Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:27])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][S:25][CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.[C:28](O)(=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32].[I-].[K+]>CC(C)=O.Cl.O1CCOCC1>[ClH:1].[C:31]([CH2:30][CH2:29][C:28]([S:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:5]([CH:2]2[CH2:4][CH2:3]2)=[O:27])[CH2:15]/[C:16]/1=[CH:21]\[C:22]1[N:23]=[N:24][S:25][CH:26]=1)=[O:34])([OH:33])=[O:32]
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2csnn2)C1
Reactant: O=C(O)CCC(=O)O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1csnn1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanyl-3-[(1,2,3-thiadiazol-4-yl)methylidene]piperidine hydrochloride (100 mg) in acetone (10 ml) were added anhydrous succinic acid (26 mg) and potassium iodide (45 mg) with stirring at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, anhydrous succinic acid (130 mg) and potassium iodide (180 mg) were further added, and the resulting mixture was furthermore stirred at room temperature for 1.5 hours. After the reaction mixture was evaporated in vacuo, the residue was purified by chromatography on a silica gel column using methanol and dichloromethane (1:50) as the eluent. The amorphous solid obtained was dissolved in a 4N solution of hydrogen chloride in dioxane (2 ml), and the resulting mixture was evaporated in vacuo to afford the title compound (40 mg, yield: 29%) as a colourless amorphous solid.
Reaction SMILES: C[C:2]([C:9]1[C:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:11]2[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[S:16][C:12]2=[N:13][C:14]=1[CH3:15])([CH2:6][CH2:7][CH3:8])[C:3]([O-:5])=[O:4].[OH-].[Na+].Cl>CO>[CH3:15][C:14]1[N:13]=[C:12]2[S:16][C:17]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:11]2=[C:10]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:9]=1[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCC(C)(C(=O)[O-])c1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of Methyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.100 g, 0.244 mmol) in methanol (2.5 mL) was added a solution of sodium hydroxide 10 N (0.25 ml) and the mixture was heated at 100° C. for 18 h in a sealed tube. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.067 g (92%) of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:9])[CH3:8].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:7]([CH3:9])[CH3:8])\[CH3:24])[CH3:19]
Reactant: CC(C)Oc1ccccc1O
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1OC(C)C
Temperature: 23 °C
Yield: 64.2 %

Procedure:
Potassium t-butoxide (7.36 g, 0.066 mol) was added to a stirred solution of 2-isopropoxy-phenol (5.00 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 4.86 g, 0.033 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (5.60 g, 65%) as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][CH2:4]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.90 g of 4,4-difluoropiperidine hydrochloride (5.71 mmol, 1 equivalents) were initially charged in 56 ml of acetonitrile, 1.41 g of tert-butyl (2-bromoethyl)carbamate (6.28 mmol, 1.1 equivalents) and 3 ml of N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equivalents) were added and the mixture was stirred at 80° C. overnight. Twice, 0.4 equivalent of tert-butyl (2-bromoethyl)carbamate was added to the reaction solution, and in each case stirring was continued at 80° C. overnight. The mixture was concentrated and purified on a silica gel column (gradient: from cyclohexane/ethyl acetate: 3:1 to ethyl acetate). This gave 1.28 g (62% of theory; purity 73%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[N:8]#[C:9]Br.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CC(C)=O>[O:22]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:9]#[N:8]
Reactant: N#CBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)ccc1OC#N
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
At −20° C., 20.0 g (0.198 mol) of triethylamine were added with stirring to 21.0 g (0.198 mol) of cyanogen bromide in 200 ml of acetone. After 5 min, 36.9 g (0.198 mol) of methyl 5-chloro-2-hydroxybenzoate were added, and the mixture was stirred at −20° C. for 30 min. The mixture was filtered, the filter was washed with 200 ml of acetone and the combined organic phases were concentrated under reduced pressure. This gave 34.4 g of the title compound as a yellow solid which was directly reacted further.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([NH:16][O:17][CH3:18])=[O:15].NN.[ClH:21]>CO>[ClH:21].[NH2:3][O:12][CH2:13][C:14]([NH:16][O:17][CH3:18])=[O:15]
Reactant: CONC(=O)CON1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CONC(=O)CON
Reaction time: 12 h

Procedure:
2.5 g of [(1,3-Dihydro-1,3-dioxo-2H isoindole-2-yl)oxy]-N-(methoxy) acetamide made as in Example 2(a) is dissolved in 50 ml CH3OH at 0° C. with stirring. A solution of 0.35 g hydrazine in 10 ml methanol is added and stirring at 0° C. is continued for 12 hours. After this time an equivalent amount of hydrochloric acid in 5 ml CH3OH is added and the precipitate formed is filtered off. The mother liquor is evaporated to dryness and 2-(aminooxy)-N-(methoxy)acetamide, hydrochloride as a residual oil is formed and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH2:17])=[O:16])[CH:11]=[N:10]2)=[N:7][CH:8]=1.[N:20]1([CH:26]2[CH2:31][CH2:30][C:29]([C:32]3[C:37]([CH3:38])=[CH:36][C:35](Br)=[CH:34][N:33]=3)=[CH:28][CH2:27]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][S:47]([OH:50])(=[O:49])=[O:48]>O1CCOCC1.C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[S:47]([OH:50])(=[O:49])(=[O:48])[CH3:46].[CH3:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][N:7]=2)[N:10]=[CH:11][C:12]=1[C:15]([NH:17][C:35]1[CH:34]=[N:33][C:32]([C:29]2[CH2:30][CH2:31][CH:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH2:27][CH:28]=2)=[C:37]([CH3:38])[CH:36]=1)=[O:16]
Reactant: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(N2CCOCC2)CC1
Temperature: 100 °C

Procedure:
A suspension of 1-(5-trifluoromethylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxamide (2.2 g) described in Reference Example 120, 2-(4-(morpholin-4-yl)cyclohex-1-en-1-yl)-3-methyl-5-bromopyridine (2.75 g) described in Reference Example 107, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (152 mg), palladium acetate (39 mg) and cesium carbonate (4.01 g) in 1,4-dioxane (30 ml) was stirred at 100° C. After the reaction, the reaction solution was left stand, ice water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with ethanol and the resulting solid was filtered and dried at 60° C. in vacuo to give a white solid. Methanesulfonic acid (0.326 ml) was added to a solution of the resulting solid in chloroform (200 ml) and stirred at room temperature for three hours. Then, the solvent was evaporated, ethanol was added and the precipitated solid was filtered and dried at 60° C. in vacuo to give the titled compound (2.9 g) as a white solid.
Reaction SMILES: [Na].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]=1[OH:24])([CH3:13])([CH3:12])[CH3:11].Cl>>[C:20]([C:16]1[CH:17]=[C:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH:19]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[OH:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCCCCCO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na]
Product: CC(C)(C)c1cc(CCCCCCO)cc(C(C)(C)C)c1O
Temperature: 225 °C
Yield: 66.6 %

Procedure:
To 1.15 grams of metallic sodium (0.05 moles) was added to 59 grams of 1,6-hexanediol (0.5 moles) in a 250 ml flask fitted with a water trap and the mixture was stirred until the sodium dissolved. There was then added 20.6 grams of 2,6-di-tert.-butylphenol (0.1 mole) and the mixture was heated for 7.5 hours at 225° C. The mixture was allowed to cool and the base was neutralized by the addition of 5 ml. of concentrated hydrochloric acid. Sodium chloride from neutralization of the base was removed by filtration and the filtrate was distilled under vacuum. There was obtained 20.4 grams (66.6% yield) of 6-(3,5-di-tert.-butyl-4-hydroxyphenyl)hexanol.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[C:32](Cl)(=[O:34])[CH3:33]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and acetyl chloride. Light-yellow foam. MS (m/z): 455.5 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][NH:23][C:24](=[S:27])[NH:25][NH2:26].O>CN(C)C=O>[CH3:22][N:23]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:26][N:25]=[C:24]1[SH:27]
Reactant: CNC(=S)NN
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(S)nnc1-c1ccccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
15 g of pyridine-2-carboxylic acid (121.8 mmol) were dissolved in 150 ml of dimethylformamide. At room temperature, 29.6 g (181.8 mmol) of carbonyldiimidazole were slowly added, during which gas was evolved. Reaction was allowed to take place at 100° C. for 30 min, and then 25.6 g (242.7 mmol) of 4-methyl-3-thiosemicarbazide were added, and the mixture was stirred at 100° C. for a further 2 h. The reaction mixture was mixed with 300 ml of water. After cooling in an ice bath, the precipitated crystals were filtered off with suction and washed with a little water. The crystals were taken up in 390 ml of 1M sodium bicarbonate solution and heated to reflux for 3 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Cl-].[NH4+].Cl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:26])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dimethyl formamide (10 mL) was added HOBT (0.043 g, 0.28 mmol), EDCI (0.058 g, 0.3 mmol), DIPEA (0.097 g, 0.75 mmol) and ammonium chloride (0.0133 g, 0.25 mmol). The reaction mixture was stirred at room temperature for 20 hr, cooled and poured into water (10 mL). The solution was acidified to pH=3 with 1N aqueous hydrochloric acid. Then the solution was extracted with dichloromethane (70 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, condensed in vacuum and separated by silica gel chromatography (ethyl acetate:methanol=1:0 to 10:1) to afford 0.005 g 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxamide as a solid (yield: 7.8%). 1H-NMR (400 MHz, DMSO-d6) δ 7.37-7.40 (m, 1H), 7.46-7.56 (m, 3H), 7.97-8.05 (m, 3H), 8.38 (s, 2H); LC-MS (ESI) m/z 257 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]1[CH2:31][NH:32][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][N:32]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of 2-bromomethyl-5-cyano-benzoic acid methyl ester and 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester in CH3CN with DIPEA, KI, and DMAP gave 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(1-pyridin-2-yl-ethyl)amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3) δ 1.56-1.59 (m, 3H), 1.71 (s, 9H), 3.86 (s, 3H), 4.23 (s, 1H), 4.28-4.30 (m, 2H), 4.40-4.47 (m, 2H), 7.10-7.16 (m, 1H), 7.24-7.32 (m, 3H), 7.42-7.46 (m, 1H), 7.51-7.66 (m, 2H), 7.71-7.76 (m, 1H), 7.82 (d, 1H, J=1.7 Hz), 7.92 (d, 1H, J=8.0 Hz), 8.53 (d, 1H, J=4.8 Hz).
Reaction SMILES: C1C2C(COC(N[C@H](C(OC(C)(C)C)=O)CSC[C@@H](CCCCCCCCCC([O-])=O)CCCCCCCCCCC([O-])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:56]([O:69][C@H:70]([CH2:96][O:97][C:98](=[O:110])[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107]CC)[CH2:71][S:72][CH2:73][C@@H:74]([C:93]([OH:95])=[O:94])[NH:75][C:76](=[O:92])[O:77][CH2:78][CH:79]1[C:91]2[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=2[C:85]2[C:80]1=[CH:81][CH:82]=[CH:83][CH:84]=2)(=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]CC>>[C:56]([O:69][C@H:70]([CH2:96][O:97][C:98](=[O:110])[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH3:107])[CH2:71][S:72][CH2:73][C@@H:74]([C:93]([OH:95])=[O:94])[NH:75][C:76](=[O:92])[O:77][CH2:78][CH:79]1[C:91]2[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=2[C:85]2[C:80]1=[CH:81][CH:82]=[CH:83][CH:84]=2)(=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CC(C)(C)OC(=O)[C@H](CSC[C@H](CCCCCCCCCCC(=O)[O-])CCCCCCCCCC(=O)[O-])NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCC

Procedure:
The product was prepared from (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diylbis(decanoate) by following the procedure described for compound 6.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[N:9]=[C:5]2[CH:4]=1.B(Br)(Br)Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[CH:19][C:6]2=[N:7][N:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=3)[N:9]=[C:5]2[CH:4]=1
Reactant: COc1ccc2nn(-c3ccc(N(C)C)cc3)nc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1ccc(-n2nc3ccc(O)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.2 %

Procedure:
Under N2, 130 mg (5 mmol) of 9f was dissolved in (5 ml) CH2Cl2, at 0° C. was slowly added 0.458 ml (50 mmol) of BBr3. The solution was stirred overnight at room temperature. The reaction was poured into ice/water and alkalinized with Na2CO3 (aqueous) and the organic layer was extracted and dried over Na2SO4. After removing the solvent by evaporation, the residue was purified by chromatography (dichloromethane/ethyl acetate, 95/5). The solvent was evaporated to obtain 91 mg (74%) of 9h as yellow solid.
Reaction SMILES: [N:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[N:5]=1)=[N+]=[N-].[CH3:17]O>[Pd]>[CH3:16][O:15][C:6]1[N:5]=[C:4]2[N:1]=[CH:17][NH:10][C:9]2=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1cc([N+](=O)[O-])c(N=[N+]=[N-])nc1OC
Agent: [Pd]
Product: COc1cc2[nH]cnc2nc1OC

Procedure:
A suspension of 11.6 g of 2-azido-5,6-dimethoxy-3-nitropyridine (example E5) in 600 ml methanol was treated with 1.7 g Pd/C (10% Pd) and hydrogenated for 16 h under atmospheric pressure. The reaction mixture was rapidly filtered through a plug of CELITE® (diatomaceous earth), the filtrate was concentrated under vacuum and the residue was refluxed in 100 ml of formic acid for 18 h. The formic acid was removed under vacuum and the resulting residue was dried under vacuum at 100-110° C. to yield crude 5,6-dimethoxy-1H-imidazo[4,5-b]pyridine (as formic acid salt and/or as free base) that was used for the following step without further purification (MS (MH+ found)=180.2).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]4=[C:26]([CH:49]=3)[N:27]=[C:28]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:29][C:30]([C:32](=[O:40])[N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])=[CH:31]4)=[CH:18][CH:17]=2)=[O:15])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[C:32]([C:30]1=[CH:31][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]([N:11]4[CH2:12][CH2:13][C@@H:9]([OH:8])[CH2:10]4)=[O:15])=[CH:17][CH:18]=3)=[CH:49][C:26]=2[N:27]=[C:28]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:29]1)=[O:40])[CH2:38][CH3:39]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O[Si](C)(C)C(C)(C)C)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (1E,4E)-8-(4-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (225 mg, 0.327 mmol) in THF (4 mL) at 0° C. was added a solution of TBAF (0.34 mL, 0.34 mmol, 1 M solution in THF). The resulting mixture was warmed to room temperature and stirred for 1.5 hr. The reaction mixture was diluted with EtOAc and washed with brine (2×). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude tert-butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate that was used directly without further purification. MS APCI (+) m/z 575 (M+1) detected.
Reaction SMILES: Cl[C:2]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]1[F:5].NCCN>[Ni].C(O)C>[F:5][CH:3]1[CH2:4][CH:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C1(Cl)CC1F
Agent: [Ni]
Solvent: NCCN
Solvent: CCO
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 1-chloro-2-fluoro-1-cyclopropanecarboxylate (cis:trans=1.4:1), 0.5 ml of Raney nickel and 5 ml of ethanol were fed thereinto. Then 0.18 mg of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (10 kgf/cm2) for 48 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 95%, the yield was 81% and the cis:trans ratio was 0.3:1.