sodium bicarbonate solution and twice with respectively 10 ml. of water. The product is dried with magnesium sulfate, evaporated under vacuum, and the residue of the evaporation is recrystallized from methylene chloride-isopropyl ether, thus obtaining 710 mg. of the title compound as colorless crystals (yield: 87.5% of theory).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a mixture of tert-butyl 4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)piperidine-1-carboxylate (63 mg) and methanol (1.3 mL) were added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.15 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (27 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2cc(C)ccc2N)cc1
Product: COc1ccc(NC(=O)c2cc(C)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 46 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (1.3 mmol) and 2-amino-N-(4-methoxyphenyl)-5-methylbenzamide (1.2 mmol) yielded 0.23 g (47%) of the title compound.