Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10]([CH3:12])=[O:11].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:9][S:10]([CH3:12])=[O:11])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: CS(=O)CC(=O)c1ccccc1O
Product: CCCCN=C(CS(C)=O)c1ccccc1O
Yield: 95 %

Procedure:
A solution of 2'-hydroxy-2-(methylsulfinyl)acetophenone (15 g, 0.076 mole) in n-butylamine (75 ml) was stirred at room temperature for 16 hrs. The reaction mixture was poured into petroleum ether (500 ml) and the product, which precipitated, was filtered off. Recrystallization from ethylacetate-cyclohexane gave yellow crystals (18.2 g, 95%), mp 128°-129°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][C:3]1[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg), methanesulfonyl chloride (120 mg) and triethylamine (162 mg) in dichloromethane (3 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with 1N-hydrochloric acid, aqueous saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate and concentrated in vacuo. The residual oil was crystallized from ethanol to give 6-[2,6-dichloro-3-bis(methanesulfonyl)aminobenzoyl-amino]-1,2,3,4-tetrahydrodibenzofuran (87 mg).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=O.Cl.[CH3:25][O:26][NH2:27]>O1CCCC1.O>[CH3:25][O:26][N:27]=[CH:1][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 24 h

Procedure:
To a solution of 3-formyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (35 mg) in tetrahydrofuran (3 ml) is added a solution of O-methylhydroxylamine hydrochloride (13 mg) in water (1.5 ml), and the mixture is left standing for 24 hours. After evaporation of the tetrahydrofuran at room temperature, the separated yellow oil is extracted with ethyl acetate. The extract solution is washed with water, dried and evaporated to leave pale yellow foam which gives crystals of 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (37 mg; nearly quantitative yield) by recrystallization from ether and ethyl acetate. m.p. 186°-189° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:17][N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[S:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1
Yield: 87.6 %

Procedure:
1-fluoro-4-nitrobenzene (5.0 g), 2-mercapto-1-methylimidazole (4.04 g) and potassium carbonate (14.7 g) were added to. DMF (100 ml), and the mixture was stirred for 2 hours under argon atmosphere at 130° C. After the mixture was allowed to be at room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water three times, further washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether, to give 1-methyl-2-[(4-nitrophenyl)thio]imidazole (7.29 g) as yellow crystals.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O:7]C)=O)(=[O:3])[CH3:2].C(C(CCCCC)C(O)=O)(=O)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:55][CH:56]([C:58]1[C:59](=[O:73])[NH:60][C:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=2)=[N:62][N:63]=1)[CH3:57]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([NH:55][CH:56]([C:58]1[C:59](=[O:73])[NH:60][C:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=2)=[N:62][N:63]=1)[CH3:57])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCC(C(C)=O)C(=O)OC
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)cc2)[nH]c1=O

Procedure:
1.29 g (6.91 mmol) of methyl 2-acetylheptanoate (Example 16A) are hydrolysed to 2-acetylheptanoic acid according to Example 17A. The acid in 20 ml of dichloromethane is reacted analogously to Example 23A with 903 mg (6.90 mmol) of 1-hydroxy-1H-benzotriazole, 2.02 g (20 mmol) of 4-methylmorpholine, 1.32 g (6.90 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 890 mg (3.4 mmol) of 6-(1-aminoethyl)-3-(4-methoxybenzyl)-1,2,4-triazin-5(4H)-one (Example 10A) to give 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}heptanamide.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][N:13]=1.C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.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>[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:18]#[C:19][C:7]2[C:2]([Cl:1])=[N:3][C:4]([NH2:10])=[N:5][C:6]=2[CH3:9])=[CH:16][CH:17]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.7 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 1.7 g (15 mmol) 2-amino-5-ethynyl-pyridine (GP15) using 106 mg (0.56 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 8 mL (55 mmol) triethylamine in 12 mL dry DMF. For the work-up water is added to the reaction mixture. The precipitate is collected, dried at 40° C. and re-crystallized from MeOH. Yield: 1.5 g (83%, approximately 80% pure).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)C.[C:17]([O-])(=O)C([O-])=O>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH:9]([CH3:17])[CH2:10][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: Cc1cccc(C)c1CC(C)c1c[nH]cn1
Product: Cc1cccc(C)c1C(C)Cc1c[nH]cn1

Procedure:
According to the same method, the following compounds were prepared: 4-[2-(2,6-dimethylphenyl)-1-methylethyl]imidazole. M.p. of the oxalate 161°-5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@H:28]2[CH2:33]N[CH2:31][CH2:30][NH:29]2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[F:18][C:19]([F:34])([F:35])[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@@H:28]2[NH:29][CH2:30][CH2:31][N:17]([C:6]3[C:5]4[CH:4]=[C:3]([CH3:2])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:33]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: FC(F)(F)c1cccc(CC[C@H]2CNCCN2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(C(F)(F)F)c2)C1
Temperature: 105 °C
Reaction time: 64 h
Yield: 40.6 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 370.6 mg (41%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=471.1.
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].ClCCl.[CH2:17]([OH:21])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[P:1]([O:21][CH2:17][CH:18]([CH3:20])[CH3:19])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2]
Reactant: CC(C)CO
Reactant: CCCCOP(=O)(Cl)OCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOP(=O)(OCCCC)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of di-n-butyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane containing 55.37 g (0.70 mole) of pyridine was cooled to 0° C. Isobutanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off, and the solution was washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (25×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded di-n-butyl isobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 94.8% di-n-butyl isobutyl phosphate (DBIBP).
Reaction SMILES: [C:1](O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].B1C2CCCC1CCC2>>[CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Agent: B1C2CCCC1CCC2
Product: CCCCCCCCCCCCO

Procedure:
Following the procedure of Example 1, one mole of lauric acid is reacted with three moles of 9-BBN, added in increments. The reaction mixture is heated under reflux conditions for three hours. Following hydrolysis, an essentially quantitative yield of lauryl alcohol is obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([CH:22]1[CH2:27][O:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[O:24][CH2:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1C=CC=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH:25]3[O:24][CH2:23][CH:22]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:27][O:26]3)=[CH:33][CH:32]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCC1COC(c2ccc(O)cc2)OC1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC1COC(c2ccc(OC(=O)c3ccc(CCCC)cc3)cc2)OC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
A mixture of 4-n-butylbenzoyl chloride (0.98 g. 0.005 m), p-(5-n-octyl-1,3-dioxan-2-yl)phenol (1.37 g, 0.005 m), benzene (40 ml) and pyridine (2 ml) was stirred at room temperature for six hours. The resulting reaction mixture was poured into cold water. The organic layer was separated and washed with diluted hydrochloric acid solution, diluted potassium hydroxide solution and water, then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(5-n-octyl-1,3-dioxan-2-yl)phenyl p-n-butylbenzoate (1.1 g. 51%) CN 65.5°-66.5° C., NL 141°-142° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:8]([C:12]1[C:13]([CH:28]2[CH2:30][CH2:29]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:9][CH2:10][CH3:11].[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.CCOCC>[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH:8]([C:12]2[C:13]([CH:28]3[CH2:30][CH2:29]3)=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)[CH2:9][CH2:10][CH3:11])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCC(Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
231 mg (0.7 mmol) cesium carbonate was added to a solution of 210 mg (0.59 mmol) [rac]-5-(1-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 30D]) and 151 mg (0.59 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 28C]) in 3 ml DMF. After stirring for 3 h at RT, the reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:9 providing 257 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>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.C(COC)OC>[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnccc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cnccc1-c1ccccc1C
Temperature: 80 °C
Yield: 95.7 %

Procedure:
A mixture of 1.2 g (6.9 mmol) methyl 4-chloronicotinoate, 20 ml dimethoxyethane, 6.4 ml 2 N sodium carbonate solution, 0.4 g (0.34 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.4 g (10.3 mmol) o-tolylboronic acid was heated under argon at 80° C. for 18 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate), evaporated and dried in vacuo. The crude oil was subjected to column chromatography to yield 1.5 g (97%) of the title compound as an oil that crystallized upon storage at 0° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(NC(C)C)(C)C>C1COCC1.O.[Cu]I>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]#[C:3][CH2:2][CH2:1][C:5]2[CH:16]=[CH:15][C:8]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 200 mg (0.94 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine, 222 mg (0.94 mmol) 2,5-dibromopyridine, 13.2 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium, 3.6 mg (0.02 mmol) CuI and 0.27 mL diisopropylamine in 10 mL THF is heated for 4 h at 40° C. under an argon atmosphere. The reaction mixture is diluted with water, exhaustively extracted with EtOAc, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: CO.[Li+].[BH4-].C([O:7][C:8](=O)[C:9]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][C:17]([C:25](OCC)=[O:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])C.Cl.[Cl-].[NH4+]>ClCCl>[OH:7][CH2:8][C:9]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:25][OH:26]
Reactant: CCOC(=O)C(C)(CCCSCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCSCCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
Under nitrogen atmosphere, methanol (1.60 g, 50.5 mmol) was added drop-wise to a suspension of LiBH4 (1.10 g, 50.5 mmol) in dichloromethane (20 mL) at rt. A solution of 5-(4-ethoxycarbonyl-4-phenyl-pentylsulfanyl)-2-methyl-2-phenyl-pentanoic acid ethyl ester (7.75 g, 16.5 mmol) in dichloromethane (100 ml) was added drop-wise at gentle reflux. The mixture was stirred under reflux for 16 h, then cooled to rt and carefully hydrolized with 2 N hydrochloric acid (50 mL) and saturated ammonium chloride solution (100 mL). The aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous MgSO4. The filtrate was evaporated to yield the crude product (5.55 g) as a colorless, viscous oil. This residue was purified repeatedly by column chromatography on silica gel (120 g, first with dichloromethane/ethyl acetate=1:1, second with dichloromethane/ethyl acetate=7/1), and dried at 100° C. for 2.5 h under high vacuo to give 5-(5-hydroxy-4-methyl-4-phenylpentylsulfanyl)-2-methyl-2-phenylpentan-1-ol (3.06 g, 41%) as a colorless viscous oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.30 (m, 8H), 7.20 (m, 2H), 3.65 (m, 2H), 3.50 (m, 2H), 2.32 (m, 4H), 1.82 (dt, J=3.9, 9.6 Hz, 2H), 1.60-1.37 (m, 6H), 1.32 (s, 6H), 1.20-1.25 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 144.58, 128.60, 126.81, 126.35, 72.56, 43.42, 37.60, 32.74, 32.71, 23.93, 23.91, 21.6. HRMS (LSIMS, gly): Calcd. for C24H35O2S (MH+): 387.2358, found: 387.2350.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]1[C:21]([CH3:22])=[C:20]([C:23](O)=[O:24])[C:19](=[O:26])[N:18]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:23]([C:20]3[C:19](=[O:26])[N:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:17]([CH3:16])[C:21]=3[CH3:22])=[O:24])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 4-(4-aminophenoxy)pyridin-2-amine (101 mg, 0.5 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (118 mg, 0.51 mmol) in DCM (5 mL) was added EDCI (115 mg, 0.6 mmol) and HOAT (13.6 mg, 0.1 mmol). The reaction was stirred at 45° C. for 3 hours, and then quenched with water (20 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to give the title compound as a light grey solid (110 mg, 49.2%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([NH:21]C(=O)C(F)(F)F)[CH:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].CO.O.O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of N-(3-{[2-(acetylamino)-1,3-benzothiazol-6-yl]oxy}phenyl)-2,2,2-trifluoroacetamide (10.0 g, 25.3 mmol) in tetrahydrofuran (50 mL) were added methanol (25 mL), water (25 mL) and lithium hydroxide monohydrate (1.50 g, 35.7 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added water (200 mL) and ethyl acetate (250 mL), and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/80→0/100), and triturated with ethyl acetate/hexane to give the title compound (3.10 g, 41%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH2:10][CH3:11])=[O:18]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Br
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and ethyl-2-bromoisobutyrate (450 μl; 3.0 mmol) in DMF (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and heated at 120° C. for 4.5 hours. Water was added and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow sticky solid (320 mg; 83%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:21][O:22][C:24]([CH3:29])([CH3:25])[O:23]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CC(O)CO)cnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CC1(C)OCC(Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 810.9 %

Procedure:
A solution of 3-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-propane-1,2-diol (1.67 g, 5.03 mmol), p-toluene sulfonic acid (96 mg, 0.5 mmol) and 2,2-dimethoxy-propane (3.1 mL, 25.2 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (1.51 g, 81%) as a white solid: LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.0.