Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[F:17][C:18]([F:35])([F:34])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:9]1[CH2:14][CH2:13][CH:12]([NH:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:34])[F:35])=[CH:21][CH:22]=3)=[CH:27][CH:28]=2)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A4) (1.09 g, 1.2 equiv), ({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amine hydrochloride (Int. A2) (1.28 g, 1.0 equiv), DCE (21 ml) and acetic acid (0.27 ml, 1.1 equiv) was stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (1.42 g, 1.5 equiv) was added and stirring continued for 3 hours. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 45 min, then the mixture was partitioned with a mixture of diethyl ether/THF and water. The organic extracts were backwashed with water and brine, and dried over sodium sulfate and evaporated in vacuo. The desired product was obtained as a light yellow solid (2.14 g) which was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([O:26]C)=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:28]=[CH:29][CH:30]=[C:4]12)[CH3:2].B(Cl)(Cl)Cl>>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([OH:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:28]=[CH:29][CH:30]=[C:4]12)[CH3:2]
Reactant: CCC1c2cccn2-c2cc(OC)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Agent: ClB(Cl)Cl
Product: CCC1c2cccn2-c2cc(O)c(F)cc2N1S(=O)(=O)c1ccc(O)c(C)c1

Procedure:
The title compound was prepared from the product of Example 73 following the procedure of Example 5 but using 4 equivalents of boron trichloride to yield light tan crystals, mp 194-196° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17](OC(C)(C)C)=[O:18].[O-]CC.[Na+]>CCO>[OH:18][N:17]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)ON=O
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)C(=NO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-phenyl-1-p-tolylethanone (5.0 g, 23.78 mmol) in EtOH (475.0 mL) at room temperature was added dropwise tert-butyl nitrite (5.5 mL, 46.2 mmol) followed by sodium ethoxide (4.07 g, 59.8 mmol). The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an orange oil (5.31 g). LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.Cl[CH2:14][CH:15]=[CH2:16].Cl>CCOCC>[CH3:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:16][CH:15]=[CH2:14])=[CH:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C=CCCl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=CCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a Grignard reagent prepared from 12 g magnesium, 250 ml ether and 100 g 1-bromo-4-(1,1-dimethylethyl)benzene were added 50 g 3-chloro-1-propene dissolved in 150 ml ether. After the addition, the mixture was refluxed for one hour and kept stirring overnight at room temperature. The reaction mixture was then poured onto crushed ice and acidified with hydrochloric acid to dissolve any precipitated solid. The ether solution was separated, washed with water, and dried with anhydrous sodium sulfate, solvent removed and product distilled to provide 40 g of 1-(1,1-dimethylethyl)-4-(2-propenyl)benzene, listed in Table 1 as compound I-1. The product was characterized by a boiling point of 65°-66° C. at a pressure of 0.25 mm Hg.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([S:58]([CH:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)(=[O:60])=[O:59])[CH:53]=1>CC#N.O>[CH:61]1([S:58]([C:54]2[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C@@H:10]([C:12]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:18]4[C:13]=3[CH:14]=[CH:15][C:16](=[O:30])[NH:17]4)[OH:11])[CH:57]=[CH:56][CH:55]=2)(=[O:60])=[O:59])[CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: O=c1ccc2c([C@@H](O)CNCc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(=O)(=O)C4CCCC4)c3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 25.2 %

Procedure:
5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one (40 mg) was dissolved in MeCN (2 ml). N,N,-diisopropylethylamine (0.03 ml) and 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v) (30 mg) were added and the reaction mixture was heated at 80° under nitrogen for 48 h. The mixture was then diluted with water and extracted with EtOAc. The organic phases were combined, dried (MgSO4), and evaporated in vacuo. The residue was purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures, to give the title compound, (13 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:33])[C:14]1[N:19]=[C:18]([C:20](O)=O)[N:17]=[C:16]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:15]=1>>[F:33][CH:13]([F:12])[C:14]1[CH:15]=[C:16]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:17]=[C:18]([C:20]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[N:19]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)F)n1
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 6-difluoromethyl-4-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.3) (0.16 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.066 g, 30%). MS (ISP) 435.1 [(M+H)+]; mp 219° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=[C:34]([CH2:41][CH2:42][CH3:43])[CH:33]=3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:41]([C:34]1[CH:33]=[C:32]([N:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:22][CH:21]=3)(=[O:25])=[O:24])[CH2:31][CH2:30]2)[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=1)[CH2:42][CH3:43]
Reactant: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 4-chloro-7-trifluoromethylquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine to give 1-(3,5-dipropylphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.2 G. of 4-chloro-5-cyano-2-(4-n-butylphenyl)-pyrimidine are reacted in 230 ml. of 50% dioxane with 21.7 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-butylphenyl)-pyrimidine as colorless crystals of melting point 108.6°-109.5° C., which on cooling are nematic (monotropic) at 101.5° C. The substance is identical with the compound obtained according to Example 8.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][Cl:16].BrCCBr>O1CCCC1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:14][CH2:15][Cl:16])[C:4]1=[O:12])[CH3:2].[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2]
Reactant: ClCCBr
Agent: CCn1c(=O)[nH]c2ccccc21
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCn1c(=O)n(CCCl)c2ccccc21

Procedure:
When an equivalent amount of 3-ethyl-2-benzimidazolinone is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using tetrahydrofuran as solvent, 2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol1-yl)ethyl chloride is isolated after column chromatography (3-ethyl-2-benzimidazolinone, Aldrich, 6%, A).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([NH2:12])[CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([NH:12][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][CH2:2]2)[CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCC1
Reactant: Clc1cnccn1
Solvent: O
Product: C1=CN(NC2CCC2)CC=N1
Temperature: 110 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 2-chloropyrazine (26.12 g, 228.0 mmol) and cyclobutylamine (40.00 mL, 468.5 mmol) was heated in a pressure reaction flask with stirring to 110° C. for 16 hours. The brown reaction was allowed to cool to room temperature and was diluted with water (750 mL). The aqueous solution was extracted with ethyl acetate (2×250 mL). The combined organic solutions were washed with water (1×250 mL), saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. The crude product was purified by MPLC (20% ethyl acetate-40% ethyl acetate/hexanes) to afford N-cyclobutylaminopyrazine (EX-115A) in 93% yield: 1H NMR (300 MHz, DMSO) δ 7.97-7.96 (m, 1H) 7.82-7.79 (m, 2H), 5.12 (br s, 1H), 430-4.18 (m, 1H) 2.51-2.39 (m, 2H), 1.97-1.73 (m, 4H); 13C NMR (75 MHz, DMSO) δ 149.3, 137.6, 128.3, 126.9, 42.2, 26.7, 10.7; HRMS (ES) calcd for C8H12N3 150.1031, found 150.0992.
Reaction SMILES: [C:1]([NH:8][OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:30])[CH:16](OS(C)(=O)=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:13]>CN(C=O)C>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([O:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:13]
Reactant: CCOC(=O)C(CCc1ccccc1)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)ONC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To a solution of BocNHOH (958 mg, 7.2 mmol) in DMF (15 mL) was added NaH (60% in mineral oil, 320 mg, 8 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 15 min. The compound from Step 9a (1.81 g, 6 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×15 mL), dried (Na2SO4) and filtered. The organic solvent was removed under reduced pressure and residue was purified by flash chromatography (Hexanes/EtOAc=3/1), giving 1 g (50%) of the title compound. 13C NMR (CDCl3): δ17172.0, 156.6, 141.3, 128.8, 128.7, 126.3, 83.3, 82.2, 61.5, 33.0, 31.7, 28.5, 14.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:23](=[O:25])[CH3:24])[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Product: CC(=O)n1ccc2c1C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: [CH2:1]([S:8]([OH:11])(=[O:10])=[O:9])[CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].O.O.O.O.O.O.O.O.[OH-].[Sr+2:21].[OH-]>O>[Sr+2:21].[CH2:3]([S:4]([O-:7])(=[O:6])=[O:5])[CH2:2][CH2:1][S:8]([O-:11])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)CCCS(=O)(=O)O
Agent: [OH-]
Agent: [Sr+2]
Solvent: O
Product: O=S(=O)([O-])CCCS(=O)(=O)[O-]
Temperature: 4 °C
Yield: 63 %

Procedure:
A mixture of 222 g of 70% 1,3-propanedisulphonic acid in water (0.76 mol) and 200.4 g of strontium hydroxide octahydrate (0.75 mol) in 200 ml of water is heated at reflux for 3 hours. The reaction mixture is filtered hot and then cooled to 4° C. The precipitate formed is removed by filtration and 500 ml of 96% ethanol are added to the filtrate. The precipitate is filtered off, rinsed with 250 ml of a 70/30 ethanol/water mixture and dried to obtain 139 g of a white crystalline product of 1,3-propanedisulphonic acid strontium salt (yield 63%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[Br:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Br:9][C:10]1[CH:11]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:13]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: OCc1nc2ncc(Br)cn2n1
Temperature: 60 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (6.29 g, 33.12 mmol) in acetic acid (25 ml) was added bromomalonaldehyde (5 g, 33.12 mmol). The mixture was heated at 60° C. for 5 hours, and then cooled to room temperature. The light yellow solid was formed. After the solid were removed by filtration followed by drying in vacuum oven provides the light yellow solid as desired product, the filtrate was concentrate by rotary evaporation to give yellow oil. The crude oil was purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light yellow solid (combine total 6.5 g, 86% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 4.65 (d, J=5.46 Hz, 2H) 5.50-5.67 (m, 1H) 8.94 (d, J=2.45 Hz, 1H) 9.83 (d, J=2.26 Hz, 1H). MS: (APCI) 230 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-pentyloxyethoxy)phenyl borate (180 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-pentyloxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 106) (188 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:30][O:31][CH:32]1[CH2:35][NH:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:34]4[CH2:35][CH:32]([O:31][CH3:30])[CH2:33]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Agent: Cl
Product: COC1CN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4cccc(F)c4)nc3c2)C1
Yield: 14.1 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 158 μmol) and 3-methoxyazetidine hydrochloride (58.5 mg, 473 μmol) as starting materials. The reaction affords 4-(3-methoxy-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (10 mg, 14.1%) as white solid. mp.: 255-257° C., MS: m/z=450.0 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]1[C:22]([OH:23])=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:19]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:17][C:18]1[C:22]([O:23][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:19]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(=O)OC(C)(C)C)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
tert-Butyl 2-bromoacetate (0.55 ml, 3.41 mmol) was added dropwise to a stirred solution of diethyl 3-(benzyloxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (23) (1.0 g, 2.28 mmol) and K2CO3 (0.63 g, 4.55 mmol) in DMF (20 mL). The reaction mixture was stirred at RT for 18 h, and partitioned between EtOAc (200 mL) and sat. NaHCO3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHCO3 (aq.) (2×200 mL), dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The residue was purified by silica gel chromatography (120 g, 0-20% EtOAc in isohexane) to afford diethyl 3-(benzyloxy)-4-(2-(tert-butoxy)-2-oxoethoxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-028) (912 mg, 72%) as a pale yellow oil: m/z 554 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.49-7.44 (m, 2H), 7.43-7.31 (m, 3H), 7.15-7.08 (m, 2H), 6.94-6.88 (m, 2H), 5.12 (s, 2H), 4.59 (s, 2H), 4.02-3.94 (m, 4H), 3.79 (s, 3H), 1.40 (s, 9H), 1.02 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=O)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16]C(N)=O>>[C:1]1([CH:7]2[CH2:12][C:13](=[O:15])[NH:16][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=O
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Product: O=C1CC(c2ccccc2)CC(=O)N1

Procedure:
29.0 g (139 mmol) 3-phenylglutaric acid and 8.4 g (139 mmol) urea are stirred at 150° C. for 1.5 hours. After cooling, the reaction mixture is recrystallized from methanol: Yield 20.9 g (79%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29]C1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:27]2)[CH2:21][CH2:22]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[F:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(F)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Fc1ccc2c(c1)CNC2
Yield: 0.1 %

Procedure:
The procedure of Reference Example 6-(3) was followed using 10.2 g of 2-(p-toluenesulfonyl)-5-fluoroisoindoline, 10 g of phenol, 150 ml of 48% hydrobromic acid, and 25 ml of propionic acid. Purification of the crude product by vacuum distillation gave 5.0 mg of 5-fluoroisoindoline.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[C:6]1([C@@H:5]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:4][OH:3])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](OC1CCCCO1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC[C@H](OC1CCCCO1)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 4 g (15.1 mmole) of (R)-(−)-ethyl-2-phenyl-2-(tetrahydropyranyloxy)acetate (8) in 75 ml of dry ether was added dropwise to a stirred suspension of 1.72 g (45.3 mmole) of lithium aluminium hydride and 50 ml of ether at room temperature. After the addition was completed, the mixture was refluxed for additional 2 h, then cooled in an ice bath, and treated carefully subsequently with 1.72 ml of water, 1.72 ml of 15% sodium hydroxide, and 5.4 ml of water. After being stirred for additional 30 min, the mixture was filtered with suction, and the precipitate (aluminum salts) was washed with ether. The combined ethereal solution was dried over magnesium sulfate, and the solvent was evaporated to leave 3.3 g of a clear oil (97%).