Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F: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:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([Cl:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH2:71])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([Cl:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH:71][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:64][CH:63]=1
Reactant: NCCNc1ccc(C(=O)Nc2ccc(Cl)cc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccc(Cl)cc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-chlorophenyl)-6-(2-aminoethylamino)nicotinamide (321 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (446 mg, 76%) as a yellow solid. LC-MS (m/z) 588 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: O=S1(=O)Nc2ccccc2C1=Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C2c3ccccc3NS2(=O)=O)cc1
Yield: 80 %

Procedure:
To a cooled solution of 3-(4'-hydroxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (273 mg, 1 mmol) in dry pyridine (0.5 ml) is added acetic anhydride (204 mg, 2 mmol) and the mixture maintained at 0°-5° C. overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroform-methanol to yield pure 3-(4'-acetoxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (80% yield). C16H13NO4S calcd: C 60.94 H 4.15 N 4.44 S 10.17 found: C 60.85 H 4.05 N 4.34 S 10.19 MS (m/z): 315
Reaction SMILES: CN(C=O)C.[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[OH:9].N1C=CN=C1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[O:9][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 15 h
Yield: 100.6 %

Procedure:
To a stirred DMF (65 mL) solution containing (R)-2-iodo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.7 g, 28 mmol), imidazole (5.25 g, 77 mmol), and 4-dimethylaminopyridine (0.30 g, 2.46 mmol) was added t-butyldimethylsilyl chloride (5.0 mL, 29.8 mmol). After 15 hours, the completed reaction was diluted with EtOAc (200 mL) and heptane (70 mL). The organic phase was washed 1×100 mL H2O, 2×100 mL aq. sat. CuSO4, 1×100 mL H2O, 1×100 mL sat'd brine, and dried over Na2SO4. The filtrate was concentrated in vacuo to give 15.81 g of a tan solid which was dissolved in ~125 mL CH2Cl2 and diluted with 650 mL heptane. The mixture was concentrated in vacuo at 40° C. to 42° C. until solids were seen (~105 mL distillate were collected), cooled to ~15° C. and filtered. The collected solids were washed with heptane and dried in vacuo at 45° C. to give 11.1 g (70%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:26](OC)([CH3:28])[CH3:27]>CC(C)=O.[Cu](Cl)Cl>[CH3:27][C:26]1([CH3:28])[O:1][C@@H:2]([C@@H:6]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](CCCc2ccc(OC(F)(F)F)cc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,3R)-2-hydroxy-3-{3-[4-(trifluoromethoxy)phenyl]propyl}butanedioic acid (5.58 g; 16.6 mmol; 1.0 eq.) in acetone (61 mL) was added 2,2-dimethoxypropane (3.5 mL; 28.2 mmol; 1.70 eq.) and copper(II) chloride (220 mg; 1.66 mmol; 0.1 eq.). The resulting reaction mixture was stirred 14 h at RT. The reaction mixture was evaporated and the residue taken up in Et2O and filtered on a pad of cellite. The liquids were evaporated again and the residue was treated with activated charcoal in Et2O and filtered on a pad of cellite to give the title product as a greenish oil used in the next step without further purification. (5.85 g; 93.7%). M+(ESI): 377.0; M−(ESI): 375.1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:15]([C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
A solution of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (10.0 g.) and p-nitrobenzoyl chloride (14.2 g.) in methylene chloride (40 ml.) was placed on a cold water bath with mechanical agitation and treated with aluminum chloride (15.3 g.) portionwise over 5 minutes. The bath was then heated at 80°-90° C. for 1 hour and removed, and the mixture diluted with 100 ml. of methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Product: CCOC(=O)[C@@H]1CCCN1c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344; found, 344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:28]
Reactant: O=C(CBr)c1nccs1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetylthiazole hydrobromide (A. Dondoni, A. Marra, and P. Merino, J. Am. Chem. Soc., 1994, 116, 3324).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23]([OH:25])=O)[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl.[NH2:28][C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1>>[N:31]12[CH2:30][CH:29]([NH:28][C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:16]4[O:15][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][C@@H:12]5[C:16]5[CH:17]=[CH:19][CH:20]=[CH:21][CH:22]=5)=[N:18][C:17]=34)=[O:25])[CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)O)cccc3o2)CC1
Agent: Cl
Product: CN1CCN(c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)[C@@H](c2ccccc2)C1

Procedure:
Following general procedure GP-C1, a mixture of 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide which was converted to the dihydrochloride salt following general procedure GP-D1 and isolated as a mixture of diastereomers. 1H NMR and MS consistent.
Reaction SMILES: FC1C=C(O)C=CC=1C1N=C2NN=C(C)C2=C(CN2CCNCC2C2C=CC=CC=2)C=1.C([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:47]=[C:48]([C:62](O)=O)[C:49]3[C:54]([CH3:55])=[N:53][N:52](C4CCCCO4)[C:50]=3[N:51]=2)=[C:42]([F:65])[CH:41]=1)C1C=CC=CC=1.[CH3:66][C:67]1([CH3:75])[O:72][CH2:71][C:70]([CH3:74])([CH3:73])[NH:69][CH2:68]1>>[F:65][C:42]1[CH:41]=[C:40]([OH:39])[CH:45]=[CH:44][C:43]=1[C:46]1[N:51]=[C:50]2[NH:52][N:53]=[C:54]([CH3:55])[C:49]2=[C:48]([CH2:62][N:69]2[C:70]([CH3:74])([CH3:73])[CH2:71][O:72][C:67]([CH3:75])([CH3:66])[CH2:68]2)[CH:47]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CC1(C)COC(C)(C)CN1
Agent: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCNCC3c3ccccc3)c12
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)OCC3(C)C)c12

Procedure:
The title compound was prepared in analogy to Example 1 steps (d) to (g) starting from 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 2,2,5,5-tetramethyl-morpholine, however, in the last step only the THP-protecting group on the pyrazole ring was removed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29](=[O:32])[NH:30][CH3:31])[CH2:5][C:6]1[C:7]([CH3:25])=[C:8]([CH3:24])[C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[CH2:33](C([Sn])=C(CCCC)CCCC)[CH2:34]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29](=[O:32])[NH:30][CH3:31])[CH2:5][C:6]1[C:7]([CH3:25])=[C:8]([CH3:24])[C:9]([CH:33]=[CH2:34])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(OS(=O)(=O)C(F)(F)F)c(C)c2C)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(C(=O)NC)c(F)c2)c(C)c1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of methyl 5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.28 g) in DMF (6.00 mL) were added tributylvinyltin (0.29 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithium chloride (0.19 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.19 g).
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:11][C:12]1[CH:19]=[C:18]([N:1]2[CH:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C1CC[C@@H]2NCCC[C@@H]2C1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCCC3CCCCC32)cc1Cl
Yield: 68 %

Procedure:
A solution (2 mL) of cis-decahydroquinoline (447 mg), 2-chloro-4-fluorobenzonitrile (500 mg) and lithium carbonate (237 mg) in dimethyl sulfoxide was reacted at 140° C. for 10 min in a microwave reaction apparatus. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give the title compound as a colorless oil (yield: 600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.CN(C)C1C=CN=CC=1>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid (0.10 g, 0.212 mmol) in dichloromethane (4 ml) was added 4-dimethylaminopyridine (0.039 g, 0.318 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.318 mmol) and tert-butyl 1-piperazinecarboxylate (0.041 g 0.222 mmol). The resulting mixture was stirred overnight at ambient temperature. It was then diluted with dichloromethane and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (0.110 g, 85% yield).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[C:10](=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)NC3=O)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)NC3)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a solution of N-(2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (example 1.7, 111 mg, 0.26 mmol) in dry THF (1.6 mL) was added borane dimethyl sulfide complex (0.78 mL, 1.56 mmol, 2M in THF) under N2. The reaction mixture was heated up to 65° C. for 7 hours, then stirred at room temperature for overnight. Quenched reaction by carefully addition of 0.5 N HCl (0.5 mL) solution and the mixture was refluxed for 2 hours, then basified the reaction mixture with 1N NaOH aqueous to pH=8-9, extracted 2× with ethyl acetate, this was separated. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 5-10% MeOH in DCM (0.5% NEt3 added), 22.2 mg (21%) of the product was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.CCOC(C)=O>[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[N:27]=1
Reactant: OCc1csc(Br)n1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (239 mg), (2-bromothiazol-4-yl)methanol (330 mg) and triphenylphosphine (669 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (597 mg), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc, washed with water and brine successively, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (185 mg) as a white solid.
Reaction SMILES: II.[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[OH-].[K+].[O-:15]S([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:15])[NH:8]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=S([O-])[O-]
Agent: II
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Cc2c(Br)cccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
Add a solution of I2 (2.62 g, 10.30 mmol) in DMF (10 mL) dropwise to a solution of 4-bromoindole (2.00 g, 10.20 mmol) and KOH (1.43 g, 25.5 mmol) in DMF (40 mL). Stir for 30 min at room temperature and add saturated aqueous Na2SO3. Stir at room temperature for 15 min, then dilute reaction mixture with ethyl acetate (100 mL). Wash organics three times with H2O, dry organics (MgSO4) and concentrate to a brown oil. Dissolve oil in 2-methoxyethanol (40 mL) and heat to 100° C. Add H3PO4 (9 mL) and heat to reflux for 48 h. Cool to room temperature and dilute with H2O (75 mL). Extract into ethyl acetate, dry MgSO4) and concentrate organics to a dark brown oil. Chromatograph on silica gel (90 g), eluting with 20% to 40% ethyl acetate/hexanes to afford 121 mg (6%) of the title compound as a tan solid. MS (ES) 212,214 (M+H), 210,212 (M−H); HPLC shows 76% purity.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH2:30][CH3:31]>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:33]1[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=[C:32]1[CH2:29][CH2:30][CH3:31])=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCCc1nc2ccccc2[nH]1
Product: CCCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-propylbenzimidazole were reacted to give 233. LCMS m/z: 533.3 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].Cl.[CH3:15][N:16](C)CCCN=C=NCC.CN>C(Cl)Cl.CO>[CH3:15][NH:16][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzoic acid (4.0 g, 21.6 mmol) and EDC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (4.36 g, 28.1 mmol) in methylene chloride (100 mL) was added methylamine (11.3 mL of a 2 M solution in MeOH, 22.7 mmol) and the solution was stirred at room temperature overnight. The solution was washed with 1 N HCl, dried over MgSO4 and concentrated to a solid. The solid was triturated with butyl chloride and collected by filtration to give the N-methyl-3-fluoro-4-nitrobenzamide (3.81 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:28]
Reactant: COC(=O)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(tert-Butoxycarbonyl)piperazine (2.50 g; 13.4 mmol) and triethylamine (1.77 g; 2.43 mmol) are dissolved in methylene chloride (40 mL). The solution is cooled in an ice-bath and a solution of methyl 3-chloro-3-oxopropionate (2.02 g; 14.8 mmol) in 10 mL methylene chloride is added dropwise over a 10-minute period. The ice-bath is removed and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured onto ice-cold 0.1N HCl (100 mL) and extracted with methylene chloride (200 mL). The organic extract is washed with saturated sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (60%→80% ethyl acetate in hexanes) to afford the desired product as a white solid. ESMS: MH− 287.2
Reaction SMILES: [CH2:1]([OH:26])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][C:11]#[C:12][C:13]#[C:14][CH2:15][CH2:16][C:17]#[C:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[CH2:27]([N:36]=[C:37]=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35].[O:39]1CC[CH2:41][CH2:40]1>>[NH:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:25][CH2:24][CH3:23])=[O:35].[CH2:24]([OH:25])[CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:18]#[C:17][CH2:16][CH2:15][C:14]#[C:13][C:12]#[C:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:26]
Reactant: C1CCOC1
Reactant: O=C=NCCCCCCN=C=O
Agent: OCCCCC#CC#CCCC#CC#CCCC#CC#CCCCCO
Product: CCOC(=O)NCCCCCCNC(=O)OCC

Procedure:
In a reaction vessel 1.73 parts CF4 diol produced from Example 23, was reacted with 0.84 parts hexamethylene diisocyanate in 70 parts of tetrahydrofuran at room temperature for 4 hours in the presence of a catalytic amount of DBTE and TEA. The product was precipitated with heptane and filtered. After washing several times with heptane, it was vacuum dried to yield 1.7 parts of XXV, a light tan fluffy material, melting point, 161.3° to 165.1° C.