Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.N1CCCC1>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)=[C:13]2[C:24]1[C:33]2[CH2:32][CH:31]=[C:30]([Cl:34])[CH2:29][C:28]=2[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(O)Cn1c(CN2CCCC2)c(-c2ccnc3c2CC=C(Cl)C3)c2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
1-Bromo-2,5-pyrrolidinedione (165 mg) was added to a solution of the product from Example 27 (0.3 g) in DMF (3 ml), and the solution stirred for 10 min. Pyrrolidine (0.5 ml) was then added and the mixture stirred for a further 30 min. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid which was filtered off and dried to yield the title compound as a white solid (70 mg).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(=O)C>[CH2:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:20]=2[OH:21])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCc1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(C)=O
Solvent: CC(=O)O
Product: CCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.3 %

Procedure:
2-Oxopropanal methylhydrazone (8.6 mmol, 861 mg) synthesized in Reference Synthetic Example 1 and (4-n-pentylphenyl)(oxo)acetaldehyde (8.6 mmol, 1.757 g) synthesized in Reference Synthetic Example 6 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the desired product as an orange solid (252.5 mg, yield 10.3%, crude).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(OCC)(=O)C>O1CCCC1.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.40 g of sodium hydride (purity: 60%) was suspended in 60 ml of tetrahydrofuran. To the suspension was dropwise added 13.5 g of ethyl diethylphosphonoacetate with ice-cooling. The mixture was stirred for 30 minutes at room temperature. To the resulting reaction mixture was dropwise added a solution of 9.06 g of 4-methoxy-3-nitrobenzaldehyde dissolved in 30 ml of tetrahydrofuran, with ice-cooling. The mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 100 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain ethyl (E)-3-(4-methoxy-3-nitrophenyl)acrylate.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:17]([CH2:20][CH2:21][CH3:22])([O-:19])=[O:18]>>[F:8][C:5]([F:6])([F:7])[CH:4]([OH:9])[CH:20]([N+:17]([O-:19])=[O:18])[CH2:21][CH3:22]
Reactant: CCOC(O)C(F)(F)F
Reactant: CCC[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-nitropropane (10 mL), trifluoroacetaldehyde ethyl hemiacetal (20.2 mL), and potassium carbonate (15.4 g) was stirred at 25° C. for 48 h. The solution was made acidic by addition of 1N hydrochloric acid and the product extracted into dichloromethane. The solution was dried (MgSO4) and the solvent evaporated to give an oil, which was distilled (60° C., 133 Pa) to provide 1,1,1-trifluoro-3-nitro-2-pentanol (15 g) as a mixture of diastereoisomers; MS: m/z=188(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[C:15](=O)[CH2:16][CH2:17][CH2:18][C:13]=2[O:12][N:11]=1)([O-])=[O:2].Cl.O1CCCC1>[Pd].CO>[NH2:11][C:10]1[C:5]2[C:4]([N+:1]([O-:2])=[C:15]3[C:14]=1[C:13](=[O:12])[CH2:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCCc2onc(-c3ccccc3[N+](=O)[O-])c21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c2c([n+]([O-])c3ccccc13)CCCC2=O
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 6,7-dihydro-3-(2-nitrophenyl)-1,2-benzisoxazole-4(5H)-one, (7.0 g), 5% palladium-on-carbon (0.7 g), 5% hydrochloric acid (11 ml), and tetrahydrofuran (200 ml) was hydrogenated at 50 psi. After one hr, methanol (1l) was added, and the mixture was filtered through celite. The flitrate was concentrated, and the concentrate was flash chromatographed (silica, 3-20% methanol/ethyl acetate; 40% methanol/dichloromethane). The appropriate fractions were collected and concentrated. The residue was triturated with methanol/diethyl ether to yield 5.4 g (83%) of product, mp 290° C. (dec).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]([C:19](Cl)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]2[C:19](=[O:20])[C:14]3[C:13]([C:9]=2[CH:8]=1)=[CH:18][CH:17]=[CH:16][N:15]=3
Reactant: COc1cccc(-c2cccnc2C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1cccnc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (7.33 g) is added to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carbonyl chloride (crude, 5.40 g) in dichloromethane (100 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room temperature overnight. The mixture is then poured on crushed ice and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with aqueous NaHCO3 solution and dried (Na2SO4). The solvent is evaporated and the residue is triturated with a mixture of cyclohexane and ethyl acetate (1:1) and dried to give the title compound as a yellowish solid. Yield: 3.00 g (65% of theory); LC (method 1): tR=2.84 min; Mass spectrum (ESI+): m/z=212 [M+H]+.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].P(Cl)(Cl)(Cl)=O.[CH2:12]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[C:2]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:1]
Reactant: c1ccc(Cc2cc3ccccc3[nH]2)cc1
Reactant: CC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(Cc2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of 29.5 g (39 mmol) of dimethylacetamide was added dropwise under ice-cooling 7.00 g (76.9 mmol) of phosphorus oxychloride. After stirring for 30 min at room temperature, to the mixture was added 8,00 g (38.6 mmol) of 2-benzylindole (prepared in accordance with the literature (Khim.Geterotsikl.Soedin.1994,p133)). After stirring for 2 hours at 100° C., the mixture was poured to ice-water, neutralized with 2N NaOH, extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The obtained crystal was washed with n-hexane to give 5.1 g of the titled compound. Yield: 52%.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:26]23[CH2:33][CH2:32][C:29]([NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])([CH2:30][CH2:31]2)[CH2:28][CH2:27]3)[N:7]2[C:12]3[CH:13]=[CH:14][N:15]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:11]=3[N:10]=[CH:9][C:8]=12)C=C.C[N+]1([O-])CCOCC1.C(Cl)Cl.[O:52]1[CH2:57][CH2:56][O:55]CC1>O.[Os](=O)(=O)(=O)=O>[OH:52][CH:57]([CH2:56][OH:55])[CH2:1][C:4]1[N:5]=[C:6]([C:26]23[CH2:31][CH2:30][C:29]([NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])([CH2:28][CH2:27]2)[CH2:32][CH2:33]3)[N:7]2[C:12]3[CH:13]=[CH:14][N:15]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=4)(=[O:17])=[O:18])[C:11]=3[N:10]=[CH:9][C:8]=12
Reactant: C1COCCO1
Reactant: C=CCc1nc(C23CCC(NS(=O)(=O)C4CC4)(CC2)CC3)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(CC(O)CO)nc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reaction time: 15 h
Yield: 3 %

Procedure:
To a solution of N-(4-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo-[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 0.47 mmol, prepared using E with 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], K with cyclopropylsulfonyl chloride, H from Preparation #12, HATU and DIEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate) in 1,4-dioxane (10 mL) and water (1 mL) was added N-methylmorpholine-N-oxide (0.22 g, 1.8 mmol) followed by osmium tetroxide (4 wt % in water, 0.36 mL, 0.047 mmol). The reaction mixture was stirred for about 15 h and then DCM (20 mL) and water (10 mL) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 10-50% MeCN in DCM, to provide N-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.009 g, 3%): LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z: 612 (M−H)−.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.Cl.[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][N:39]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2cccc(Cl)c2)CC1)O3
Temperature: 50 °C
Yield: 47.4 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (647 mg, 1.44 mmol), 3-chlorophenyl-piperazine hydrochloride (1.0 g, 4.3 mmol) and diisopropylethylamine (0.75 mL, 4.3 mmol) in anhydrous DMSO (6 mL) were heated at 50° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (5% MeOH/CH2Cl) afforded 280 mg (68%) of the desired product as a beige solid: mp 110–112° C.; MS (ESI) m/z nnn [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]3[O:29][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:26](=[O:35])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4].[C:39](=O)([O-])[O-].[K+].[K+].CI.O>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([N:15]([CH3:39])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]3[O:29][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:26](=[O:35])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c2nc(C(=O)OC)cc(NS(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CI
Product: CCCc1c2nc(C(=O)OC)cc(N(C)S(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of step (a) (5.38 g, 0.01 mol) was suspended in N-methyl pyrrolidone (40 ml), and potassium carbonate (1.38 g, 0.01 mol) added, to give on stirring at room temperature for five minutes a deep red solution. Methyl iodide (2 ml) was then added, and the whole warmed to 40° C., and stirring continued for one hour. The solution was poured into water (150 ml), to give the sub-title compound on filtration, as a white powder, 5.44 g, (98.6%), m.p. 173°-174° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:18]1[C:24]2=[C:25]3[C:30](=[N:31][C:32]4=[CH:33][CH:34]=[CH:35][C:22](=[C:23]24)[O:21][CH:20]([CH2:36][CH3:37])[C:19]1=O)[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH2:11]([N:18]1[C:24]2=[C:25]3[C:30](=[N:31][C:32]4=[CH:33][CH:34]=[CH:35][C:22](=[C:23]24)[O:21][CH:20]([CH2:36][CH3:37])[CH2:19]1)[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC1CN(Cc2ccccc2)c2c3c(nc4cccc(c24)O1)CCCC3
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 11.75 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.57 g) in portions. The mixture was stirred for five mins. 1-Benzyl-3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.37 g) was added and stirring was continued for three hrs. The reaction mixture was quenched with ethyl acetate (200 ml), 10% sodium hydroxide solution (200 ml) was added, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. Trituration of the residue with pentane followed by recrystallization from methanol gave 2.86 g (68%) of product, mp 147.5°-149° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17]I.O>CN(C)C=O>[CH3:17][O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.5 mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (5.0 g, 24.8 mmol) in dimethylformamide (30 mL) and the mixture was stirred for 5 minutes. Methyl iodide (4.64 mL, 74.5 mmol) was added and the mixture was stirred for 30 minutes. Water (50 mL) was added and the mixture was extracted with diethyl ether (2×50 mL). The combined organic fractions were washed with water (4×50 mL) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (5.3 g, 99%). m/z (ES+) 216 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)([OH:28])[CH:15]2[CH2:20][CH2:19][N:18](C(N(CC)CC)=O)[CH2:17][CH2:16]2)=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[OH:28])=[CH:10][CH:9]=1
Reactant: CCN(CC)C(=O)N1CCC(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CCNCC1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a slurry of 8.5 g (0.225 mole) of lithium aluminum hydride in 400 ml of anhydrous tetrahydrofuran was added a solution of 39.2 g (0.09 mole) of 4-[bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-1-piperidinecarboxamide in 400 ml of tetrahydrofuran in a stream over a 15 min period. The mixture was heated at reflux for 24 hr, cooled, and treated successively with 8.5 ml of water, 25 ml of a 3N sodium hydroxide solution and 8.5 ml of water. The mixture was stirred for 0.5 hr and then filtered. The filtrate was concentrated under reduced pressure to give a gum which crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and recrystallized from benzene to yield 10.5 g (35%) of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 184°-188° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[CH2:4][NH2:1])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Temperature: 50 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a stirred solution of 1-azidomethyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzene from the previous step (10.9 g, 36.73 mmol) in THF (60 mL) and water (6 mL) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 50° C. and stirred for 18 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography using a gradient elution of 2%, 3%, 4%, 5% A in dichloromethane (A=95:5 MeOH:NH4OH). Concentration of product-containing fractions in vacuo gave 2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamine as a solid (8.8 g, 88% yield). TLC Rf=0.3 (95:5:0.25 CH2Cl2:MeOH:NH4OH); HPLC RT=2.64 min, method A; LC-MS m/z=271; 1H NMR (CDCl3, 400 MHz) 7.21-7.52 ppm (m, 3H); 4.32 ppm (b d, 2H); 3.90 ppm (s, 2H); 1.44 ppm (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:42])[C:6]([C:16]#[C:17][CH2:18][C:19]([OH:41])([C:37]([F:40])([F:39])[F:38])[CH2:20][C:21]([C:24]2[C:32]3[O:31][CH2:30][CH2:29][C:28]=3[CH:27]=[C:26]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:25]=2)([CH3:23])[CH3:22])=[C:7]([NH:9]C(=O)C(F)(F)F)[CH:8]=1)#[N:2].CN(C)C(N(C)C)=N.C(OCC)(=O)C>CS(C)=O.ClCCl>[OH:41][C:19]([C:37]([F:39])([F:40])[F:38])([CH2:20][C:21]([C:24]1[C:32]2[O:31][CH2:30][CH2:29][C:28]=2[CH:27]=[C:26]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:25]=1)([CH3:22])[CH3:23])[CH2:18][C:17]1[NH:9][C:7]2[C:6]([CH:16]=1)=[C:5]([CH3:42])[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2
Reactant: Cc1cc(C#N)cc(NC(=O)C(F)(F)F)c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC(C)(C)c3cc(S(C)(=O)=O)cc4c3OCC4)C(F)(F)F)cc12
Yield: 17.7 %

Procedure:
A solution of N-{5-cyano-2-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-3-methylphenyl}-2,2,2-trifluoroacetamide (154 mg, 0.25 mmol) in 0.6 mL of anhydrous DMSO was heated in the presence of 1,1,3,3-tetramethylguanidine (0.094 mL, 0.75 mmol) in a microwave at 140° C. for 10 minutes. The reaction was quenched with a mixture of 1 N sulfuric acid and 10 mL of crushed ice. The resulting precipitate was filtered, washed with water, and dried. Preparative TLC chromatography (50% ethyl acetate in hexanes, followed by 15% ethyl acetate in dichloromethane) gave 23 mg of the title product as an off-white solid (18% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[C:5]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:4]=1.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:33][CH:34]([Cl:38])[C:35]1[N:13]2[C:7]3[CH:6]=[C:5]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[C:8]=3[C:9]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[N:10][CH2:11][C:12]2=[N:14][N:15]=1
Reactant: CCCS(=O)(=O)c1cc2c(c(C(F)(F)F)c1)C(c1ccc(OCC)cc1)=NCC(NN)=N2
Reactant: O=C(Cl)C(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCS(=O)(=O)c1cc2c(c(C(F)(F)F)c1)C(c1ccc(OCC)cc1)=NCc1nnc(C(Cl)Cl)n1-2

Procedure:
In the manner given in Example 1, 6-trifluoromethyl-8-propylsulfonyl-5-(p-ethoxyphenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with dichloroacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 1-(dichloromethyl)-7-trifluoromethyl-9-propylsulfonyl-6-(p-ethoxyphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH2:6][NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12](=[O:20])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[CH:16][N:15]=3)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH2:6][NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12](=[O:20])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[CH:16][N:15]=3
Reactant: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3[N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 2.6 %

Procedure:
466 (21 mg, 0.6 mmol) was dissolved in MeOH (130 mL) then reduced by flow chemistry on an H-Cube instrument (Pd/C cartridge, flow rate of 1.9 mL/min, 10 bar). The reaction solution was concentrated and purified via prep-LC-MS to provide 467 (5 mg, 24% yield) as a white powder. LC-MS (M+H=317, obsd.=317). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (d, J=9.0, 2H), 8.22 (s, 1H), 8.07 (d, J=8.6, 1H), 7.42 (s, 1H), 7.34 (d, J=5.0, 1H), 6.84 (m, 2H), 6.66 (dd, J=7.5, 20.2, 2H), 6.34 (s, 1H), 6.20 (s, 2H), 5.46 (s, 2H), 5.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH:4]([CH3:5])[C:3]1([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#N.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:28]>C1C=CC=CC=1.C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1([Cl:14])[CH:4]([CH3:5])[C:3]1([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[O:28]
Reactant: O=S(=O)(O)O
Reactant: CC1C(Cl)(Cl)C1(C#N)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1C(Cl)(Cl)C1(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
7.5 g (0.033 mol) of 2,2-dichloro-3-methyl-1-phenylcyclopropane carbonitrile were dissolved in 70 ml of dry benzene, and cooled with ice. To the resulting solution were dropwise added 25 ml of a 25% solution of diisobutylaluminium hydride in toluene in nitrogen atmosphere. The reaction mixture was stirred in nitrogen atmosphere at room temperature for 24 hours, and then further stirred at 35° C. for 5 hours. The reaction solution was cooled with ice, and admixed with 20 ml of methanol to decompose the excess diisobutylaluminium hydride. Thereafter, the reaction solution was poured into 150 ml of saturated aqueous ammonium chloride solution, and stirred for 20 minutes. 40 ml of a 10% dilute sulfuric acid were added to the reaction mixture to separate the organic phase. The aqueous phase was extracted with ether. The combined organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The inorganic substances were filtered off, and the organic solvent was distilled off under a reduced pressure. The resultant oily residue was subjected to a distillation operation under a pressure of 0.1 mmHg (118°-119° C.) to obtain 4.5 g of 2,2-dichloro-3-methyl-1-phenylcyclopropanecarbaldehyde. Yield: 60%.