Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:45][O:46][CH2:47][CH2:48]Br.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:48][CH2:47][O:46][CH3:45])[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: COCCBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(=O)n(Cc2ccc(OC)cc2OC)c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (0.977 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.271 mmol) of cesium carbonate and 149 mg (1.075 mmol) of 2-bromoethyl methyl ether were added and the mixture was stirred at RT for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 453 mg (74% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:34]=1[CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][C:34]3[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:33]=3[F:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: Fc1ccc(F)c(CBr)c1
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cc(F)ccc2F)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2,5-difluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.37 (m, 1H) 6.97-7.09 (m, 3H) 6.87-6.96 (m, 1H) 6.68-6.80 (m, 1H) 5.92-6.02 (m, 1H) 5.73-5.90 (m, 2H) 5.13-5.45 (m, 1H) 4.13-4.27 (m, 2H) 3.62-3.74 (m, 3H) 2.59-2.78 (m, 2H) 2.05-2.17 (m, 2H) 1.91-2.05 (m, 3H) 0.97-1.22 (m, 9H); LCMS (m/z) ES+=551 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][S:13][C@H:12]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20](O)=[O:21])[N:11]2[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][NH2:40]>C(Cl)Cl.CCOC(C)=O>[NH:39]([C:20]([C@H:19]1[N:11]2[C@@H:12]([S:13][CH2:14][CH2:15][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]2=[O:23])[CH2:16][CH2:17][CH2:18]1)=[O:21])[NH2:40]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)NN)N2C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
To a solution of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (121 mg, 0.351 mmol) and N-methylmorpholine (0.048 mL, 0.44 mmol) in DCM (2 mL) at 0° C. was added isobutyl carbonochloridate (0.053 mL, 0.40 mmol). The mixture was stirred at 0° C. for 40 min. Then, hydrazine (0.044 mL, 1.4 mmol) was added and the reaction was stirred at rt for 1 hr. The mixture was diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated to give tert-butyl (4S,7S,10aS)-7-(hydrazinecarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (125 mg, 0.349 mmol, 99% yield) as a white solid. Anal. Calcd. for C15H26N4O4S m/z 358.4. found: 359.1 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2].[NH2:12][C:13]1[C:18](N)=[CH:17][CH:16]=[CH:15][N:14]=1.C(N[C@H](C(O)=O)CS)(=O)C>CO>[N:2]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:1]=1[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: Nc1cccnc1N
Agent: CC(=O)N[C@@H](CS)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc2cccnc2[nH]1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
A mixture of tert-butyl cyanomethylcarbamate (1.61 g; 10 mmol), 2,3-diaminopyridine (0.56 g; 5 mmol), N-acetylcysteine (1.68 g; 10 mmol) in 10 ml of CH3OH was heated at 50° C. for 89 h. It was then concentrated, and the residue was taken up in a little CH3OH and filtered through an acidic ion exchanger (acetate on polymeric support). Renewed concentration and chromatography on silica gel (CH2Cl2/CH3OH 5%) afforded 1.09 g of the required product;
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:11])([CH2:8][CH2:9][NH2:10])[Si:4]([CH3:7])([CH3:6])[CH3:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:2][Si:3]([CH3:11])([CH2:8][CH2:9][N:10]=[C:12]=[O:13])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)Cl
Reactant: C[Si](C)(C)[Si](C)(C)CCN
Agent: Cl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)[Si](C)(C)CCN=C=O

Procedure:
50 g of 2-(pentamethyldisilanyl)ethylamine hydrochloride is suspended in 100 ml of dry toluene in a 250 ml two-neck flask fitted with a gas inlet tube and reflux condenser. A powerful stream of gaseous phosgene is then passed through the solution while stirring. At the same time the solution is heated to boiling. The conversion of the hydrochloride to the isocyanate is terminated when a clear toluene solution has been produced. Subsequently, the excess toluene is distilled off in a water-jet vacuum and the residue left behind is fractionated in an oil-pump vacuum.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH3:25][N:26]([NH2:28])[CH3:27]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][N:26]([CH3:27])[CH3:25])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CN(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NN(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.9 ml (0.025 mol) of unsym-dimethylhydrazine in 30 ml of DMF were reacted affording a residue which was recrystallized in hot hexane to give 4.57 g (83.8%) of product as a yellow solid; mp 97°-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([NH:27][CH:28]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:29]([O:31]C)=[O:30])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].[OH-].[Na+].O.Cl>C1COCC1.CO>[C:38]([O:37][C:35](=[O:36])[CH2:34][CH2:33][CH:28]([NH:27][C:25]([C:22]1[CH:21]=[C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:42]=[CH:43][CH:44]=[C:10]([NH:9][C:7]([C:3]4[O:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:8])[CH:11]=3)[CH:19]=[CH:18][N:17]=2)[NH:24][CH:23]=1)=[O:26])[C:29]([OH:31])=[O:30])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate (170 mg, 0.28 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 2 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid as white solid. Yield: 145 mg, 87%.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([C:22]([CH3:24])=[CH2:23])[C:14]2=[O:25])=[CH:9][CH:8]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:53][C@H:52]([CH2:51][O:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH2:54][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([C:22]([CH3:24])=[CH2:23])[C:14]2=[O:25])=[CH:11][CH:12]=1
Reactant: C=C(C)n1c(=O)n(-c2ccc(CCN)cc2)c2ncccc21
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)c2ncccc21
Yield: 28.3 %

Procedure:
3-[4-(2-Aminoethyl)phenyl]-1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one formate (0.32 g, 0.96 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.433 g, 1.07 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.19 g, 0.272 mmol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>CS(C)=O>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CS(C)=O
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (22 mg, 0.09 mmol) in dimethyl sulfoxide (1 ml) was stirred at 180° C. for 2 hr. Thereafter, the reaction solution was allowed to cool to room temperature and was then concentrated by removal of the solvent under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole (4 mg, 20%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[CH:25][CH:24]=1>>[O:34]=[C:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:26]1[CH:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCCN1c1ccc(O)cc1
Product: N#Cc1ccc(N(CCOc2ccc(N3CCCC3=O)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 1-(4-hydroxyphenyl)-2-pyrrolidinone (step A above): MS (APCI) m/z 472 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:26](=[O:27])[N:25]([CH3:24])[CH3:37])[CH:29]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(C(=O)N(C)C)c4)c(C(=O)O)s3)c2cc1OC
Yield: 4 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-dimethylcarbamoylphenylboronic acid (29 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-dimethylcarbamoyl-phenyl)-thiazole-5-carboxylic acid (1.8 mg, 4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 7.84 (s, 1 H); 7.73-7.79 (m, 2H); 7.44-7.59 (m, 3 H); 7.40 (s, 1 H); 3.91 (s, 3 H, NCH3), 3.86 (s, 3 H); 3.01 (s, 3 H); 2.74 (s, 3 H). MS 453 m/z (M+1).
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:36])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]([CH3:35])[CH3:34])(=O)C.C(Cl)(C)=O>CC(O)=O>[Cl:36][C:22]1[N:21]=[C:20]2[C:25]([NH:26][CH:27]=[N:19]2)=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]([CH3:35])[CH3:34])[N:23]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4C(C)C)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(C)c1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 20 h
Yield: 45.1 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-isopropylimidazol-1-yl)purine (2.96 g, 5.7 mmol, contaminated with 2-isopropylimidazole) was dissolved in HOAc (190 mL). To the solution was added AcCl (1.9 mL, 2.10 g, 26.7 mmol), and the mixture was stirred at 65° C. for 20 h in a sealed flask (reaction was complete, TLC). Volatiles were evaporated in vacuo, and the residue was washed (CH2Cl2) and dissolved in 0.1 N NaOH/H2O (200 mL). Precipitation with CO2 gave 2-chloro-6-(2-isopropylimidazol-1-yl)purine (0.675 g, 54%). This solid was washed (boiling MeOH/iPrOH) to give the title compound (0.60 g, 48%): mp 268-268.5° C.; UV (MeOH) max 213, 254, 288 nm (∈ 26 100, 4600, 13 100), min 239, 257 nm (∈ 3700, 4600); 1H NMR (500 MHz, DMSO-d6) δ 14.06 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 7.07 (d, J=1.6 Hz, 1H), 3.93 (br s, 1H), 1.29 (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 156.4, 154.3, 151.0, 146.5, 145.8, 127.9, 122.0, 120.4, 27.7, 21.6; HRMS m/z 285.0626 (MNa+[C11H11ClN6Na]=285.0631). Anal. Calcd for C11H11ClN6: C, 50.29; H, 4.22; N, 31.99. Found: C, 50.12; H, 4.27; N, 32.16.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=4)=[N:7][C:8]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-tert-butyl-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 558.2 [(M+H)+]; mp 258-259° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:18]([N:20]1[CH2:25][CH2:24][C@@:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([OH:26])[C:22]([CH3:35])([CH3:34])[CH2:21]1)=[O:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@:23]2([OH:26])[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C@H:3]([NH:2][C:41]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:42])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:21][C:22]2([CH3:35])[CH3:34])=[CH:32][CH:31]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1(C)CN(C(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)CC[C@]1(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C2CCCC2)CC[C@]1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Benzyl (R)-4-amino-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-5-oxopentylcarbamate hydrochloride (50.5 mg, 0.096 mmol) was dissolved in dichloromethane (0.5 mL) and added cyclopentane carbonylchloride (14 μL, 0.12 mmol) followed by DIPEA (42 μL, 0.24 mmol). The solution was stirred for 2 h, concentrated, and partitioned between EtOAc (2 mL) and aq NaHCO3 (0.5 mL). The EtOAc layer was separated, dried over magnesium sulfate, and concentrated to give benzyl (R)-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-(cyclopentanecarboxamido)-5-oxopentylcarbamate which was used without further purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]NC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:67][O:68][C:69]1[CH:70]=[C:71]([NH:75][C:76]2[C:85]3[C:80](=[C:81]([CH3:111])[CH:82]=[C:83]([S:86]([C:89]4[CH:94]=[CH:93][CH:92]=[C:91]([C:95](=[O:110])[NH:96][C:97]5C=CC(C#CCCC=O)=[CH:99][C:98]=5[CH3:109])[CH:90]=4)(=[O:88])=[O:87])[CH:84]=3)[N:79]=[CH:78]C=2C(N)=O)[CH:72]=[CH:73][CH:74]=1>>[Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:97]([NH:96][C:95]([C:91]2[CH:90]=[C:89]([S:86]([C:83]3[CH:84]=[C:85]4[C:80](=[C:81]([CH3:111])[CH:82]=3)[N:79]=[CH:78][C:58]([C:59]([NH2:60])=[O:66])=[C:76]4[NH:75][C:71]3[CH:72]=[CH:73][CH:74]=[C:69]([O:68][CH3:67])[CH:70]=3)(=[O:87])=[O:88])[CH:94]=[CH:93][CH:92]=2)=[O:110])=[C:98]([CH3:109])[CH:99]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCC=O)cc5C)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5C)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 148, using Intermediate 117 in place of Intermediate 112. ES/MS calcd. for C52H56N6O9SSi 978.4. Found m/z=979 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:36]([N-]C(C)C)(C)C.[Li+].P([O-])([O-])([O-])=O>C1COCC1>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)N(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise a solution of lithium diisopropylamide (LDA) (2.0 N in heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over a period of 10 min. After completion of the addition, the stirring was continued for an additional 20 min at the same temperature. To the resulting mixture was added dropwise Mel (0.5 mL) at 0° C., and stirred at room temperature for 15 h. The mixture was poured into a solution of phosphate buffer (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.64 (2H, d, J=8.3 Hz), 7.53-7.25 (7H, m), 6.89 (1H, s), 3.65-3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([S:10](=[O:29])(=[O:28])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[CH3:30].I[CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([S:10](=[O:29])(=[O:28])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[CH3:30].[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([S:10](=[O:29])(=[O:28])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[CH3:30]
Reactant: CCCI
Agent: CCCN(c1ccc(-c2ccc(O)cc2)cc1)S(=O)(=O)c1ccc(C)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc(N(CCC)S(=O)(=O)c3ccc(C)c(C(=O)OC)c3)cc2)cc1
Temperature: 56 °C
Yield: 17 %

Procedure:
A mixture of 5-[(4′-hydroxy-biphenyl-4-yl)-propyl-sulfamoyl]-2-methyl-benzoic acid methyl ester (100 mg, 0.25 mmol), 1-iodopropane (36.7 μl, 0.38 mmol) and potassium carbonate (52 mg, 38 mmol) in 5 ml acetone was heated at 56° C. under nitrogen overnight. Additional 1-iodopropane was added (35.7 μl, 0.38 mmol) and the mixture was heated at 56° C. under nitrogen overnight. The reaction mixture was then cooled to room temperature and diluted with 40 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 30 ml water and 30 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparative thick layer chromatography (silica gel), eluting with 3:1 toluene/ethyl acetate to yield the title compound as an off-white solid (21 mg, 17% yield) along with 5-[(4′-hydroxy-biphenyl-4-yl)-propyl-sulfamoyl]-2-methyl-benzoic acid methyl ester (64 mg, 58% yield).