Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:25]([CH3:28])([CH3:27])[CH3:26])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[N:8]=1.Cl.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>CO.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([C:25]([CH3:27])([CH3:28])[CH3:26])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH3:16])[N:8]=1
Reactant: C[C@@H](CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1)NC(=O)OC(C)(C)C
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (2.6 g, 4.4 mmol) in methanol was treated with aqueous 12 N HCl (1.4 mL. 16.8 mmol). The reaction was heated at 60° C. for 1 h, and allowed to cool to rt. The reaction was then concentrated and dried in vacuo to give 1.6 g of a crude residue which was carried forward without further purification. The residue was treated with diisopropylethyl amine (4.6 mL, 26.3 mmol) in dry DCM (18 mL), followed by the dropwise addition of methoxyacetyl chloride (0.44 mL, 4.8 mmol). The reaction mixture was stirred at rt for 1 h, then concentrated, in vacuo, to dryness. The remaining residue was dissolved in EtOAc (40 mL) was washed with water (2×), dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (SiO2, 90:10-50:50 hexanes-EtOAc) to afford 1.3 g of (S)—N-(1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(N(CC)CC)C.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([NH:8][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(Cc1cccc(N)c1)OC
Reactant: CCCCCCCC(=O)Cl
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)Nc1cccc(CC(OC)OC)c1
Reaction time: 0.17 h

Procedure:
By the method outlined in example 9 above, 3-(2,2-dimethoxyethyl)aniline is prepared from 3-nitrobenzaldehyde. To a solution of this material (2.13 g) in dichloromethane (25 ml) is added triethylamine (1.7 ml). The solution is cooled in an ice bath, and octanoyl chloride (2.0 ml) is added dropwise with stirring. After 10 min, the solvent is removed in vacuo and the residue is taken up in ether, filtered, and washed with aqueous sodium bicarbonate. The solution is dried, filtered, and concentrated to leave N-(3-(2,2-dimethoxyethyl)phenyl)octanamide (3.4 g) as a light brown oil. By the method of example 2 above, this is converted into the title compound, mp 128°-130° after recrystallization from dichloromethane.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:12])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[N:14]#[C:15][NH2:16]>>[ClH:1].[CH2:6]([C:5]1[N:12]=[C:15]([NH2:16])[NH:14][CH:4]=1)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: C#CCCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCCc1c[nH]c(N)n1
Yield: 87 %

Procedure:
2-Amino-oct-7-ynoic acid methyl ester hydrochloride (2.90 g, 14.1 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (2.45 g, 87%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.43 (s, 1H), δ 2.44 (t, 2H), 2.14 (t, 1H), δ 2.12 (m, 2H), δ 1.64 (m, 2H), δ 1.47 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 127.6, 108.5, 83.4, 68.7, 27.7, 27.1, 23.8, 17.5 ppm; HRMS (ESI) calcd for C9H14N3 (M+) 164.1182. Found 164.1182.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)nc2)CC1
Yield: 98.2 %

Procedure:
Methyl-4-(6-nitro-pyridin-3-yl)-piperazine (1.748 g, 7.865 mmol) was stirred in 30 mL methanol with 175 mg 10% palladium on carbon under an atmosphere of hydrogen gas for 5 hours. This was filtered and concentrated in vacuo to yield 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.485 g, 7.724 mmol). MS (ESI) 193.1 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[NH:3]1.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[O:16]=[S:2]1(=[O:1])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([NH2:12])[C:4]=2[NH:3]1
Reactant: CC1c2c(Cl)ccc([N+](=O)[O-])c2NS1(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1c2c(Cl)ccc(N)c2NS1(=O)=O
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To the solution of 1,3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-nitro-2,1-benzisothiazole (50 mg, 0.19 mmol) in ethanol (5 ml), Tin (II) chloride (214 mg, 0.95 mmol) was added. The reaction mixture was stirred at reflux for about 4 hours. Then was cooled to room temperature. NaHCO3 (aqueous) was added to the reaction mixture until pH=7. Then the solution was extracted with ethyl acetate (3×). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (32 mg, 72%). EI-MS m/z 233.5 (M+)
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])[CH:7]=[C:8]([F:30])[C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.O>[F:30][C:8]1[CH:7]=[C:6](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:5]=[C:4]([F:3])[C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:23])([CH3:24])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CF)CN1C(c2c(F)cc(/C=C/C(=O)O)cc2F)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
Sodium hydroxide (184 mg, 4.61 mmol) was added to (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (217 mg, 0.46 mol) in THF (1 ml)/methanol (1 ml). The resulting solution was stirred at 20° C. for 16 hours. The reaction was diluted with water (10 ml) and the pH was adjusted to 7 by the addition of 2N HCl. The solution was extracted with EtOAc (2×20 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. The pure fractions were evaporated to give a crude material. The crude product was triturated using a diethyl ether/isohexane mixture to give the title product (53.0 mg, 25.2%) as a yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 0.54 (3H, d), 1.06 (3H, s), 1.34 (3H, s), 2.14 (1H, dd), 2.66 (1H, d), 2.83 (1H, d), 3.03 (1H, dd), 4.21 (1H, t), 4.33 (1H, t), 5.12 (1H, s), 6.73 (1H, d), 7.01 (2H, dtd), 7.14-7.28 (1H, m), 7.43 (1H, d), 7.54 (2H, s), 7.59 (1H, d), 10.50 (1H, s), 12.61 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 457 *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples, ie compound inferred to be: (E)-3-(3,5-difluoro-4-(1R)-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[S:16][CH:17]=1
Reactant: COc1cc(C=O)ccc1OCc1csc(N2CCCCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1csc(N2CCCCC2)n1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.20 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.14 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as a colorless oil (1.18 g, yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[CH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][CH:18]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=CC#N)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.28 g, 6.60 mmol) in acetonitrile (33.0 mL) was added tert-butyl 4-(3-cyanoprop-2-en-1-yl)piperidine-1-carboxylate (3.30 g, 13.2 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.987 mL, 6.60 mmol). The resulting mixture was stirred at room temperature overnight. After evaporating the reaction mixture to dryness, the residue was purified on silica gel, eluting with 0-50% EtOAc in hexanes, to give the desired product (2.35 g, 80%). LCMS (M+H) 445.2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:32])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([N+:29]([O-])=O)[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[Cl-].[NH4+].[In]>C(O)C.O>[NH2:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=2)[CH3:10])[CH:12]=1)=[O:32]
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)c1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cc(N)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a solution of (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-nitro-5-(trifluoromethyl)benzamide (74 mg, 0.16 mmol) in ethanol (3 mL) was added a solution of ammonium chloride (85 mg, 1.6 mmol) in water (1.5 mL), then indium powder (73 mg, mesh 100, 0.64 mmol). The mixture was heated at reflux for 40 hours, was allowed to cool to room temperature and was filtered through Celite. The filter cake was washed with ethanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and water (30 mL), the phases separated and the organic phase washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give (S)-3-amino-N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-5-(trifluoromethyl)benzamide (45 mg, 65%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: BrBr
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At room temperature, to 20 g (0.093 mol) of α-(p-fluorophenyl)-acetophenone in 200 ml of chloroform, are added a few drops of a charge of 4.8 ml of bromine (0.93 mol) (a deep orange-color results). The resultant solution is heated to initiate reaction (the solution turns yellow), and then cooled to 0° C., and the balance of the 4.8 ml of bromine is added dropwise. The reaction mixture is stirred at room temperature for about 16 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1.C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 84.7 %

Procedure:
3 g (31.9 mmol) of 2-aminopyridine were dissolved in 65 ml of tetrahydrofurane with magnetic stirring. The addition of 4.44 ml (31.9 mmol) of ethyl bromopyruvate caused precipitation of a solid. The heterogenous mixture was stirred with reflux for 4 h. After returning to r.t., the solid was isolated by filtration and taken up in 65 ml of ethanol in order to be stirred with reflux in 65 ml of ethanol for 16 h. After returning to r.t., the solid was isolated by filtration. The filtrate was placed in ice in order to facilitate crystallization of the product which was collected by filtration and thus so forth until the liquid phase remained limpid. The solid was rinsed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 5.14 g (yield=84%) of ethyl imidazo[1,2-a]pyridine-2-carboxylate as a white powder. LC-MS: m/z=191 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.95 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 7.98-7.80 (m, 2H), 7.46 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[CH3:15][CH:16]([CH3:23])[C:17]([O:19][CH2:20][CH2:21]Cl)=[O:18]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:21][CH2:20][O:19][C:17](=[O:18])[CH:16]([CH3:23])[CH3:15])=[O:5]
Reactant: CC(C)C(=O)OCCCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)C(C)C
Yield: 88.7 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and chloroethyl 2-methylpropanoate (0.63 g, 4.2 mmol) to afford 0.65 g (89% yield) of the title compound (42) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.93 (q, J=5.2 Hz, 1H), 6.88 (d, J=16.0 Hz, 1H), 6.81 (d, J=15.6 Hz, 1H), 3.81 (s, 3H), 2.55 (heptet, J=6.8 Hz, 3H), 1.54 (d, J=5.2 Hz, 3H), 1.18 (d, J=6.8 Hz, 6H). MS (ESI): m/z 245.05 (M+H)+.
Reaction SMILES: I[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>C(Cl)Cl>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: O=C(CI)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodo-3′,4′,5′-tribenzyloxyacetophenone (20) (5.64 g, 10 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (4.18 g, 12 mmol) was dissolved in dry DCM (50 mL) and sodium hydride (0.48 g, 20 mmol) (0.8 g 60% NaH suspension in oil)) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Excess of sodium hydride was decomposed by addition of suitable amount water. Dichloromethane was removed under vacuum in order to simplify the work up. Water (100 mL) was added and the water phase extracted with diethyl ether (4×75 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 5.1 g (65%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CO.O>[S:11]1[CH:12]=[CH:13][N:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]12
Reactant: CCOC(=O)c1ccn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2ccsc12
Temperature: 55 °C

Procedure:
A mixture of pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (5.12 mmol) and NaOH (7.68 mmol) in MeOH (5.8 mL) and water (5.8 mL) is heated to 55° C. for 23 h. The mixture is concentrated in vacuo and made acidic by addition of aq. HCl (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product.
Reaction SMILES: [Pb:1]=O.O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].N>C(O)(=O)C>[C:21]([O-:23])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4].[Pb+2:1].[C:21]([O-:23])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=[Pb]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Pb+2]
Temperature: 70 °C

Procedure:
Separately, 3.5 l of warm water maintained at 70° C. was charged in a stainless steel beaker having a capacity of 10 l, and 419 g of stearic acid was added and dissolved under heating. Then, 24.0 cc of 7 N aqueous ammonia was dropped to the solution and the mixture was stirred and homogeneously emulsified to form an ammonia soap liquid. Separately, 725 cc of a lead monoxide slurry (PbO-DS) having a concentration of 680 g/l, 1 l of water and 14.2 cc of acetic acid having a concentration of 2.7 moles/liter were charged in a high-speed stirrer-equipped stainless steel vessel having a capacity of 10 l, and the mixture was maintained at 70° C. The above-mentioned ammonia soap liquid was added to this lead monoxide slurry and reaction was carried out under agitation to form a lead stearate slurry.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCCC4)nc23)CC1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution of 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 1.0 mL pyridine was heated to 50 ° C. To this solution were then added 0.0064 mL (0.048 mMol) cyclohexanecarbonyl chloride and the reaction mixture stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and a solution of the residue in methanol passed over a VARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which had been preactivated with 10% acetic acid in methanol. The column was washed thoroughly with methanol and then the desired product eluted with 2M ammonia in methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.013 gm (87.2%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH2:57])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[O:69]1[CH2:72][CH:71]([O:73][C:74](=O)[O:75]C2C=CC([N+]([O-])=O)=CC=2)[CH2:70]1>C(#N)C>[CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH:57][C:74]([O:73][CH:71]5[CH2:72][O:69][CH2:70]5)=[O:75])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(N)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC7COC7)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 3 h
Yield: 311.9 %

Procedure:
(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.200 g, 0.22 mmol) was dissolved in acetonitrile (2.2 mL). DIPEA (0.155 mL, 0.8905 mmol) and Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester (0.059 g, 0.244 mmol) was added, and the solution was allowed to stir for about three hours. Upon completion, the crude product was purified by reverse phase HPLC (10-50% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{7-[6-(2-{1-[2-(oxetan-3-yloxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.61 g, 31% yield). LCMS-ESI+: calc'd for C51H52N8O7: 888.40 (M+); Found: 889.86 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9](O)([OH:14])[C:10]([F:13])([F:12])[F:11]>>[F:11][C:10]([F:13])([F:12])[CH:9]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])[OH:14]
Reactant: Oc1ccc(Cl)cc1
Reactant: OC(O)C(F)(F)F
Product: Oc1ccc(Cl)cc1C(O)C(F)(F)F
Temperature: 100 °C
Yield: 45 %

Procedure:
12.5 g (100 mmol) of p-chlorophenol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 6 g of hydrotalcite Mg6AlGa(O4)16.4H2O are added and the mixture is heated at 100° C. for 7 hours. After treating the reaction medium according to the protocol described in Example 1, a yield of 45% of the expected product is obtained.