Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].C1(C)C=CC=CC=1.[Cl:19][CH2:20][CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22](Cl)=[O:23]>O.[OH-].[Na+].C1COCC1>[Cl:19][CH2:20][CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:23]
Reactant: CC(C)CC(CCl)C(=O)Cl
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(CCl)C(=O)NCCCCCCCC(=O)O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
8-Amino caprylic acid (4.3 g) is dissolved in 20 ml of water containing 1.1 g of sodium hydroxide. To this is added 20 ml of THF, and 5 ml of toluene, and the solution is cooled to 5° C. 2-(Chloromethyl)-4-methylvaleryl chloride is dissolved in 10 ml of THF and added dropwise to the above solution. The pH of the reaction mixture is maintained between 8 and 9 during the reaction time by the addition of a total of 1.1 g of sodium hydroxide in 20 ml of water, as needed. After stirring at room temperature for about 16 hours, the aqueous layer is separated and acidified with 10% hydrochloric acid. Product is extracted with ethyl acetate and the ethyl acetate is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 5.6 g of product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Br[CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCO>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCCC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OCC
Temperature: 140 °C
Yield: 98.8 %

Procedure:
206 g (1 mol) of 2,4-di-tert-butylphenol were melted and heated to 140° C. under nitrogen. 185 g (1.03 mol) of a 30% strength NaOMe solution in MeOH and 245 g (1.1 mol) of ethyl 2-bromocaproate were metered in simultaneously in the course of 1 hour. During the addition, a mixture of MeOH and EtOH was distilled off. After the addition, the reaction to give the ester mixture was complete. The mixture was cooled to 80° C., 20 g of NaOMe solution were added and 750 ml of ethanol were then added in the course of 4 hours. A methanol/ethanol mixture distilled off at an overhead temperature of initially 74° to 76° C. At the end, the temperature was increased to 90° C. and pure ethanol distilled over at 78° to 79° C. For isolation, 250 ml of water were added. After separation of the phases and renewed washing with 200 ml of water, 351 g of a viscous yellow oil of the following composition (0.3% of ethyl bromocaproate, 0.7 g of residual phenol, 98% of ethyl 2-(2,4-di-tert-butylphenoxy)caproate and 0.3% of methyl 2-(2,4-ditert-butylphenoxy)caproate, remained. This corresponds to a yield of 98.8% of theory, based on the phenol employed.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1.N1C=CN=C1.C(Cl)Cl>O>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cncn1CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1cncn1CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
Tert-butyldimethylsilyl chloride (9.05 g) was added to a stirred mixture of 1-(2-hydroxyethyl)-5-methylimidazole (6.4 g), imidazole (7.5 g) and methylene chloride (30 ml) which was cooled to 0°C. The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give 1-(2-tert-butyldimethylsilyloxyethyl)-5-methylimidazole (11.7 g); NMR Spectrum: (CDCl3) −0.04 (s, 6H), 0.85 (s, 6H), 2.2 (s, 3H), 3.8 (m, 2H), 3.94 (m, 2H), 6.75 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>CN(C=O)C.O>[Cl:1][C:2]1[N:3]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:7]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:8][C:9]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)[nH]c(=O)c21
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(Cl)nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 69.7 %

Procedure:
A mixture 2-chloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.27 mmol) and cesium carbonate (0.1 g, 0.30 mmol) was taken in DMF (2 ml) and isobutyl bromide (0.055 g, 0.41 mmol) was added drop wise. The reaction mixture was stirred and heated at 60° C. overnight, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography to provide 2-chloro-8-cyclopentyl-1-isobutyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.08 g, 69%) as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O.CCOCC>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][S:20][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: CN(C)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCSc1ccc(C(=O)c2ccccc2)cc1
Yield: 55.8 %

Procedure:
12.85 g (0.064 mol) of 4-chlorobenzophenone, 13.6 g (0.13 mol) of 2-dimethylaminoethanethiol and 27.6 g (0.2 mol) of potassium carbonate in 100 ml of dimethylacetamide are kept at 100° C. for 12 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The oil which separates out is taken up in ether. The crude product is purified by means of hydrochloric acid extract and a bulb tube distillation (bath 200°-220° C./0.01 mm Hg). 10.2 g (59%) of product in the form of an oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-benzonitrile (CAS Reg. No. 17201-43-3). Light brown powder (65%). MS (Turbo Spray): m/z=492.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:21]2[C:27](=[O:28])[NH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:12])C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][NH:2][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:21]2[C:27](=[O:28])[NH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:12]
Reactant: Cc1cccc(Nc2nc(NCCCNC(=O)CN(C)C(=O)OC(C)(C)C)nc3cc[nH]c(=O)c23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NCCCNc1nc(Nc2cccc(C)c2)c2c(=O)[nH]ccc2n1
Reaction time: 1.5 h
Yield: 124.4 %

Procedure:
To a solution of 1,1-dimethylethyl methyl(2-{[3-({4[(3-methylphenyl)amino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl}amino)propyl]amino}-2-oxoethyl)carbamate (30 mg, 0.061 mmol) in Dichloromethane (DCM) (1 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1.5 h. It was concentrated and the residue was further dried under high vacuum to give 30 mg of pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Na+].[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[OH-].[Na+].CCOCC>[C:18]1([CH2:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(Oc1ccc(NC(=O)Cc2ccccc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 57.4 %

Procedure:
FIG. 2C illustrates a general reaction scheme for preparing the Group I 2-[4-(arylacetamido)phenoxy]-2-methyl propionic acids. In accordance with the illustrated scheme, 1 g (0.005 mol) of 2-(4-aminophenoxy)-2-methyl propionic acid is dissolved with stirring in 10 ml of water containing 0.41 g (0.1 mol) of NaOH. To this solution, 0.79 g (0.005 mol) of phenyl acetyl chloride in 5 ml of tetrahydrofuran (THF) is gradually added over a period of about 15 minutes. After the addition is complete the pH of the reaction mixture should be alkaline (if not a few drops of 2N NaOH is added to assure alkalinity). The reaction mixture is continuously stirred for 1 hour. Thereafter, the THF is evaporated in vacuo, and the solution is then diluted with 5 ml water and acidified with concentrated hydrochloric acid. The product is extracted with ethyl ether (2×20 ml), washed with water (3×20 ml), and then dried over anhydrous MgSO4. Upon addition of petroleum ether to the ether solution, 0.9 g (56% yield) of the 2-[4-(phenylacetamido)phenoxy]-2-methyl propionic acid product precipitates as a pale brown solid, mp 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[O:7].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Si:18]([O:11][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
Using the conditions described in Example 14c 2.05 of 3,5-dimethoxy-4-hydroxybenzaldehyde were reacted with 2.05 g of tert-butyldimethylchlorosilane in the presence of 0.91 g of imidazole and 15 ml of absolute dimethylformamide. The crude product was purified by chromatography on silica gel [Kieselgel 60 (0.063-0.200 mm)] with petroleum ether/ether (1:1) whereupon 2.91 g of the title compound were obtained in the form of crystals melting at 68° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH:37]([CH3:39])[CH3:38])[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a brown oil (62%).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:13]N1C2C(=CC=CC=2)C(C)=C1>>[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH:13]=[O:1])=[CH:5]1
Reactant: Cc1cn(C)c2ccccc12
Reactant: [OH-]
Reactant: Cn1ccc2cccnc21
Agent: [Na+]
Product: Cn1cc(C=O)c2cccnc21
Yield: 47 %

Procedure:
According to the procedure of Preparation 40 (b), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 5.3 mmole) for the 1,3-dimethylindole, the title compound (0.4 g, 47%) was prepared as a white solid: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:45])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][C:35]([O:43][CH3:44])=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][C:35]([O:43][CH3:44])=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)=[CH:27][CH:28]=1)=[O:45]
Reactant: COc1cc2c(cc1OC)CN(CCc1ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc34)cc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)CN(CCc1ccc(Nc3ncnc4ccc(NC(=O)CCN)cc34)cc1)CC2
Yield: 46.1 %

Procedure:
800 mg of [2-(4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]phenylamino}-quinazolin-6-ylcarbamoyl)-ethyl]-carbamic acid t-butylester dissolved in 16 ml of methylene chloride was reacted with 16 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 200 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure and dried to obtain the title compound (310 mg, 46%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using 4-morpholinecarbonyl chloride. The final product was obtained in 21% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.BrC1N=C(CO[CH2:38][CH2:39][N:40]2[CH2:43][C:42]3([CH2:46][CH2:45][CH2:44]3)[CH2:41]2)C=CC=1>>[CH2:41]1[C:42]2([CH2:46][CH2:45][CH2:44]2)[CH2:43][N:40]1[CH2:39][CH2:38][O:25][CH2:24][C:20]1[N:19]=[C:18]([NH:17][C:15]2[S:16][C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=3[F:1])=[CH:13][C:14]=2[C:26]([NH2:28])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: Brc1cccc(COCCN2CC3(CCC3)C2)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(COCCN4CC5(CCC5)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 251, Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (200 mg, 0.68 mmol) and 2-{2-[(6-bromopyridin-2-yl)methyoxy]ethyl}-2-azaspiro[3.3]heptane (211 mg, 0.68 mmol) as the starting materials.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:12]2([C:15]#[N:16])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: N#CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N#CC1(c2nccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product.
Reaction SMILES: CCCCC.C([Li])CCC.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=O)=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:60])([CH3:59])[CH3:58])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:58])([CH3:60])[CH3:59])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A pentane solution (2.6 ml, 4.2 mmol) of 1.6M n-butyllithium was added dropwise to a solution of n-heptyltriphenylphosphonium bromide (1.84 g, 4.2 mmol) in tetrahydrofuran (10 ml) under a nitrogen atmosphere. After stirring the mixture at room temperature for 30 min, a solution of 5-benzyloxy-4-tert-butyl-2-formylbenzofuran (1.0 g, 3.2 mmol) in tetrahydrofuran (10 ml) was added dropwise. Subsequently, the mixture was stirred at room temperature for 30 min, poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica Gel chromatography (chloroform) to afford 5-benzyloxy-4-tert-butyl-2-(1-octenyl)benzofuran [1.14 g (yield, 91%)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Product: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2OC)cc1
Yield: 80.3 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (331 mg, 1.6 mmol) according to the method of Preparation 15b to give 270 mg (77% yield) of the title compound as an oil. Purity 96%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=[O:28])[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=[O:28])[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCN(CC(=O)O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
[[3-(Benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid (70 mg, 140 μmol) was dissolved in TFA/DCM (1:1, 2 mL) and stirred at room temperature for 30 min. SiO2 (3 g) was added and the solvent was evaporated to afford a white slurry. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 58 mg (99%) of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid as a white solid. [M+H]+ 416.92; 1H NMR (400 MHz, d6-DMSO) δ 9.05 (s, 1H), 8.79 (br s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.06 (s, 1H), 6.97 (m, 2H), 6.06 (s, 2H), 4.39 (br s, 2H), 4.26 (s, 2H), 3.66 (m, 2H), 3.00 (m, 2H), 2.01 (m, 2H).