Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].C([O-])(=O)C.[Pb+4:35].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:35])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 58.3 %

Procedure:
4′-Chloro-3-ethylbiphen-4-ylboronic acid (4.2 g, 0.016 mol) is added in one portion to a mixture of lead tetraacetate (7.86 g, 0.017 mol) and mercuric acetate (0.25 g, 5 mol %) in chloroform (23 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hrs. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange colored solid. Trituration with hexanes (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (26.7 g, 0.19 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-ethylbiphen-4-yllead triacetate (5.6 g) as a cream colored solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1.[C:22](OC)(=[O:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1.CCCCCC>[CH3:24][CH:23]([CH3:25])[C:22](=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1
Reactant: COC(=O)C(C)C
Reactant: CSc1nccc(C)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of diisopropylamine (10.1 mL, 71.8 mmol) in anhydrous THF (50 mL) is added n-butyllithum (33.6 mL of an 1.6M in hexane) dropwise at 0° C. After 30 min at 0° C., 4-methyl-2-(methylthio)pyrimidine (5 mL, 35.9 mmol) is added. The resulting mixture is stirred at 0° C. for 30 min. After the addition of methyl isobutyrate (4.3 mL, 37.7 mmol) at 0° C., the reaction mixture is stirred overnight. The reaction mixture is quenched with acetic acid at 0° C., diluted with water, and extracted with ethyl ether. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/heptane 7:93 to 40:60) to give 4.3 g of 3-methyl-1-(2-methylsulfanyl-pyrimidin-4-yl)-butan-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[C:11](=[C:16]3[S:20][CH:19]=[CH:18][S:17]3)[C:10]2=[O:21])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[C:11](=[C:16]3[S:17][CH:18]=[CH:19][S:20]3)[C:10]2=[O:21])=[CH:6][CH:5]=1
Reactant: O=C1CCN(Cc2ccc([N+](=O)[O-])cc2)C(=O)C1=C1SC=CS1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCC(=O)C(=C3SC=CS3)C2=O)cc1
Yield: 100.7 %

Procedure:
1-(p-Nitrobenzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (100 mg) is dissolved in ethanol (20 ml), and thereto is added 10% Pd/C (100 mg). The mixture is subjected to catalytic reduction under atmospheric pressure. The mixture is filtered to remove the catalyst. The filtrate is distilled to remove the solvent to give 1-(p-aminobenzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (92 mg, quantitative) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:24]O.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:24][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37]
Reactant: Cc1cnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 17, 2'-chloro-5-nitro-2-[5-methyl-2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-5-nitro-2-[5-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([N:8]1[C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>>[ClH:28].[CH2:1]([N:8]1[C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:10]2([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(C)(C)CO2
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)COC2(CCNCC2)CN1Cc1ccccc1
Reaction time: 18 h
Yield: 86 %

Procedure:
Tert-butyl 8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (89 mg, 0.24 mmol) was treated with hydrogen chloride solution in dioxane (240 μL of 4 M, 0.95 mmol). The reaction mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo to provide 8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (56 mg, 86%). ESI-MS m/z calc. 274.4. found 275.5 (M+1)+; Retention time: 0.80 minutes (3 min run).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[CH:37][CH:38]=1)#[N:41]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a 40 mL vial charged with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (500.00 mg, 1617 μmol) was added dioxane (3.2 mL, 1617 μmol), Na2CO3 (3.234 mL, 647 μmol) and 4-bromobenzonitrile (294.3 mg, 1617 μmol). The reaction mixture was purged with nitrogen prior to the addition of PdCl2(dppf)-CH2Cl2 (132.1 mg, 162 μmol). The reaction mixture was heated to 110° C. for 24 h. The dark reaction mixture was cooled to RT and water was added. The resulting reaction mixture was extracted with ethyl acetate, and the combined organics were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure. The crude black oil was chromatographed ramping 0% EtOAc in hexanes to 25% over 5 min, then remaining at 5% for 15 min, then ramping to 100% over 5 min providing isolation of tert-butyl 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (390.00 mg, 84.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.ClC1C=C(C(OO)=[O:21])C=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Brc1cnccc1OCC1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of 3-Bromo-4-cyclopropylmethoxy-pyridine (Example 53a, 1 g, 4.38 mmol) in dichloromethane was added 3-Chloro-benzenecarboperoxoic acid (1.47 g, 6.58 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 250 mL dichloromethane and extracted with 75 mL of an aqueous solution 1M sodium bicarbonate. The organic layers was collected, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (954 mg, 89%) as a white solid. MS (ESI, m/z): 244.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Br.Br.[NH:16]1[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:16]2[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: OC1CNCCNC1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Agent: Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnn(CC(F)F)c1N1CCNCC(O)C1
Temperature: 130 °C
Yield: 90.8 %

Procedure:
A mixture of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (800 mg, 3.78 mmol), 1,4-diazepan-6-ol dihydrobromide (1.58 g, 5.67 mmol) and DIPEA (2.5 mL, 14.35 mmol) in EtOH (6 mL) was heated at 130° C. in a microwave for 3 hr. The solvent was removed under reduced pressure and the residue was passed through an SCX column washing with DCM and 1:1 MeOH:DCM and MeOH and eluting with 1N ammonia in MeOH to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-6-ol as a pale yellow gum (1.0 g). This gum (1.0 g, 3.44 mmol) was dissolved in DCM (100 mL) and treated with di-tert-butyl dicarbonate (2.25 g, 10.31 mmol) and DIPEA (2.4 mL, 13.75 mmol). The reaction mixture was stirred at room temperature for 1.5 hr and washed with saturated aqueous NaHCO3 solution (100 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100%) EtOAc/isohexane gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a pale green gum (46% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 6.18 (tdd, J=55.6, 5.6, 3.2 Hz, 1H), 4.49-4.31 (m, 2H), 4.19-2.95 (m, 10H), 1.60-1.40 (m, 9H).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]([CH2:7][C:8]1[C:9]2[CH2:10][C:11]3[N:16]4[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:15]4[C:14](=[O:25])[NH:13][C:12]=3[C:26]=2[CH:27]=[CH:28][CH:29]=1)=[O:6]>O1CCOCC1>[CH3:3][NH:4][C:5]([CH2:7][C:8]1[C:9]2[CH2:10][C:11]3[N:16]4[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:15]4[C:14](=[O:25])[NH:13][C:12]=3[C:26]=2[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)NC)c1C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Reaction time: 2 h

Procedure:
8.2 ml of 1N sodium hydroxide solution are added dropwise, under a stream of nitrogen and at a temperature in the region of 20° C., to a suspension of 1 g of ethyl 9-(N-methylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate in a dioxane distilled water (100/27 by volume) mixture. The reaction is continued for 2 hours at the same temperature. The light-grey insoluble material is filtered, washed with acetone and then taken up in 15 ml of distilled water. This aqueous solution is filtered and then acidified to pH 1 with N hydrochloric acid. The precipitate formed is filtered and washed with water, with acetone and then with ethyl ether to result in 0.59 g of the trihydrate of 9-(N-methylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid in the form of a white powder, the melting point of which is greater than 260° C. (Analysis C17H14N4O4.3H2O; % Calculated C: 60.35, H: 4.17, N: 16.56; % Found C: 60.0, H: 4.1, N: 16.3; 1H NMR spectrum in CD3CO2D, T=300K, δ in ppm (300 MHz): 2.7 (3H, s, NCH3), 3.9 (2H, s, CH2CO), 4.1 (2H, s, CH2), 7.2 (1H, d, J=8 Hz, arom. CH), 7.4 (1H, t, J=8 Hz, arom. CH), 7.7 (1H, d, J=8 Hz, arom. CH), 8.5 (1H, s, imidazole H)).
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]2[C:5](=[N:6][CH2:7][N:8]2[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:4](Cl)([NH2:20])[N:3]=1.[CH:22]1(N)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: NC1CCCCC1
Reactant: NC1(Cl)N=C(Cl)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 229.1 %

Procedure:
A mixture of 2,6-dichloroadenosine (1.0 g) and cyclohexylamine (0.926 g) in ethanol (30 ml) was heated at reflux for 6 hours then cooled to room temperature. The mixture was concentrated under vacuo. The residue was purified on the silica gel column using MeOH—CH2Cl2 (1:6 to 1:5). The combined fractions were concentrated and dried under vacuum to provide 2-chloro-N6-cyclohexyladenosine as a white solid (2.600 g). 1H NMR (DMSO-D6): δ 1.12-1.21 (m, 2H), 1.33-1.43 (m, 3H), 1.63-1.86 (m, 6H), 3.57-3.62 (m, 1H), 3.66-3.69 (m, 1H), 3.97 (d, J=3 Hz, 1H), 4.16 (d, J=3.3 Hz, 1H), 4.54 (d, J=5.4 Hz, 1H), 5.08-5.11 (m, 1H), 5.24 (d, J=4.8 Hz, 1H), 5.51 (d, J=5.7 Hz, 1H), 5.85 (d, J=5.7 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.41 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]S(C)=O.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:18]([CH3:35])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: COC(=O)C(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate (250 mg, 0.58 mmol) was dissolved in THF (5 mL) and 60% oil dispersion NaH was added (24 mg, 0.6 mmol). After 1 h, added DMSO (2 mL) followed by MeI (5.8 mmol). After 72 h, the reaction was quenched with MeOH then poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 215 mg (83% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate. MS found: (M+H)+=447.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([F:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[C:13]([F:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cnc(F)c(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(F)c(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)c1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-fluoro-5-methyl-pyridin-3-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=427.0814 ([M+H]+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12](S(C3C=CC=CC=3)(=O)=O)[CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.CC(O)C.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (5.50 g), tetrahydrofuran (25 mL), 2-propanol (25 mL) and methanol (20 mL) was added a 1 mol/L aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give the title compound as a yellow solid (yield 3.59 g, 92%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=32)=[N:8][CH:7]=1)=O)C.NC1SC2C=CC=C(C)C=2N=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]3[C:6]([CH2:4][OH:3])=[CH:7][N:8]=[C:9]3[S:10][C:11]=2[CH:17]=1
Reactant: CCOC(=O)c1cnc2sc3cc(F)ccc3n12
Agent: Cc1cccc2sc(N)nc12
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnc2sc3cc(F)ccc3n12

Procedure:
A solution of 7-fluoroimidazo[2,1-b]benzothiazole-3-carboxylic acid ethyl ester, (synthesized from 2-amino-methylbenzothiazole according to a modification of the procedures described by Fajeli et al., Heterocycles, 1986, 24, 379) (1.93 g) in dry THF (50 mL) at 0° was treated with LiAlH4 (0.36 g) and reacted at 25° for one hour. The suspension was quenched by serial addition of water and 15% sodium hydroxide. The suspension was filtered and the filtrate was evaporated to yield crude 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) (1.59 g). Crystallization of crude 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) from acetonitrile gave pure 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) (1.3 g), m.p. 240-241°.
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-]>CO.O>[OH:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1OC(C)=O
Yield: 79.7 %

Procedure:
A solution of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (150 mg, 0.36 mmole) in methanol (5 mL) and a saturated solution of ootassium carbonate (3 mL) was stirred at room temperature for 5 minutes. The reaction was poured in water, extracted with methylene chloride, washed with brine, dried (Na2SO4), and concentrated in vacuo to yield 107 mg (79%) of 2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:2]1.[C:22]([O:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>ClCCl>[C:25]([O:24][C:22]([N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[C:30]([O:29][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: c1ccc(CCCCCCNCCCc2ccoc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCCCCc1ccccc1)CCCc1ccoc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above crude N-[3-(3-furyl)propyl]-6-phenylhexylamine in 100 ml of dichloromethane, 2.49 g (11.4 mmol) of di-tert-butyl dicarbonate was added, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield N-(tert-butoxycarbonyl)-N-[3-(3-furyl)propyl]-6-phenylhexylamine as a mixture with di-tert-butyl dicarbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])[CH2:14][CH2:13]3)[C:9]3=[CH:26][C:27]([CH3:29])=[CH:28][N:8]3[CH2:7][C:6]=2[CH:30]=1.[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])[CH2:16][CH2:17]3)[C:9]3=[CH:26][C:27]([CH3:29])=[CH:28][N:8]3[CH2:7][C:6]=2[CH:30]=1
Reactant: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2N1CCN(CC(C)(C)C(=O)O)CC1
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a suspension of methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (28.0 g, 65.27 mmoles) in a mixture of isopropyl alcohol (150 mL) and water (150 mL) add sodium hydroxide (3 equiv; 7.83 g, 195.82 mmoles) and heat at 70° C. for 4 h to give a clear solution. Heat at 70° C. for a further 1 h then cool slightly. Add 5M hydrochloric acid to give pH 8 and precipitate a white solid. Add further 5M hydrochloric acid to give a pH between 6.5 and 7. Reduce the volume of solvent by half and then chill the flask in a fridge for 0.5 h. Collect the resulting white solid by filtration and dry overnight in a vacuum oven at 40° C. over phosphorus pentoxide to give 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid (26.5 g, 98% yield). MS (m/z): 415.3 (M+1). DSC melting point=246.5° C. (onset).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([CH2:15][OH:16])[CH:14]=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([CH2:15][OH:16])[CH:14]=1
Reactant: Nc1ccc(OC(F)(F)F)c(CO)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: OCc1cc(Cl)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
t-Butyl nitrite (2.49 g, 24.2 mmol), copper (II) chloride (2.71 g, 20.2 mmol), and acetonitrile (100 mL) were added to a round-bottom flask. The resulting mixture was cooled to 0° C. (5-Amino-2-trifluoromethoxy-phenyl)-methanol (1.67 g, 8.1 mmol) in acetonitrile (10 mL) was slowly added to the reaction over a period of 5 min. The reaction was warmed up to room temperature and stirred overnight. The mixture was then poured into 20% HCl (100 mL) and extracted with ether (100 mL). The organic layer was washed with 20% HCl (100 mL) and dried over MgSO4. The ether was removed in vacuo and the residue was chromatographed with 4:1 hexanes:EtOAC to give 1.2 g (66%) of (5-chloro-2-trifluoromethoxy-phenyl)-methanol as a yellow solid.