Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CI.[C:69]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH3:69])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (29 mg) was reacted with methyl iodide and K2CO3 in DMF to give (S)-2-({(3S,8S)-7-[2-(acetyl-methyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS (m/z): 982) according to General Procedure O. This product (26 mg) was hydrolyzed according to General Procedure B to furnish the title compound (22 mg). LCMS (m/z): 0.924.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28]>CN(C=O)C.O>[Si:6]([O:29][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 1265.9 %

Procedure:
Imidazole (9.29 g (136 mmol) was dissolved in 50 ml of DMF under nitrogen with stirring. To this solution was added 18.75 g (17.74 mmol) of t-butyldiphenylsilyl chloride and 5.27 g (5.55 mmol) of 4-pentyn-1-ol and the mixture was stirred at room temperature for 2 h. The mixture was carefully diluted with 300 ml of water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 22.66 g of a yellow oil which was purified by passing through 150 g pad of silica gel eluting with hexane and 3% ethyl acetate in hexane affording 17.56 g (86.8%) of the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH:37](C)[CH3:38]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH:37]([CH3:38])[CH3:36])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-4′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.342 mmol). Added to the flask was 4N HCl in dioxane (2 mL). The flask was capped and the contents were stirred at room temperature for 1 h. The solution was concentrated in vacuo. Added to the flask in succession were dichloromethane (3 mL) and N,N-diisopropylethylamine (0.200 mL). The flask was cooled to 0° C. in an ice bath. In a separate vial, isobutryl chloride (0.348 mmol) was taken up with dichloromethane (2 mL) and was added to the cold solution dropwise via pipette. The reaction was stirred for 2 h while the ice bath was allowed to warm to room temperature. The reaction was then diluted with dichloromethane (20 mL) and washed with saturated aq NH4Cl. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (65 mg, 43%). MS(ES)+ m/e 439.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])O[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8]([O:11][CH2:14][CH3:15])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC([O-])[O-]
Reactant: CC(=O)NC1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC1=CCC(NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.7 g. of 4-acetamidocyclohexanone [prepared by the method of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970)], in 150 ml. of anhydrous ethanol were added 25 ml. of ethyl orthoformate containing a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred at ambient temperature for about 16 hours, after which time the volatile constituents were removed by evaporation in vacuo. The residue comprising the diethylketal was dissolved in 200 ml. of toluene and the toluene was removed by distillation under a nitrogen atmosphere, until all of the diethylketal had been converted to the 1-ethoxycyclohexene derivative. The solution was cooled, washed with aqueous sodium bicarbonate and dried. Evaporation of the toluene yielded a residue comprising 4-acetamido-1-ethoxycyclohexene melting at 100°-102° C. after recrystallization from an ether-hexane solvent mixture; yield=6.2 g.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[F:14][C:15]([F:25])([F:24])[S:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([S:16][C:15]([F:25])([F:14])[F:24])=[CH:18][CH:19]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Product: CN(C)c1ccc(CC(=O)Nc2ccc(SC(F)(F)F)cc2)cc1

Procedure:
The product was prepared from 2-(4-(dimethylamino)phenyl)acetic acid (23 mg) and 4-trifluoromethylthioaniline (28 mg) according to Method C: 1H NMR (300 MHz, CDCl3) δ ppm 2.98 (s, 6 H), 3.66 (s, 2 H), 6.72-6.78 (m, 2 H), 7.14-7.19 (m, 2 H), 7.19 (s, 1 H), 7.43-7.51 (m, 2 H), 7.52-7.57 (m, 2 H); MS (ESI-pos) m/z 355.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]([NH2:37])=[NH:36]>C1COCC1>[NH2:36][C:35]([NH2:37])=[N:34][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccc(=O)[nH]n1
Reactant: N=C(N)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1ccc(=O)[nH]n1
Reaction time: 2 h

Procedure:
A solution of 540 mg of 3-methylsulfonyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)benzoic acid [obtainable by reacting 3-methylsulfonyl-4-chlorobenzoic acid with 3-trimethylsilyl-oxy-6-oxo-1,6-dihydropyridazine] and 300 mg of carbonyldiimidazole in 15 ml of THF is stirred at room temperature for 2 hours, and 383 mg of guanidine are then added to it. This mixture is then stirred for a further two hours. After the customary working-up, N-diaminomethylene-3-methylsulfonyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)benzamide is obtained, m.p. 268-270°.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:19][C:20]1[C:24]([C:2]2[CH:18]=[CH:17][C:5]3[NH:6][C:7](=[O:16])[O:8][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:4]=3[CH:3]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)OC(=O)N2

Procedure:
6-Bromo-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (150 mg, 0.493 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (208.5 mg, 1.480 mmol), 1,1′-bis(diphenylphosphino)ferocene-palladium(II)dichloride dichloromethane complex (80.5 mg, 0.099 mmol) are added to a microwave vessel. A saturated acqueous solution of sodium carbonate (1 mL) and dimethoxyethane (2 mL) are added. The vessel is purged with argon for 10 min. The reaction mixture is heated in a microwave reactor for 90 minutes. The mixture is filtered and the filter cake is washed with dichloromethane. The volatiles are removed on in vacuo and the residue purified by reversed phase HPLC.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][CH2:28][C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ncc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (400 mg, 1.41 mmol) and (2-methylpyrimidin-5-yl)methanamine (400 mg, 3.25 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light brown solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:24]=1[C:25](O)=[O:26]>>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)[C:24]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4c(F)cccc4-c4ncccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 14. MS (ESI): mass calculated for C24H23F4N7O, 501.49; m/z found 502.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.86-8.63 (m, 2H), 8.22-8.05 (m, 1H), 7.56-7.40 (m, 1H), 7.29-7.18 (m, 1H), 7.12 (br s, 1H), 6.03-5.73 (m, 1H), 4.19-2.90 (m, 16H).
Reaction SMILES: C(Cl)(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:15]([CH2:21][CH2:22][CH3:23])=[N:14][C:13]=1[C:24]#[N:25]>C(O)C>[CH3:19][CH:18]([CH3:20])[CH2:17][N:16]1[C:12]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[C:24]([NH2:25])[C:13]=2[N:14]=[C:15]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc(C#N)c(-c2ccccc2N)n1CC(C)C
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Yield: 60 %

Procedure:
Under a nitrogen atmosphere, a solution of acetyl chloride (15 mmol) in anhydrous ethanol (50 mL) was stirred for 15 minutes and then added to 5-(2-aminophenyl)-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (2.75 g). The reaction was heated at reflux under nitrogen for 16 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was partitioned between 2M aqueous sodium carbonate and chloroform. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product (2.81 g) was purified by automated flash chromatography (eluting with 0% to 20% CMA in chloroform) and then recrystallized from acetonitrile (50 mL). The crystals were dried overnight at 33 Pa and 98° C. to provide 1.65 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 191-192° C.
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:12]2[CH:27]=[CH:28][CH:29]=[CH:30][C:11]=2[N:10]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[CH2:48][CH2:47][C:46]=3[C:53]3[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=3)[CH2:40][CH2:39]2)[CH:33]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([C:46]2[CH2:47][CH2:48][C:49]([CH3:52])([CH3:51])[CH2:50][C:45]=2[CH2:44][N:41]2[CH2:40][CH2:39][N:38]([C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[CH2:31][N:10]3[C:11]4[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=4[N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([OH:23])=[O:22])[C:9]3=[NH:8])[CH2:43][CH2:42]2)=[CH:58][CH:57]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3cccc(Cn4c(=NC(=O)OC(C)(C)C)n(CCCOc5cccc(C(=O)O)c5)c5ccccc54)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3cccc(Cn4c(=N)n(CCCOc5cccc(C(=O)O)c5)c5ccccc54)c3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of 3-{3-[2-[tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (0.15 g, 0.18 mmol) in dichloromethane (2.25 ml) at rt was added TFA (0.75 ml). The reaction was stirred at rt for 1 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to provide 3-{3-[3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (8.5 mg, 6%). HPLC-MS 718 [M+1]+, 360.
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1>O1CCCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:15]2[O:14][CH:13]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:16]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1ccc(-c2ccoc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(-c3ccccc3)co2)OC1(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
A solution of n-BuLi (6.2 mL, 2.5 M solution in hexane) was added drop-wise to a solution of 3-phenylfuran (1.5 g, 10.40 mmol) in dry tetrahydrofuran (100 mL) at −78° C. under nitrogen. It was warmed slowly to −40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again to −78° C. followed by the dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.72 g, 19.99 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was precipitated by cooling to afford 4,4,5,5-tetramethyl-2-(3-phenylfuran-2-yl)-1,3,2-dioxaborone as a white solid (400 mg, 14.0%). The mother liquid was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford 4,4,5,5-tetramethyl-2-(4-phenylfuran-2-yl)-1,3,2-dioxaborolane (200 mg, crude), which was used to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:12])([CH3:11])[CH3:10].[CH3:16][O-].[Na+].CI>CO>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([S:12][CH3:16])([CH3:10])[CH3:11]
Reactant: C[O-]
Reactant: COC(CC(C)CCCC(C)(C)S)OC
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(CC(C)CCCC(C)(C)SC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 10 g. of 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane, one equiv. of sodium methoxide and 100 ml. of methanol is added 1.5 equivalents of methyl iodide. The mixture is stirred for 2 hours at room temperature and then refluxed for 2 hours. After cooling to room temperature, solvent is removed by evaporation and the residue taken up in ether. The ether solution is washed with water, dried and evaporated under reduced pressure to give 1,1-dimethoxy-7-methylthio-3,7-dimethyloctane which can be purified by chromatography or distillation.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([Br:20])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1cccc2cc(C(C)=O)oc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2cc(C(C)=O)oc12
Reaction time: 1 h

Procedure:
2-Acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) was dissolved in glacial acetic acid (29 mL) followed by addition of sodium acetate (1.3 g, 15.8 mmol). The reaction was treated dropwise with a solution of bromine (0.26 mL, 5.26 mmol) in glacial acetic acid (10 mL) at room temperature followed by stirring for one hour. The solvent was removed under vacuum. The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were washed with 2% aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel using a 50-100% dichloromethane/hexane gradient affording the product as a white solid. (1.00 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.44 (s, 1H), 7.32 (d, 1H), 6.80 (d, 1H), 4.0 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:4][NH:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]([CH2:17][NH:18]C(=O)C)[CH:15]=[CH:16][C:10]=2[CH2:9][CH2:8][CH2:7]1.Cl>>[ClH:1].[ClH:1].[NH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:5][CH2:4][C@H:3]([OH:2])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12][C:11]=2[CH:13]=1
Reactant: CC(=O)NCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Agent: Cl
Product: NCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 190.5 %

Procedure:
A mixture of N-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]methyl acetamide hydrochloride (100 mg) and 1N aqueous hydrochloric acid solution (2 ml) was heated to reflux for 18 hours. The solvent was removed under reduced pressure to dryness. The residue was triturated in diisopropyl ether, and the precipitated powder was collected by filtration to afford (2S)-1-[(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-yl)amino]-3-phenoxy-2-propanol dihydrochloride (94 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:8][C:9]=1[N:10]([C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:27]([N:10]([CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)=[CH:15][CH:16]=1)[C:9]1[CH:8]=[C:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:36]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 5 h
Yield: 76 %

Procedure:
3-{(2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl)-furan-2-ylmethyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester (62 mg, 0.098 mmol) was dissolved in THF (5 mL) and water (2 mL). A solution of lithium hydroxide (13 mg, 3 eq. in 2 mL of water) was added dropwise. After first few drop, a pink color appeared and disappeared. Mixture was stirred for 5 hrs and acidified with 1N HCl-solution. The product was extracted into ethyl acetate, washed once with water, dried over magnesium sulfate. Solvent was evaporated and the residue was purified on silica gel (Bond-Elute 2 g). The product was elute with a 20 mL gradient of Hexane:EtOAc 9:1. 4:1, 7:3, 3:2, 1:1, 2:3 and EtOAc to give the desired product in 76% yield (46 mg).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][C:3]1[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cn2c(n1)CCCC2
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cnc2n1CCCC2
Yield: 25.1 %

Procedure:
375 mg of the 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-1] was dissolved in 10 mL of carbon tetrachloride, then 546 mg of N-bromosuccinimide was added, and the mixture was heated for 30 minutes under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and then by preparative thin-layer chromatography sequentially, to obtain 155 mg of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-2] as a pale yellow solid.